Skip to main content

Prospects of potential adipokines as therapeutic agents in obesity-linked atherogenic dyslipidemia and insulin resistance



In normal circumstances, AT secretes anti-inflammatory adipokines (AAKs) which regulates lipid metabolism, insulin sensitivity, vascular hemostasis, and angiogenesis. However, during obesity AT dysfunction occurs and leads to microvascular imbalance and secretes several pro-inflammatory adipokines (PAKs), thereby favoring atherogenic dyslipidemia and insulin resistance. Literature suggests decreased levels of circulating AAKs and increased levels of PAKs in obesity-linked disorders. Importantly, AAKs have been reported to play a vital role in obesity-linked metabolic disorders mainly insulin resistance, type-2 diabetes mellitus and coronary heart diseases. Interestingly, AAKs counteract the microvascular imbalance in AT and exert cardioprotection via several signaling pathways such as PI3-AKT/PKB pathway. Although literature reviews have presented a number of investigations detailing specific pathways involved in obesity-linked disorders, literature concerning AT dysfunction and AAKs remains sketchy. In view of the above, in the present contribution an effort has been made to provide an insight on the AT dysfunction and role of AAKs in modulating the obesity and obesity-linked atherogenesis and insulin resistance.

Main body

“Obesity-linked insulin resistance”, “obesity-linked cardiometabolic disease”, “anti-inflammatory adipokines”, “pro-inflammatory adipokines”, “adipose tissue dysfunction” and “obesity-linked microvascular dysfunction” are the keywords used for searching article. Google scholar, Google, Pubmed and Scopus were used as search engines for the articles.


This review offers an overview on the pathophysiology of obesity, management of obesity-linked disorders, and areas in need of attention such as novel therapeutic adipokines and their possible future perspectives as therapeutic agents.

Graphical Abstract


The outrage of obesity and its metabolic disorders is a major problem worldwide [1], and it is the cause of a higher premature death rate [2]. World Health Organization (WHO) estimated over 1.9 billion adults and older are overweight, out of which 650 million adults were obese in 2016. It is estimated that about 13% of the total world’s adult populations (11% men and 15% of women) were reported to be obese in 2016. The prevalence of obesity had tripled between 1975 and 2016 [3]. Obesity has a devastating effect on the vascular system creating adverse conditions that favor coronary artery disease (CAD). During obese state, the risk of various microvascular diseases such as hypertension, atherosclerosis, and myocardial infarction (MI) increases dramatically [4] and has been declared a major cause of death in both developed and developing nations in the twenty-first century [5]. Childhood obesity is one of the alarming concerns putting children and adolescents in poor health risk. As per the Centers for Disease Control and Prevention (CDC), the prevalence of obesity was 19.3% and affected about 14.4 million children and adolescents in the USA. Obesity prevalence was 13.4% among 2- to 5-year-olds, 20.3% among 6- to 11-year-olds, and 21.2% among 12- to 19-year-olds [6]. Therefore, obesity is not only a health hazard for the elderly but also children. Adipose tissue (AT) plays a vital role in the development of inflammation that contributes to the development of cardiometabolic risks in obesity [7, 8]. Abdominal obesity is one of the primary risk factors which is associated with blood-lipid disorders, inflammation, insulin resistance or type 2 diabetes mellitus (T2DM), thereby increasing cardiovascular morbidity [9]. Persons having abdominal obesity or with a central deposition of AT are highly susceptible to cardiovascular morbidity and mortality, including stroke, congestive heart failure and MI [10, 11]. Adipokines are generally produced by AT and involve different mechanisms such as energy homeostasis, metabolism, thermogenesis, reproduction, and immunity [12]. There are two different types of adipokine produced by fat tissue. The pro-inflammatory adipokines (PAKs) include resistin, leptin, tumor necrosis factor α (TNF-α), etc., are produced in higher quantity during obese state. The anti-inflammatory adipokines (AAKs) are adiponectin, omentin-1, secreted frizzled-related protein 5 (Sfrp5), and a few members of C1q/TNF-related protein (CTRP) family. These adipokines have a close link to inflammation and cardiovascular health via paracrine effects or by affecting endothelial function [12, 13]. During obesity, expression of PAKs is upregulated while of AAKs is downregulated. The presence of higher levels of AAKs is presumed to have protective action against obesity and associated damage and may play a crucial role in the management of obesity-linked cardiometabolic complications. Therefore, in this review we offer an overview on the pathophysiology of obesity, management of obesity-linked disorders, and areas in need of attention such as novel therapeutic adipokines and their future perspectives.

Main text

Microvascular dysfunction in adipose tissue during obesity

AT undergoes several biochemical changes that are involved in pathophysiology in the development of cardiometabolic disease (CMD). AT is known as the biological reservoir of energy (caloric). Adipocytes are the primary cell type responsible for the storage of excess calorie as triglyceride (TG) in the cellular lipid droplet without causing lipotoxicity to other cells. They expand to accommodate TG within the adipocyte [14].

Effects of expansion of fat in the microvascular system of adipose tissue

AT is composed of adipocytes, and other cell types, such as lymphocytes, macrophages, fibroblasts, and vascular cells [8]. AT expands and stores lipids in response to chronic excess caloric conditions [15], playing a vital role in appropriate angiogenesis, vascular and extracellular matrix (ECM) remodeling [16]. AT expands through the combination of adipocyte hypertrophy of pre-existing cells and hyperplasia [17]. Adipocyte hyperplasia permits healthy expansion of AT, while adipocyte hypertrophy without hyperplasia leads to lipid overload, causing adipocyte dysfunctions, resulting in cell death, initiation of AT inflammation and dysfunction followed by number of steps which leads to the development of insulin resistance and atherogenic dyslipidemia [18].

In obesity, adipocyte size gets increased, but there is no such concomitant increase in microvascular capillary density. Therefore, the demand for critical nutrients such as oxygen, glucose, and lipids could not be fulfilled due to insufficient capillary density [19], and hence, a group of adipocytes is cut off from the main supply to the vasculature, and initiates inflammatory processes [20]. AT has dense microvessels to maintain the tissue perfusion and nutrient supply adequately. It is believed that responsiveness of these microvessels is altered during obesity thereby having a significant impact on metabolism as well as nutrient transfer leading to insufficient AT perfusion and resulting in AT hypoxia.

Immune cell infiltration in AT dysfunction

Hypertrophic adipocyte necrosis (HAN) is a consequence of AT expansion; HAN contributes to the infiltration of macrophages in AT [21], thereby increasing the numbers of T cells, B cells, macrophages, neutrophils, and the mast cells. Anti-inflammatory cytokines interleukin (IL)-10 and transforming growth factor beta (TGF-β) are also released by M2 macrophage and T regulatory cells (Treg), which increases the insulin sensitivity and inhibits AT inflammation and dysfunction [22]. In lean AT mass conditions, macrophages in AT express CD206 (CD206 +) but CD11c (CD11c-) are not expressed, whereas, in obese tissue macrophages express CD11c (CD11c +) but not CD206 (CD206-) [23]. CD11c + is also known as M1 polarized, and it is believed to be the contributor to inflammation and metabolic dysfunction of AT in obesity. Polarization of M1 increases the production of hypoxia-inducible factor 1α (HIF1-α) [24], which upregulates pro-inflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1). These cytokines damage the microvessels. Damages to the AT arterioles lead to the dysregulation of the AT microcirculation [24, 25].

Other mechanisms involved in the progression of AT inflammation are endoplasmic reticulum (ER) stress and oxidative stress. Obesity induces ER stress in AT and liver tissues. Nutrients such as lipids and cytokines trigger the inflammatory kinases, e.g., c-Jun amino-terminal kinase (JNK), nuclear factor kappa-β(NF-kβ), inhibitor of kinase-β (IKK-β) at the molecular and cellular levels [26]. During ER stress, a complex response called unfolded protein response (UPR) takes place to maintain the functional integrity of the organelles through three major signaling molecules namely inositol-requiring enzyme 1 (IRE-1), PKR-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF6) [27]. The presence of ER stress activates JNK and IKK, which regulates the production of inflammatory cytokines including TNF-α. Exposure to TNF-α induces ER stress, and ER stress itself increases the expression of TNF-α resulting in more general inflammatory responses [28]. Similarly, reactive oxygen species (ROS) emerges from the mitochondria and/or ER and activates JNK and IKK, eventually, more ER stress, blocks insulin action and produces more ROS and causes broader inflammatory responses due to oxidative stress. The outcomes of oxidative stress in metabolic diseases are directly linked to diabetic complications through endothelial dysfunction [29]. In oxidative stress and insulin resistance, inflammatory pathways such as NF-kβ and JNK are activated in adipocytes, muscle cells, and impair insulin secretion in pancreatic β-cells [30]. In T2DM, β-cells synthesize and secrete insulin continuously due to its activation associated with unresolved hyperglycemia, thereby causing cellular stress that induces deterioration and apoptosis of β-cells [31].

In the obese state, the number of adipose tissue macrophages (ATMs) present in AT plays a critical role in the progression of metabolic dysfunction. ER stress has been shown to suppress M2 polarization of macrophages in obesity [32]. M2 macrophages usually generate anti-inflammatory cytokines IL-10 and IL-1 decoy receptors. M2 polarization results in increased production of “arginase”, an enzyme which blocks inducible nitric oxide synthase (iNOS) activity and competes with the arginine, a substrate required for nitric oxide (NO) production [33]. M2 polarization occurs via activation of Signal Transducer and Activator of Transcription 3 (STAT3) and STAT6 pathways by IL-4/13 and IL-10 secreted by T helper 2 (TH2) cells. On the other hand during ER stress, pro-inflammatory cytokines such as IFN-γ, TNF-α or Toll-like receptors (TLR) are released resulting in M1 polarization. AT is dominated by M1 macrophages and inflammatory pathways like NF-kβ and STAT1 are activated which suppresses the M2 polarization and resulting production of pro-inflammatory cytokines such as TNF-α, IL-6, IL-1β and consequently AT inflammation [34].

In AT dysfunction, M1 macrophages form aggregates around the necrotic lipid droplets that are formed as a result of adipocyte lipolysis [35]. After adipocyte lipolysis, the leukocyte aggregates are shared with mast cells, CD4 + and CD8 + T cells. In AT, CD4 + TH cells include Treg, TH1, and TH2 and CD8 + T regulates local inflammation through the cytokine secretion which is involved in the differentiation and polarization of macrophages [36]. Polarization of M1 macrophages stimulates the inflammatory cytokine production and increased infiltration of pro-inflammatory CD8 + T and shifts towards higher CD8 + T/CD4 + ratio [36]. In this condition, infiltration and accumulation of T cells (CD8 + , and TH1 CD4 + T) leads to loss of Treg anti-inflammatory cells followed by induction of B cells, natural killer (NK) cells, Type-1 natural killer (NKT) cells, eosinophils, neutrophils, and mast cells [37]. These cells helps in the progress of atherosclerotic progression through the release of pro-inflammatory cytokines including TNF-α, leptin, IL-6, resistin, etc. M1 macrophages are immunoreactive to oxidized low density lipids (oxLDL) resulting from lipolysis in adipocytes. The accumulation and retention of LDL within the artery walls is mediated by interaction between apolipoprotein B-100 and proteoglycan binding and undergoes oxidation and enzymatic modification and produces oxLDL [38]. Accumulation of oxLDL triggers inflammatory response and activates cells within arterial intima and induces the expression of inflammatory cytokines, chemokines and adhesion molecules. The adhesion molecules then adhere monocytes to endothelium and migrate to arterial intima [39]. Failure to remove accumulated oxLDL by scavenger receptors results in cholesterol droplets available to cytosol and transform these macrophages into foam cells, an early characteristic of atherosclerosis [40].

Fatty acid metabolism is regulated by peroxisome proliferator-activated receptor (PPAR) and liver X receptor (LXR). These two regulate fatty acid metabolism transcriptionally. PPAR controls fatty acid degradation, whereas LXR regulates the synthesis of fatty acid by activating sterol regulatory element-binding protein-1c [41]. Despite their opposite action in lipid metabolism, PPAR and LXR enjoy some common features and have anti-atherosclerotic effects. PPAR controls the cholesterol efflux in foam cell macrophages through the LXR-dependent ATP-binding cassette (ABC) pathway and activation of PPAR inhibitors foam cell formation and thereby atherosclerosis [42, 43]. Activation of the LXR upregulates the expression of ABCA1 and ABCG1 and accelerates reverse transport of cholesterol [44]. Activation of LXR also increases the expression of ABCG5 and ABCG8 in the intestine tissue, which regulates the absorption of cholesterol and protects against atherosclerosis [45]. Similar action is seen with PPAR activation in rats and mice [46]. Both LXR and PPAR facilitate the movement of cholesterol from peripheral cells to the feces and are called reverse transport cholesterol.

In obesity, oxLDL is recognized by toll-like receptor-4 (TLR-4) and plays a critical role in development of atherogenesis. Activation of TLR-4 enhances lipid uptake by macrophage thus develops foam cells [47]. Polarized M1 stimulates TLR-3, TLR-4 or TLR-9 and upregulates the expression of scavenger receptor A, macrophage receptor with collagenous structure (MARCO) and lectin like low-density lipoprotein receptor-1 (LOX-1), hence enhancing foam cell formation [48].

Role of obesity in alteration of vascular structure and function of AT

The link between obesity and vascular endothelial growth factors (VEGF) is crucial in the development of hypertension and atherosclerosis [8]. During obesity, VEGF secretion increases in an insulin-dependent manner [49]. VEGF levels also rise during the expansion of vascular adipose tissue (VAT) [50, 51]. VEGF-A improves vascularization and turns white adipose tissue (WAT) to brown adipose tissue (BAT). This is associated with an increase in energy expenditure and attenuates diet-induced metabolic effects such as insulin resistance and hepatic steatosis [51, 52]. On the contrary, in obesity, adipocytes restrict deletion of VEGF-A resulting in limited AT vascularization thereby higher AT inflammation and systemic metabolic dysfunction [4, 53]. HIF1-α is the key regulator of VEGF expression, which gets upregulated in AT expansion during obesity [53].

Fat expansion outgrows the blood supply due to deficient angiogenesis and prompt ischemia, hypoxia, necrosis, and inflammation within the adipose milieu [54]. The individuals with obesity develop capillary dropout and suffer a deficiency of vascularization, mainly in visceral fat; the ensuing consequences are inflammation and metabolic dysfunction [24, 55]. A marked difference is also observed in genetic transcription of visceral fat and subcutaneous fat in the obese state in comparison to lean state [24]. For instance a gene Angiopoietin-like 4 (ANGPTL4)is mainly expressed in AT [56], secreted by adipocytes and is known to possess pro-angiogenic effect and has been studied thoroughly due to its inhibitory effect on lipoprotein lipase, an enzyme which is responsible for TG metabolism, and responsible for the triglyceridemia when overexpressed [57, 58].

Circulating leukocyte recruitment in the endothelium represents the pathophysiology of macrovascular and microvascular diseases [59]. Under normal circumstances, endothelium does not bind/interact with circulating leukocytes. Various adhesion molecules including selectins and cellular adhesion molecules (CAMs) are expressed in the luminal surface of endothelial cell during the early stage of endothelial dysfunction and these molecules act as receptors for glycoconjugates and integrins which are present in the circulating leukocytes [60]. Traditionally, it has been believed that prolonged exposure of the vascular endothelium to elevated circulating levels of metabolites or inflammatory mediators, such as glucose, free fatty acids (FFAs), oxLDL, and cytokines, and endothelial dysfunction occurs by perturbing endothelial cell homeostasis [61]. However, as the research progressed over the periods of time, recent research emphasizes the role of AT and unbalanced secretion of mediators by adipocytes in obesity as major causes of endothelial dysfunction [62]. AT dysfunction leads to the activation of inflammatory signals that directly or indirectly act from white adipocytes and actively contributes to the circulating milieu and induces vascular dysfunction [63].

Under normal physiologic conditions, the type I transmembrane glycoprotein vascular cell adhesion molecule-1 (VCAM-1) expression is absent or very low, however, its expression can be triggered by cytokines such as TNF-α [60] and the role of VCAM-1 on atherosclerosis is well explained in animal as well as in human study[64, 65]. Apart from CAM expression, endothelium dysfunction causes loss of endothelial NO (eNO). Consequences of loss eNO are hypertension to several associated complications, including increased endothelial adhesion molecules expression which further leads to development of atherosclerosis [66]. NO possess anti-inflammatory effect and the effect is mainly based on the inhibition of the leukocyte–endothelial interactions. NO exert the anti-inflammatory effect by inhibiting exocytosis of Weibel Palade bodies and reducing NF-kβ expression [67].

Endothelial dysfunction is an early marker of cardiovascular disease (CVD), healthy endothelium is actively capable of inhibiting the pro-atherogenic process by NO pathway. AT express numbers of PAK including leptin, resistin, TNF-α, as well as AAK including adiponectin, Sfrp5, CTRPs, etc., respectively. ATMs are responsible for the production of these adipokines. Adhesion molecules such as P-selectin, E-selectin, and intracellular adhesion molecule (ICAM-1) are highly expressed in AT. Leukocyte recruitment, rolling and MCP-1 are increased with the adhesion molecule expression and promotes leukocyte transmigration and integrins, which increases the adherences to the intima [7]. In this condition phagocytosis of LDL particles by monocytes leads to formation of foam cells and develops a fatty streak followed by plaques. These plaques are very prone to rupture followed by thrombus formation which subsequently favors the occlusion of artery and infarction occurs. PAK modulates smooth muscle cell constriction, proliferation and migration. PAK also hampers the release of AAK from AT [68, 69]. TNF-α, IL-6 inhibits the expression and release of AAKs. PAKs like leptin, at high concentration, promote adhesion and transmigration of monocytes through the derived capillary endothelial cells (AT-ECs) [70]. Leptin upregulates the expression of MCP-1 and increases the production of endothelial ROS and JNK activity and also enhances the DNA binding activities of redox-sensitive transcription factors NF-kβ and activator protein-1(AP-1) [71]. Resistin also directly injures endothelium by increasing production and expression of adhesion molecule VCAM-1 and MCP-1 via endothelin-1 by endothelial cells [72]. During endothelial dysfunction circulating levels of AAKs are decreased. AAKs, e.g., adiponectin, exert anti-inflammatory effect on endothelial cells and inhibit TNF-α thereby reducing the expression of adhesion molecules and other inflammatory cytokines [73]. Therefore, the balance between AAKs and PAKs plays an important role in the development and progression of atherosclerosis.

Another most important harmful effect of obesity is arterial stiffness. Arterial stiffness is structural and functional changes in the intimal, medial and adventitial layers of the vasculature. In stiff arteries, the propagation of pulse wave is faster and due to increased velocity, an altered hemodynamic changes especially increased central systolic blood pressure and pulse pressure are observed which have an negative impact on myocardium due to increased left ventricular afterload and decreased coronary blood flow [74]. Arterial stiffness is considered one of the valuable risk factors for the CHD.

In obesity metabolic changes in AT result in altered secretion of hormones and cytokines such as TNF-α, IL-6, leptin, resistin, adiponectin, etc. Increased levels of adipocyte derived cytokines impairs the insulin sensitivity and enhances the recruitment and activation of pro-inflammatory immune cells in the vasculature which contribute in the development of arterial stiffness [75].

Obesity-induced fibrosis and remodeling of adipose tissue

Adipocytes in AT are encircled by ECM. ECM proteins provide mechanical support and regulate adipogenesis and lipid droplet growth. In the obese state, ECM undergoes modification to accommodate the adipocytes. In obesity, a rapid expansion of AT leads to ECM remodeling and thereby persistent hypoxia, which activates HIF1-α [76]. In obese state, there is 30–40% lower blood flow to AT, 44% lower capillary density and 58% lower VEGF growth [77]. Pre-adipocytes and mature adipocytes usually generate a substantial amount of macrophage migration inhibition factor (MIF). Expression levels of MIF are positively correlated with Body mass index (BMI) of an individual [78].

In obesity AT hypoxia leads macrophage infiltration to that hypoxic area of AT. Hypoxia activates macrophage, and subsequently activation of HIF1-α occurs which then inhibits differentiation of pre-adipocyte thus fibrosis of AT. Hypoxia also inhibits differentiation of adipocytes from pre-adipocytes [24]. Leptin signaling controls the inhibition of pre-adipocyte differentiation [79]. Pre-adipocyte shows higher expression of PAKs than the adipocytes. It is considered that, one per cent hypoxia is sufficient to enhance the significant release of VEGF, IL-6, and PAI-1 from pre-adipocytes; however, the hypoxic value stands for adipocyte is one and half of that of pre-adipocytes [80]. Under hypoxic conditions, adipocytes express HIF1-α and recruit HIF-1 protein [24]. Adiponectin and leptin secretion are very sensitive to hypoxic conditions of adipocytes. Hypoxia also modulates major inflammatory secretion of major inflammatory adipokines such as IL-6, MIF (macrophage migratory inhibitory factor), VEGF, serum amyloid A and matrix metallopeptidase 2 (MMP-2) and adiponectin [24]. Endotrophin, a compound generated during the cleavage of α3 subunit of collagen VI (COL 6), secreted by adipocytes promotes AT fibrosis and systemic metabolic dysfunction [81].

Obesity-linked atherogenic dyslipidemia and insulin resistance

Atherogenic dyslipidemia and insulin resistance are the two main manifestations of CMD linked to obesity. The genetic component responsible for obesity and insulin resistance has not yet been completely understood. Vascular inflammation and diabetes are common phenomena in obesity [82]. Metabolic products like lipids, hormones, and cytokines formed as a result of obesity-related biochemical processes are also responsible for insulin resistance and metabolic dysfunction. Insulin resistance hinders the insulin signaling pathways in muscles, endothelial cells and AT [83]. The mechanisms started with PAKs or metabolic excess including TNF-α, endothelin-1, FFA or ER stress which exhibit ser/Thr phosphorylation of insulin receptor substrate 1(IRS1) and cause insulin resistance. Dysregulation of insulin signaling associated with numerous disorders such as dyslipidemia, hypertension, cardiovascular disease, stroke, etc. In insulin resistance, acute and chronic inflammation plays a dynamic role and also provides information about the role of diets, physiological stress and obesity. Inflammatory cytokines like IL-6, TNF-α stimulates lipolysis and generates free fatty acid from TGs during obesity. One of the main reasons for insulin resistance and T2DM is due to heterologous and feedback inhibition of insulin signaling which is mediated by phosphorylation of IRS1. Pro-inflammatory cytokines including IL-6 and TNF-α are produced from AT during obesity. TNF-α promotes serine phosphorylation of ISR1 and IRS2 and is closely associated with insulin resistance [26]. TNFα plays an active role in insulin resistance because of its ability to bind IRS1 and IRS2 thereby phosphorylates serine residue and inhibits insulin stimulated tyrosine phosphorylation [84]. Tyrosine phosphorylation at specific sites on receptor substrates are very important for glucose uptake, lipogenesis, and glycogen and protein synthesis, as well as for stimulation of cell growth [85]. Phosphorylation of serine residue of the insulin substrate interferes with the tyrosine phosphorylation by decreasing the binding of insulin receptors or degradation of IRS1(Fig. 1) [86].

Fig. 1
figure 1

Inflammatory adipokines suppress insulin signaling resulting in insulin resistance. IRS1/2 phosphorylated on specific tyrosine residues activates the phosphatidyl inositol 3-kinase (PI3K)-AKT/protein kinase B (PKB) pathway and Ras-mitogen-activated protein kinase (MAPK) pathway. PI3K-AKT signaling pathway regulates metabolic processes such as glucose uptake(muscle and adipocytes), glycogen synthesis (muscle and liver), protein synthesis(muscle and liver), and gluconeogenesis (liver). Inflammatory signals, TNF-a, IL-6, Leptin and saturated free fatty acid, activate inhibitory molecules such as SOCS and JNK to suppress insulin signaling resulting in insulin resistance. PI3K-dependent PDK1 activation is negatively regulated by phospholipid phosphatases such as phosphatase and tensin homolog (PTEN) that degrade PIP3 [86]. doi: 10.3389/fendo.2013.00071, Reproduced with permission Frontiers in Endocrinology)

Ubiquitin-mediated degradation of IRS1 and IRS2 is another mechanism which promote cytokine induced insulin resistance and have contribution in diabetes as well as in β cells dysfunctioning. Suppressor of cytokine signaling (SOCS) 1 and 3 are proteins which bind to distinct domains of insulin receptor and plays important role in insulin receptor mediated phosphorylation of IRS1 and IRS2. SOCS1 overexpression in the liver inhibits IRS2 tyrosine phosphorylation and SOCS3 overexpression decreases tyrosine phosphorylation in both IRS1 and IRS2 [87]. Resistin and leptin increase the expression of SOCS1/3 in liver which causes insulin resistance and upregulates the key regulator for the production of fatty acid synthesis and sterol regulatory element-binding protein 1c (SREBP-1c) expression. Thus, SOCS1 and SOCS3 are linked to inflammation, metabolic stress, insulin resistance and glucose intolerance.

Mitochondria is the major site of lipid degradation and plays an important role in metabolic health as mitochondrial dysfunction is associated with the ageing process as well as metabolic disorders [88].Maintenance of the intracellular redox environment (RE) is crucial in order to carry out cellular vital functions [89]. Mitochondria maintains intracellular RE and constitutes subcellular compartments with peroxisomes, the area for lipid degradation [90]. Fatty acids (FAs) are degraded by β-oxidation and its rate depends upon demand such as increased work and ATP utilization proceeds faster oxidative phosphorylation (OxPhos) and tricarboxylic acid (TCA) cycle activity.

Lipids are usually presented as albumin bound FAs by AT or by coronary vascular endothelial lipoprotein lipase as a catabolized very low density lipid (VLDL) complex. Long-chain FA (LCFA)transport occurs across sarcolemma through the carrier such as, fatty acid transporter protein 1(FATP1); plasma membrane-associated fatty acid-binding protein (FABP); long-chain fatty acid transporter (LCFAT); plasma membrane sodium-dependent carnitine transporter (OCTN2); fatty acid translocase CD36(FAT/CD36). Similarly in mitochondria, carnitine palmitoyltransferase 1(CPT1); carnitine acylcarnitine translocase (CACT).

LCFA when enters the cell, it forms thioesters with coenzyme A (CoA) and are oxidized in the mitochondria via β-oxidation or forms triacylglycerol (TAG) via esterification. TAG is stored in the form of lipid droplets. Activation of LCFA occurs by long-chain acyl-CoA synthetase in mitochondrial outer membrane. However, mitochondrial inner membrane limits the entry of acyl-CoAs. The transporter protein CPT1 plays an important role and converts long-chain acyl CoA to long-chain acylcarnitine, which is subsequently entered into the mitochondria [91].

A prominent theory states that the relation between the FA oxidation and insulin resistance. It suggests that muscle insulin resistance occurs due to the impaired mitochondrial uptake and fatty acid oxidation [92]. It explains that long-chain acyl-CoA derived from lipids or intramuscular triacylglycerol (IMTG) are diverted away from CPT1, the mitochondrial enzyme responsible for first and essential step in β-oxidation of LCFA. On the contrary, it is moved towards the synthesis of signaling intermediates such as diacylglycerol (DAG) and ceramide. Accumulation of these and other lipid molecules engaged stress activated serine kinases which interfere with insulin signal transduction[93, 94].

Dyslipidemia is a disorder in the contents of lipids, where cholesterol and TGs are the key factors that play a crucial role in the development of atherosclerosis. Atherogenic dyslipidemia is characterized by an elevated level of TG, and lower levels of high-density lipid cholesterol (HDL-C). The link between dyslipidemia, obesity and atherosclerosis have been studied thoroughly by many researchers. The formation of atherogenesis is influenced by diverse adipokines. Atherogenesis is not only about deposition of fat into the arterial wall but the role of the adaptive and innate immune system have to be considered [95]. Atherogenesis starts in the specific site where endothelium is submitted to shear stress clearly at aortic root, aortic arch, superior mesenteric artery, and renal arteries [96]. In this position, endothelial dysfunction and permeability of the intimal layer occurs which favors the migration of LDL particles to sub-endothelial space [97]. In the presence of leptin, TNF-α, endothelial dysfunction and transmigration of LDL particles get worse. Here, LDL particles are oxidized (oxLDL), which can be positively related to MCP-1 level. The presence of MCP-1, IL-6, leptin and TNF-α increases the expression of adhesion molecules such as VCAM-1 and ICAM-1 in endothelium and enhances leukocyte transmigration. Under the influence of MCP-1 monocytes are developed into macrophage and phagocytes oxLDL and turn into foam cells [98]. IL-6 is produced by smooth muscle cells (SMC) under the influence of angiotensin-II. IL-6 and MCP-1 increase the recruitment and proliferation of SMC and extracellular matrix to form a fibrous cap around the necrotic lipid core. In the presence of matrix metalloproteinases and prothrombotic molecules, MCP-1 and leptin help in rupturing the plaque formed and thrombus formation [96]. The atherosclerotic plaque thus formed causes occlusion of the coronary artery, thereby reducing the blood supply to the heart. Due to complete blockage of the coronary artery, the heart muscle does not get enough supply of oxygen and starts to die causing ischemia and eventually MI.

Although the treatment regime for the treatment of LDL cholesterol, blood pressure and glycemia have improved, atherogenic dyslipidemia remains as a silent killer due to being underdiagnosed and undertreated in clinical practice [99]. Atherogenic dyslipidemia is commonly associated with CVD, T2DM and contributes both macrovascular as well as microvascular residual risks. To reduce the residual risks of patients with atherogenic dyslipidemia, a residual risk reduction initiative was established to address this clinical issue. In 2014, a meeting with European experts in CVD and lipid was convened in Paris, France, to discuss atherogenic dyslipidemia, lipid and its associated CV risks. They concluded that elevated levels of LDL-c have greater risk for CV than low LDL-c and could be treated with statins. However, even after treating with statins some patients have abnormal lipid profiles especially with elevated levels of TGs, low levels of HDL-c which presents residual CV risk. Therefore, it was recommended to measure the levels of TGs and HDL-c to manage the overall residual CV risk. They recommended use of statin along with other lipid lowering drugs such as fenofibrate to achieve clinical benefits [100, 101]. Therefore, to counter atherogenic dyslipidemia along with proper diagnosis statin-combination therapy is recommended to get more clinical benefit patients with residual risk. However, this is not a proper treatment regime that can be completely safe and effective, therefore researchers focus on new drugs with more efficacy and ensuring the effectiveness is still awaiting in atherogenic dyslipidemia. Since adipokines levels change during dyslipidemia and AAKs have been reported to have anti-atherogenic effects, it would be interesting to see the adipokines' role as a marker and therapeutic agent in treating atherogenic dyslipidemia in the near future.

Adipokines in atherogenic dyslipidemia and insulin resistance

Adipokines came to attention when the leptin, an AT specific adipokine, proved to be an important regulator for food intake and energy expenditure [102]. Since the discovery of leptin, new adipokine attracted the attention of researchers due to its utter responses between CVDs, obesity and metabolic disorder. This new adipokine plays numerous roles in the microcirculation of AT and affects target organs through autocrine, paracrine or endocrine pathways [103]. Adipokines are being classified according to their beneficial and harmful effect on the body. The beneficial effects of adipokines are cardioprotection, promoting endothelial function, angiogenesis, and insulin-sensitizing effect, whereas harmful effects include atherosclerosis, insulin resistance and inflammation [104]. The beneficial action of the adipokines are mostly exerted by AAKs, whereas PAKs are responsible for the deleterious effect. A list of preclinical and clinical studies of the AAKs are listed in Tables 1 and 2

Table 1 Preclinical evidence of anti-inflammatory adipokines in insulin resistance and atherogenic dyslipidemia
Table 2 Clinical evidence of anti-inflammatory adipokines in insulin resistance and atherogenic dyslipidemia

It is important to know that the former effects are exerted by AAKs whereas later by PAKs, whereas many adipokines function are yet to be reported. Most of the adipokines are derived from either VAT and subcutaneous adipose tissue (SAT) [51, 105]. Although there are numbers of AAKs and PAKs that act directly and indirectly on metabolic health of humans, in this article the adipokines which are actively and mostly found to be associated with atherogenic dyslipidemia and insulin resistance are considered for discussion. The PAKs are upregulated during obesity and can promote obesity-linked CMDs. Most of the PAKs that researchers think to be involved with the metabolic diseases are leptin, TNFα, IL-6 and resistin. Alternatively there are AAKs that are thought to be useful in the prevention or therapeutic intervention of the metabolic diseases are adiponectin, omentin-1, some members of CTRP family and Sfrp5. The level of these PAKs and AAKs changes in metabolic complications; therefore, function and therapeutic intervention of the adipokines/or with the adipokines can be a game changer in the management or therapeutic prospects and their potential utility as a biological marker in the management of CMDs.

Pro-inflammatory adipokines (PAKs)

Tumor necrosis factor (TNF-α)

TNF-α is secreted from myeloid cells via activation of mitogen-activated protein kinase (MAPK) and NFkB signaling and responsible for secretion of other inflammatory cytokines, e.g., IL-1 and IL-6 [106]. It is the first WAT-derived PAKs reported to involve in initiation and progression of insulin resistance [26]. TNF-α are released by AT-resident macrophages and found to be overexpressed in obese animals AT [107]. It was observed that mice lacking TNF-α or its receptor are resistant to the development of insulin resistance [108]. TNF-α is higher in AT in obese human subject and positively correlated with insulin resistance[109, 110]. Long term treatment of anti-TNF-α inhibitor treatment patients with metabolic syndrome reported to be improved in fasting blood sugar and increased adiponectin levels[111]. TNF-α is involved in phosphorylation of IRS-1 receptors and has direct negative inference in the insulin signaling pathway [112]. TNF-α also affects the adipocyte differentiation and lipid metabolism, thereby indirectly induces insulin resistance. TNF-α increases hepatic glucose production due to its action in promoting lipid metabolism and secretion of free FA [113]. TNF-α hinders the conversion of pre-adipocyte to mature adipocytes through the downregulation of adipogenic genes such as peroxisome proliferator-activated receptor gamma (PPAR-γ) and CCAAT/enhancer binding protein (C/EBP) thus leads to expansion of AT mass [114]. TNF-α also activates NF-κβ genes and downregulates mRNA levels of adiponectin [115, 116]. However, the effect on immune response of TNF-α is mainly due to the enhancing secretion of other cytokines, such as IL-6, rather than direct effect [117].


Leptin is 16-kd protein and was identified in obese gene (ob)of ob/ob mice [118]. Leptin is AT specific adipokines that regulates appetite, energy expenditure, behavior and glucose metabolism [119]. Mice lack of leptin shows hyperphagia, obesity, and insulin resistance. However, delivery of leptin in ob/ob mice reverses the conditions [120]. When leptin is injected to ob/ob mice, it has multiple beneficial effects in health such as reduction in food intake, body mass, increased it has shown rapid reduction in food intake, body mass, increased energy expenditure and restored euglycemia [121]. However, leptin is positively correlated with AT mass, obesity and increased levels of leptin does not have any expected decrease in food intake, signifying that leptin resistance occurs during obesity [120]. In normal circumstances, leptin mediates its anorexic actions in hypothalamus, by binding to the leptin receptor b (LRb) and through the activation of janus kinase 2/ Signal transducer and activator of transcription 3 (JAK2/STAT3) signaling. However, in obesity this pathway is blocked by several mechanisms. One of the mechanisms includes, STAT3-mediated induction of SOCS3 protein, impairs leptin induced signaling by binding to phosphorylated Tyr985 residues of LRb [122]. Animal studies proved that SOCS3 is responsible for leptin resistance [123]. In inflammation leptin levels are increased in AT as well as in serum and acts on monocytes/macrophages, neutrophils, and T cells, and enhance the production of the pro-inflammatory cytokines and suppresses anti-inflammatory cytokines [124, 125]. Leptin suppresses the production of TH-2 type cytokine, IL-4 and increases the TH1 type cytokines and polarized T cells towards TH1 phenotype [124, 126]. Many preclinical and clinical studies have proved the link of leptin with atherogenesis and metabolic syndrome. Circulating levels of leptin is positively correlated with metabolic syndrome and cardiovascular disease [127]. Increased leptin levels significantly alarms the pathogenic risk of coronary heart disease (CHD) [128]. Leptin levels are increased after myocardial infarction in humans [129]. Greater cardiac hypertrophy was observed in leptin deficient mice and provided greater cardiac remodeling in response to chronic ischemic injury [130, 131].

Leptin shows both insulin sensitizing and insulin resistance effects. However, these effects if we consider directly attributed to leptin is debatable. This is because of AT, a dynamic endocrine organ where when leptin concentration changes, may lead to changes in other metabolically active hormones also [132]. Leptin acts both peripherally (skeletal muscle, liver, pancreas, and fat) as well as centrally via central nervous system (CNS) to control basal and insulin-mediated glucose homeostasis. In-vitro studies suggest that leptin has an important inhibitory role in glucose metabolism. However, insulin sensitizing effect also has been proposed in in-vivo studies which depends on the central mechanism.

Interleukin-6 (IL-6)

IL-6 is a versatile, pleiotropic adipokine reported to be engaged in vital roles such as regulation of inflammation, hematopoiesis, immune responses, and host defense mechanisms [133]. It is a PAK, and AT is responsible for secretion of 15–30% of IL-6 in normal healthy people [134].IL-6 is produced by macrophages, fibroblast and the stromal vascular fraction of visceral WAT [51]. VAT releases more IL-6 than SAT and acts as a marker for visceral adiposity [120]. IL-6 is one of the major PAK which is actively involved in chronic inflammatory disease such as atherosclerosis [135]. Genetic polymorphism studies have confirmed the linkage of IL-6 receptor signaling and its association with CAD [136]. IL-6 levels are positively correlated with increased risk of MI [137]. Further, IL-6 and its receptor are linked to plaque instability [138]. It is believed that production of IL-6 is stimulated by TNF-α.

The link between obesity and T2D has been well documented and suggests the relation between obesity and insulin resistance. It should be noted that circulating levels of IL-6 is two or three fold higher in obese patients with T2D compared to normal person [139]. However, obesity and its link to metabolic syndrome is controversial [140]. Some researchers suggest the existence of a relationship with elevated levels of IL-6 and insulin resistance or T2D [141, 142]; however, several argue against the existing relationship. They suggest that increased fat mass and elevated IL-6 levels are not independent risk factors for development of insulin resistance [143]. This is because visceral fat releases a much higher quantity of IL-6 and is a stronger predictor of diabetes than total fat mass [144].


Resistin is 10 KDa polypeptide with 114 amino acids in roden, similar in molecular structure to adiponectin and first identified in obese mice, affects in glucose homeostasis and mediate insulin resistance [117, 145]. Large population based studies confirm the positive correlation between circulating resistin and fasting serum TG [146]. Resistin levels are increased in obesity and insulin resistance in rodents [147]. Insulin resistance is mainly due to the interference in normal insulin signaling by decreasing the expression of insulin receptors, IRS1 and IRS2 [148]. Resistin also decreases the activation of AMPK which is a potential insulin sensitizing molecule [149]. Recombinant resistin administration to normal animals produce insulin resistance, however, immune neutralization of resistin improves insulin sensitivity in obese animals with insulin resistance [147]. Resistin injures endothelium by inducting adhesion molecules VCAM-1 and MCP-1 expression and secretions and synthesizing endothelin-1 by endothelial cells [72]. Insulin resistance in humans by resistin is not clear as in rodents. Resistin is expressed in macrophage in humans, signifying a pro-inflammatory action rather than their involvement in glucose metabolism. Resistin induces oxidative stress and inhibits eNOS in human endothelial cells [150]. In human macrophages, resistin support foam cell formation and induce platelet activation by increasing P-selectin expression [151, 152]. Therefore, the findings suggest that human resistin might play an important role in development of atherosclerosis.


Visfatin is produced mainly by the adipocyte in visceral AT. It is a 52 kDa multifunctional protein with several activities. Visfatin, also known as nicotinamide phosphoribosyl transferase (NAMPT), or pre-B cell colony-enhancing factor (PBEF), is known to play a crucial role in regulating numerous pathophysiological functions [153]. In metabolic disease, circulating visfatin level increases and has been positively correlated with cardiovascular diseases. High plasma levels of visfatin are also associated with vascular inflammation, endothelial dysfunction and atherosclerotic plaque destabilization [154].

Anti-inflammatory adipokines(AAKs)

Adipokines have diverse functions depending on their properties. However, there are certain adipokines that are beneficial for human health and categorized as AAKs. Numbers of adipokines are available with their categorized functional properties, but in this paper we are discussing those AAKs which have direct or indirect impact on the metabolic health considering atherogenic dyslipidemia and insulin resistance as reference. The reason for choosing few adipokines can be explained by their exploratory role mainly on atherogenesis, and insulin resistance.


Adiponectin is adipocyte-derived hormones comprising of four distinct domains, e.g., a signal peptide at the N terminus, a short variable region, collagenous domain and a C-terminal globular domain homologous to C1q [155]. Mouse and human adiponectin have 83% homology and contain 247 and 244 amino acid sequences, respectively [156]. The crystal structure of adiponectin is similar to that of TNF-α [157]. Adiponectin and C1q/TNF-related protein (CTRP) share the common structure as mentioned earlier. Adiponectin exists in three multimeric forms: a trimer, low molecular weight (LMW), a hexamer medium multimer and larger multimeric high molecular weight (HMW) [156, 158]. Adiponectin is secreted by adipocytes and its expression is ≈100 fold during adipocyte differentiation [159]. In healthy adults, the adiponectin concentration varies in human serum from 1.9 to 17.0 g/ml [159]. Plasma level of adiponectin in healthy people or mice is 1000 times higher than leptin accounting 0.01% of total plasma protein [160]. Adiponectin is a well-established biomarker of increased risk of insulin resistance, CVDs, etc. [161]. Despite adiponectin being secreted exclusively by AT, during obesity the level of adiponectin decreases, but paradoxically increases during caloric restriction (CR), anorexia nervosa (AN). The paradox of adiponectin may be explained in this way that in insulin resistance or obesity with insulin resistance state, decreased adiponectin may results from the decreased expression and transcript protein of adiponectin which may be from mitochondrial dysfunction, hypoxia and or ER stress [162]. However, the increased expression of adiponectin in CR and AN remained unclear although few studies have shown increased expression of adiponectin in extensive CR [163]. Most of the study including animals and humans reported that serum adiponectin levels are increased with prolonged CR and weight loss, but not from the WAT or without affecting expression or secretion in WAT [164, 166].  Moreover, the human subject shows decrease in adiponectin expression in WAT during AN and clearances of adiponectin remain unaltered during CR [163, 166]. Moreover, changes of circulating adiponectin in response to treatment with insulin or thiazolidinedione are also not related to adiponectin transcript expression in WAT [167]. The question is during CR or AR, where does adiponectin come from if the expression of adiponectin remains unaltered in WAT? The question remained unanswered until Cawthorn et al. investigated the bone marrow AT (MAT) that secret adiponectin in the circulation [168]. In normal healthy subjects, MAT comprises 13% of total adipose mass, where as in AN, 31.5% MAT clearly suggest that the expansion of MAT. In AN subject, MAT comprises 30% of total body fat and is sufficient to be a major contributor of adiponectin to the circulating adiponectin [168]. Using Wnt10b mice with specific MAT ablation with CR, shows increased resistance in both MAT and serum adiponectin without having any impact on WAT mass as well as adiponectin expression in WAT. On the other hand, MAT expansion increases serum adiponectin and adapts skeletal muscle during CR. Thus, all the evidence gives conclusive results that MAT is a key source of adiponectin and reaches the circulation through endocrine action [168].

Adiponectin regulates endothelial function by influencing adhesion and transmigration of leukocyte and macrophages which are mediated by ICAM1, VCAM and E-selectins. Adiponectin level is decreased in obesity and in insulin resistance and low adiponectin levels are found to be associated with endothelial dysfunction [169]. Animal disease model and in-vivo study confirms the lower adiponectin level exacerbates vascular injury and overexpression of adiponectin protects from atherosclerosis [170, 171]. Adiponectin protects vascular endothelium by anti-inflammatory action against oxidative stress and inflammatory cytokines suggests molecular mechanism involves mainly inhibition of inflammatory signal in-vivo [172]. Adiponectin deficiency enhances leukocyte–endothelial cell interactions via reduced availability of eNO at the vascular wall and upregulation of endothelial CAMs, leading to vascular inflammation and atherosclerosis [61]. Administration of pharmacologically active doses of the recombinant globular adiponectin (gAd) reverts the endothelial dysfunction associated with adiponectin deficiency and attenuates cytokine-induced vascular inflammation in wild type (WT) mice and maintains the expressing of physiologic concentrations of adiponectin in the blood [61]. Adiponectin deficiency increases the leukocyte rolling and adhesion. Increased leukocyte rolling flux decreases the velocities of rolling leukocytes and increases the adhesion to the vascular wall. WT mice when treated with gAd, show normalized leukocyte rolling flux, leukocyte rolling velocity and leukocyte adhesion which supports the hypothesis that vascular inflammation due to adiponectin deficiency may be treatable with the with similar adiponectin isoforms, i.e., gAd [61]. gAd has been reported to reverse the TNF-α induced leukocyte-endothelium interactions in WT mice. TNF-α downregulate eNOs/NO signaling and upregulates endothelial CAM [66, 173]. Treatment with gAd inhibits TNF-α mediate leukocyte–endothelial interaction and reverses the TNF-α signaling in endothelial cell culture study [61, 174]. Endogenous adiponectin and gAd regulates the availability of NO in endothelium. Adiponectin deficiency shows 40% reduction in eNO availability, and treatment with gAd maintains the physiological levels of adiponectin. The ability to suppress TNF-α till 55% clearly demonstrates the anti-inflammatory action of adiponectin [61]. The ability to mitigate the anti-inflammatory effect in endothelium, suppression of CAM and availability of eNO reflects the possibilities of anti-atherogenic activity of adiponectin, thereby cardioprotection.

Adiponectin exerts its anti-inflammatory action through its receptor Adiponectin R1 (adipoR1), adiponectin (adipoR2) and T-cadherin [175]. Numbers of study reported direct action of adiponectin on inflammatory cells and NF-κβ. Adiponectin suppress foam cell transformation from macrophages by inhibiting the function of mature macrophages [176], stimulates the macrophage production of anti-inflammatory cytokine IL-10 and inhibits TNF-α induced VCAM-1, E-selectin expression on endothelial cells [177], inhibits NF-κβ activation in macrophages which is induced by TLR [178]. Adiponectins action on NF-κβ is complex presenting both inhibitory as well as stimulatory effects. Adiponectin possess inhibitory action on NF-κβ, inhibits lipopolysaccharide (LPS) induced NF-κβ activation in adipocytes [179],TNF-α induced NF-κβ pathways in endothelial cells [174]and NF-κβ pathway in macrophage [180]. Inhibition of NF-κβ pathway results in anti-inflammatory action of adiponectin and decreases the pro-inflammatory cytokines. On the other hand, the action of gAd and high molecular weight (HMW) adiponectin were compared on NF-κβ pathways in vascular endothelial cells [181]. High molecular weight (HMW) adiponectin when undergoing proteolytic cleavage forms globular adiponectin. HMW adiponectin activates NF-κβ modestly compared to gAd which activates very strongly. HMW requires a shorter period to inhibit TNF-α induced NF-κβ activation, whereas gAd induces expression of various PAKs, adhesion molecules and requires a longer period to inhibit cytokine-induced NF-κβ activation. Therefore, HMW adiponectin may act as an anti-inflammatory whereas cleavage of adiponectin at an inflammatory site may enhance inflammation. However, the dual nature of adiponectin is not clearly understood, and questions remain unresolved regarding the timing of the effects.

Researchers have unveiled the link between adiponectin and its microvascular connection in the regulation of insulin. Skeletal muscle acts as a major organ participating in insulin stimulated glucose metabolism accounting 80% of total body glucose [182]. Insulin is secreted by the pancreatic β-cells, and to act in the muscle it has to be delivered to the muscle cells via capillaries nurturing the muscle cells followed by transportation through the capillary endothelium which enters interstitial space where they bind to the insulin receptor called myocyte to exert metabolic action [183].

Muscle microvasculature plays critical roles in the regulation of insulin secretion in muscle. Insulin action in the muscle cells starts, when it is delivered to the capillaries which nurture the muscle cells, followed by transportation of insulin through capillaries of endothelium to enter the interstitial space [184]. Microcirculation comprises all vessels including venules, arterioles and venules (< 150 µm in diameter). Their functions are to deliver and exchange an adequate amount of nutrients, hormones, oxygen, between the plasma and tissue interstitium. During normal or rested state approximately 30% of the capillaries are functionally perfused, but in response to increased demand especially during exercise more capillaries become functionally perfused via more relaxation of the pre-capillary terminal arterioles [82]. This process is called microvascular recruitment. Insulin mediated microvascular recruitment dispossesses insulin mediated glucose in muscle and blocks the insulin's action on microvascular recruitment. It is reported that insulin-mediated capillary recruitment in skeletal muscles is impaired with diabetes mellitus (DM) [185]. A clinical study reported that obesity blunts the insulin mediated microvascular recruitment in forearm muscle. They assumed that the blunted recruitment in obese individuals are involved at least one part of the insulin mediated glucose disposal and absence of microvascular response [186]. Therefore, insulin and microvascular are appeared to be important for enhancing delivery of insulin and glucose to skeletal muscle and the impaired responses to insulin in the obese subjects might contributes impaired metabolic response. Adiponectin is a potent vasodilator and the action is mediated via NO-dependent mechanisms [187]. Adiponectin modulates muscle insulin action and the expansion of endothelial exchange surface area due to its potent vasodilatory effect via NO-dependent mechanism [183, 187]. Muscle microvasculature is the regulatory site of insulin’s metabolic action and mounting evidence suggests that since adiponectin has both vasodilatory and insulin sensitizing actions, adiponectin modulate microvascular recruitment thereby insulin delivery as well as action in muscle [183].


The endemic problem of the T2DM is a major problem associated with the modern sedentary lifestyle. Importantly, early diagnostic tools are needed for detection of insulin resistance. Moreover, novel therapeutic agents also need to be explored. One such molecule is omentin-1. It has multiple activities including insulin-sensitizing activity. Omentin-1 is a novel 34KDa adipokine first identified in human omental AT, also called intestinal lactoferrin receptor [188, 189]. The physiological, pathophysiological and clinical features of omentin-1 have gained attention due to its experimental and clinical evidence showing its involvement in metabolic disorders [190, 191]. In obesity, plasma omentin-1 and mRNA expression was decreased in VAT [192]. Reduced omentin-1 levels are found to be closely related to metabolic syndrome in morbidly obese women [193]. The expression of omentin-1 is most abundantly found in epicardial adipose tissue (EAT) and visceral fat surrounding the heart and coronary arteries [194]. EAT is attached to the myocardium. Therefore, omentin-1 secreted in EAT directly affects the cardiac function [195]. Omentin-1 suppresses ICAM-1, VCAM-1 and cyclooxygenase-2(COX-2) in human umbilical vein endothelial cells (HUVECs) through ERK/NF-kβ, JNK/AMP-activated protein kinase (AMPK), and eNOS signaling pathways [196, 197]. Omentin-1 does not affect monocyte differentiation to macrophages but is responsible for shifting the balance differentiation preferentially in favor of anti-inflammatory M2 macrophages instead of M1 phenotype [198]. Omentin-1 level is negatively correlated with waist circumference, BMI, systolic blood pressure, carotid intima-media thickness, stiffness, and insulin resistance [199]. It inhibits vascular inflammation and pathological remodeling that are involved in the development of atherosclerosis and also possesses vasodilatory effects as well. Omentin-1 suppresses oxidation of LDL thereby inhibiting the formation of foam cell by downregulating scavenger receptors like CD36, scavenger receptor type A and the ratio of acyl-coenzyme A and cholesterol acyl-transferase-1 in human monocyte-derived macrophages [198].

It is well documented that omentin is a protective adipokine for CVD as it induces vasodilation, reduces endothelial dysfunction, and inhibits vascular inflammation and angiogenesis. These beneficial effects of novel adipokine omentin can be expected to play more roles in the protection of CVD in the future.

Secreted frizzled-related protein 5 (Sfrp5)

Secreted frizzled-related protein 5 (Sfrp5) is an adipocytokine, highly expressed in mature adipocytes of WAT [200] and its detectable in plasma [201]. It inhibits wingless-type family member 5A (WNT5A) signaling pathways, including non-canonical WNT5A/Ca2 + and WNT5A/c-jun N-terminal kinase (JNK) signaling pathways [202]. The expression of WNT5A has been reported to play a crucial role in the development of obesity, T2DM and atherosclerosis [203]. The link between obesity, insulin resistance and T2DM has been discussed in many research articles. Insulin resistance is considered as the main responsible factor involved in the pathogenesis of T2DM. Insulin resistance is a low grade inflammation linked to macrophages mediated inflammation in AT [26]. Sfrp5 is an anti-inflammatory adipokine which is capable of inhibit endogenous WNT5A pathways, might be effective to prevent macrophage mediated inflammation in AT to improve insulin sensitivity, thereby prevent development of T2DM [204]. Mice lacking Sfrp5 show impaired glucose clearance with high macrophage mediated AT inflammation and reduced insulin sensitivity, however, administration of Sfrp5 increases insulin sensitivity [200]. Furthermore, upregulation of Sfrp5 in 3T3 –L1 adipocyte cell line prevents inflammation and insulin resistance via blocking WNT5A. Although preclinical study in animal and cell line shows the protective role of Sfrp5 in T2DM, but clinical study has shown controversial results. Therefore, it is necessary that Sfrp5 deserves more clinical study with a large sample size, along with many ethnic group to further explore its role.

The involvement of Sfrp5, in cardiometabolic health, deserves more exploration. Serum levels of Sfrp5 are decreased in patients with CAD indicating the association of the adipokines in atherosclerosis [204]. Depletion of Sfrp5 in mice causes cardiac ischemia reperfusion injury along with increased inflammation and higher rates of cardiomyocyte deaths. Deficiency of Sfrp5 enhances WNT5A influx into the ischemic limb and also impairs revascularization [205]. Numbers of studies have demonstrated the atheroprotective role. Low serum levels of Sfrp5 are linked to CAD [206]. Sfrp5 were found to be inversely associated with multiple CMDs [207]. Higher levels of Sfrp5 inhibit endothelial dysfunction and arterial stiffness via downregulating Wnt5a/JNK pathways with reduced NO production [208]. The evidence provided by the different studies suggests that Sfrp5 may attenuate cardiometabolic symptoms and can be useful in the treatment or management of cardiometabolic diseases.

C1q/TNF-related proteins (CTRPs)

CTRPs are a new family of secreted proteins which have sequence homology with the adiponectin [208]. Till now 15 functional CTRPs have been identified which have different actions [209]. Out of 15, only a few numbers of CTRP have been ascribed to have implication in metabolic disorders whereas many others are still under investigation. All the CTRPs have common feature with four distinct domain, namely a signal peptide at N-terminus sequence, a short non-homologous or variable region, a collagenous domain consist of variable numbers of Gly-X–Y repeats and C-terminal globular domain homologous to complement factor C1q domain [210]. Most CTRPs are expressed in AT and can be detected in plasma. CTRPs have unique biological and signaling properties and they exist in the circulation as trimmers, assembling themselves into hexamaric and high molecular weight oligomeric complexes with their basic structural unit [211].

Sex, age and genetic background modulate the metabolic hormone levels as well as signaling pathways in both human and animals, and thus have variable impact in the development obesity and other metabolic disorders such as insulin resistance, and T2D [212, 213]. Interestingly, most of the CTRPs also circulate in the blood with variable concentration as per the sex and genetic background. A study reported that serum levels of adiponectin, CTRP1, CTRP2, CTRP3, CTRP5 and CTRP6 in six different genetic background mice showed significant variation [214]. The selected strain for the study was taken with varying degrees of susceptibility to insulin resistance or diabetes or diet-induced obesity. Biological activity of CTRPs depends on their multimeric forms. All CTRPs exist as trimer forms, however, accumulating evidence suggests that CTRPs, e.g., CTRP3, CTRP5, CTRP9, CTRP6, CTRP8, CTRP10, CTRP11, CTRP12, CTRP13 and CTRP15 happen to occur into multimeric complexes, via N-terminal cysteine residue or by oxido-reductase [207]. Adiponectin and CTRP 9 assemble to heterotrimers and exert the same biological action, i.e., cardioprotection via the same receptor [214]. Apart from forming as homo-oligomer, CTRP6/ CTRP1, CTRP7/CTRP2, and CTRP2/adiponectin form heterotrimers and generates functionally distinct ligands for secreted glycoproteins to provide new outline of action in normal and disease condition [215]. CTRP 9 exists as two isoforms namely 9A and 9B and CTRP 9B requires interaction with CTRP 9A and adiponectin for its action [216].

CTRPs are secreted as hormones and subjected to post translational modifications at their highly conserved residues. CTRP 12 has isomeric forms after post translational modifications such as glycosylated on the 39th asparagine amino acid and 85th cysteine modified with oligosaccharides [217]. The two isomeric forms of CTRP12 diverge from the oligomeric structure and function. It is reported that full length CTRP 12 activates Akt signaling in adipocytes, however, the globular form activates the MAPK signaling [218]. Adiponectin exists in multimeric forms where trimers and hexamers activate AMPK signaling in muscle thereby enhancing glucose uptake, deposition of glycogen as well as fatty acid oxidation. However, high molecular weight oligomers act on the liver and decrease glucose production [219]. Distinctively, CTRP1 and CTRP 2 are primarily secreted as trimmers in transfected HEK-293 cells. Primarily, CTRP2 in the mouse serum was found to be trimer form. Though CTRP3 secreted as trimmers, hexamers and HMW oligomers in transfected cells, it exists as HMW oligomers in mouse serum. Similar to CTRP3, CTRP5 also secreted in their multimeric forms but exists as trimmers in mouse serum. During exercise and treatment of metabolic complications such as obesity, T2DM, etc., the ratio of oligomeric CTRPs changes. The ratio of HMW and trimers CTRPs has been reported to serve as an index of insulin sensitivity. However, it is still required to determine whether metabolic disorders hinder the distribution of CTRPs oligomeric forms presence in the serum and their biological activities of these oligomeric proteins [220].

CTRPs reported to possess biological activity

Out of several CTRPs many of them possess biological activities and may be beneficial in the management or treatment of dyslipidemia and insulin resistance. CTRP1 has important roles in glucose metabolism by activating serine/threonine protein kinase Akt and MAPK p42/44 signaling in mouse myotube [210]. CTRP1 has been reported to possess anti-thrombotic properties and blocks platelet activation and aggregation by specifically binding to fibrillar. CTRP1 shows anti-thrombotic action by indirectly acting on the von Willebrand factor. CTRP1 creates an environment where less binding efficient COL-III is formed by inhibiting binding of the A3 domain of von Willebrand factor to COL-I without affecting the association of the A3 domain with platelet [214]. Therefore, the anti-thrombotic activity of CTRP1 may protect MI and stroke following rupturing of atherosclerotic plaques [214]. CTRP1 has been reported to prevent neointimal formation following arterial injury via a cAMP-dependent pathway by suppressing vascular smooth muscle cell growth [221]. In obesity and hypertension, inflammatory cytokines induce CTRP1 where there is a deficiency of adiponectin. Drug rosiglitazone found to be elevating CTRP1 level. Since CTRP1 administration reduces the blood glucose; it can be considered that the increased CTRP1 in obesity may be the compensatory action towards its resistance [205]. The pre-clinical and clinical data of CTRPs family members are been listed in Tables 1 and 2.


As obesity is responsible for various diseases, including CVDs and metabolic disorders. Management of obesity and its co-morbid diseases are major challenges for the medical community. Alteration of the normal physiology of microcirculation in AT builds favorable conditions for the development of CMD. The knowledge of AT microcirculation is necessary to understand the underlying mechanism that regulates metabolic health. Despite the advancement of anti-obesity drugs, the main objective of sustained and non-recurrent weight loss could not be achieved due to the variable efficacy. Inherent side effects of drugs and poor patient compliance is also a major issue.

We are still in quest of an ideal agent for the management of obesity to prevent its comorbidities. Adipokines represent a very promising avenue in this regard. AAKs have a profound protective effect against metabolic risk. These agents conserve the normal physiology in AT microcirculation, prevent hypoxia and block polarization of M1 macrophage. AAKs suppress the oxidative stress and reduce ER stress via numerous pathophysiological pathways. AAKs are very potent anti-obesity molecules, higher levels of AAK in leaner patients in comparison to obese patients, and patients with disturbed lipidemic profile substantiate their anti-obesity and anti-atherogenic potential. Although the clinical efficacy of the AAKs is under the pipeline of research and development, some of the promising adipokines that can act as promising therapeutic agents include adiponectin, omentin-1, Sfrp5 and a few members of CTRP family which are shown in Tables 1 and 2.

Adiponectin is beneficial agents for obesity, as they inhibit gluconeogenesis in hepatocytes, thus controlling the deposition of fat. It also modulates angiogenesis and endothelial function and plays a crucial role in metabolic disorders like insulin resistance through the AMPK pathway. It also has an anti-atherogenic and anti-thrombotic effect, and thus if used for therapeutic purposes, it can be beneficial for management and treatment of metabolic disorders.

Similarly, omentin-1 is also a novel adipokine. It suppresses ICAM-1, VCAM-1, COX-2 and oxidation of LDL, thus inhibiting the formation of foam cells from macrophages, and plays an important role in the prevention of atherosclerosis. Proper modulation of its activity can be very useful for management of disorders of metabolic diseases.

Sfrp5 is among one of the AAKs which inhibits endothelial dysfunction, arterial stiffness and exhibits atheroprotective activity. CTRPs are the paralogs of adiponectin, and some members of CTRPs enhance insulin sensitivity and glucose metabolism. These members of CTRPs improve mitochondrial dysfunction, inhibit platelet activation and aggregations thereby reducing the risk of CAD thus preventing MI and stroke. They enhance the uptake of glucose by adipocytes thus conferring glucose homeostasis and also enhance cardiomyocyte survival and reduce fibrosis.

If properly designed and delivered, AAKs can represent a novel approach for anti-obesity, insulin sensitizing agents and anti-atherogenic therapies. For now, we can say that though novel and efficacious, adipokines still need to undergo considerable research for clinical safety and efficacy before we can see them in the market. At last we conclude that the diverse action of AAks has gained the attention of prominent researchers across the world and in future we may expect the use of these AAks as therapeutic agents for the metabolic disorders and its associated comorbidities.

Availability of data and materials

All data available in this article wherever applicable are collected from published articles and were cited. Figure 1 has been reproduced with due permission from the author (doi: 10.3389/fendo.2013.00071. eCollection 2013, From journal “Frontiers of Endocrinology” entitled “Adipokines mediate inflammation and insulin resistance” reference 86).



Anti-inflammatory adipokines


ATP-binding cassette


Anorexia nervosa


Angiopoietin-like 4


Activator protein-1


Adipose tissue


Adipose tissue


Activating transcription factor 6


Adipose tissue macrophages


Brown adipose tissue


Body mass index


Carnitine acylcarnitine translocase


Coronary artery disease


Cellular adhesion molecules


Centers for Disease Control and Prevention


Coronary heart disease


Cardiometabolic disease


Central nervous system


Coenzyme A




Carnitine palmitoyltransferase 1


Caloric restriction


C1q/TNF-related protein


Cardiovascular disease


Diabetes mellitus


Epicardial adipose tissue


Extracellular matrix


Endoplasmic reticulum


Fatty acids


Fatty acid-binding protein


Fatty acid translocase CD36


Fatty acid transporter protein 1


Free fatty acids


Hypertrophic adipocyte necrosis


High-density lipid cholesterol


Hypoxia-inducible factor 1α


High molecular weight


Human umbilical vein endothelial cells


Intracellular adhesion molecule


Interferon gamma


Inhibitor of kinase-β




Intramuscular triacylglycerol


Nitric oxide synthase


Inositol-requiring enzyme 1


Insulin Receptor Substrate 1


Janus kinase 2


C-Jun amino-terminal kinase


Long-chain FA


Long-chain fatty acid transporter


Low molecular weight


Low density lipoprotein receptor-1


Leptin receptor b


Liver X receptor


Mitogen-activated protein kinase


Macrophage receptor with collagenous structure


Bone marrow adipose tissue


Monocyte chemoattractant protein-1


Myocardial infarction


Macrophage migration inhibition factor


Matrix metallopeptidase 2


Nicotinamide phosphoribosyltransferase


Nuclear factor kappa-B


Natural killer cells,


Type-1 natural killer


Obese gene


Oxidized low density lipid


Oxidative phosphorylation


Pro-inflammatory adipokines


PKR-like endoplasmic reticulum kinase


Phosphatidylinositol 3-kinase


Protein kinase B


Peroxisome proliferator-activated receptor


Redox environment


Reactive oxygen species


Subcutaneous adipose tissue


Secreted frizzled-related protein 5


Suppressor of cytokine signaling


Sterol regulatory element-binding protein 1c


Signal transducer and activator of transcription 3


Type 2 diabetes mellitus




Tricarboxylic acid




Transforming growth factor beta


T helper 2


Toll-like receptors


Tumor necrosis factor-α


T regulatory cells


Unfolded protein response


Vascular adipose tissue


Vascular cell adhesion molecule-1


Vascular endothelial growth factors


Very low density lipid


White adipose tissue


World Health Organization


  1. Green M, Arora K, Prakash S (2020) Microbial medicine: prebiotic and probiotic functional foods to target obesity and metabolic syndrome. Int J Mol Sci 21(8):2890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Krzysztoszek J, Laudanska-Krzeminska I, Bronikowski M (2019) Assessment of epidemiological obesity among adults in EU countries. Ann Agric Environ Med 26(2)

  3. World Health Organization (2019) Obesity and Overweight, . WHO Fact sheet, Updat. June 2016. 2011. Accessed on 11th November 2019

  4. Nakamura K, Fuster JJ, Walsh K (2014) Adipokines: a link between obesity and cardiovascular disease. J Cardiol 63(4):250–259

    Article  PubMed  Google Scholar 

  5. Francisco V, Ruiz-Fernández C, Pino J, Mera A, Gonzalez-Gay MA, Gómez R, Gualillo O (2019) Adipokines: linking metabolic syndrome, the immune system, and arthritic diseases. Biochem Pharmacol 165:196–206

    Article  CAS  PubMed  Google Scholar 

  6. Malecka-Tendera E, Mazur A (2006) Childhood obesity: a pandemic of the twenty-first century. Int J Obes 30(2):S1–S3

    Article  Google Scholar 

  7. Wolf D, Ley K (2019) Immunity and inflammation in atherosclerosis. Circ Res 124(2):315–327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhao S, Kusminski CM, Scherer PE (2021) Adiponectin, leptin and cardiovascular disorders. Circ Res 128(1):136–149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lemieux I, Després JP (2020) Metabolic syndrome: past, present and future. Nutrients 12(11):3501

    Article  PubMed  PubMed Central  Google Scholar 

  10. Van Gaal LF, Mertens IL, De Block CE (2006) Mechanisms linking obesity with cardiovascular disease. Nature 444(7121):875–880

    Article  PubMed  Google Scholar 

  11. Longo M, Zatterale F, Naderi J, Parrillo L, Formisano P, Raciti GA, Beguinot F, Miele C (2019) Adipose tissue dysfunction as determinant of obesity-associated metabolic complications. Int J Mol Sci 20(9):2358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Smekal A, Vaclavik J (2017) Adipokines and cardiovascular disease: a comprehensive review. Biomed Pap 2017.

  13. Weschenfelder C, Schaan de Quadros A, Lorenzon dos Santos J, Bueno Garofallo S, Marcadenti A (2020) Adipokines and adipose tissue-related metabolites, nuts and cardiovascular disease. Metabolites 10(1):32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Guzmán-Ruiz R, Tercero-Alcázar C, Rabanal-Ruiz Y, Díaz-Ruiz A, El Bekay R, Rangel-Zuñiga OA, Navarro-Ruiz MC, Molero L, Membrives A, Ruiz-Rabelo JF, Pandit A (2020) Adipose tissue depot-specific intracellular and extracellular cues contributing to insulin resistance in obese individuals. FASEB J 34(6):7520–7539

    Article  PubMed  Google Scholar 

  15. Sharma BR, Kanneganti TD (2021) NLRP3 inflammasome in cancer and metabolic diseases. Nat Immunol 22(5):550–559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chait A, Den Hartigh LJ (2020) Adipose tissue distribution, inflammation and its metabolic consequences, including diabetes and cardiovascular disease. Front Cardiovasc Med 25(7):22

    Article  Google Scholar 

  17. Hammarstedt A, Gogg S, Hedjazifar S, Nerstedt A, Smith U (2018) Impaired adipogenesis and dysfunctional adipose tissue in human hypertrophic obesity. Physiol Rev 2018:98

    Google Scholar 

  18. Fuster JJ, Zuriaga MA, Ngo DTM, Farb MG, Aprahamian T, Yamaguchi TP et al (2015) Noncanonical wnt signaling promotes obesity-induced adipose tissue inflammation and metabolic dysfunction independent of adipose tissue expansion. Diabetes 64

  19. Hu D, Remash D, Russell RD, Greenaway T, Rattigan S, Squibb KA et al (2018) Impairments in adipose tissue microcirculation in type 2 diabetes mellitus assessed by real-time contrast-enhanced ultrasound. Circ Cardiovasc Imaging 11

  20. Trayhurn P(2013) Hypoxia and adipose tissue function and dysfunction in obesity. Physiol Rev 93

  21. Van Meijel RL, Blaak EE, Goossens GH (2019) Adipose tissue metabolism and inflammation in obesity. Mech Manifestations Obes Lung Dis, pp 1–22, Academic Press

  22. Saraiva M, Vieira P, O’garra A (2020) Biology and therapeutic potential of interleukin-10. J Exp Med 217(1)

  23. Fuster JJ, Ouchi N, Gokce N, Walsh K (2016) Obesity-induced changes in adipose tissue microenvironment and their impact on cardiovascular disease. Circ Res 118(11):1786–1807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gonzalez FJ, Xie C, Jiang C (2019) The role of hypoxia-inducible factors in metabolic diseases. Nat Rev Endocrinol 15(1):21–32

    Article  CAS  Google Scholar 

  25. Martínez-Martínez E, Souza-Neto FV, Jiménez-González S, Cachofeiro V (2021) Oxidative stress and vascular damage in the context of obesity: The hidden guest. Antioxidants 10(3):406

    Article  PubMed  PubMed Central  Google Scholar 

  26. Sethi JK, Hotamisligil GS (2021) Metabolic Messengers: tumour necrosis factor. Nat Metab 3(10):1302–1312

    Article  CAS  PubMed  Google Scholar 

  27. Maamoun H, Abdelsalam SS, Zeidan A, Korashy HM, Agouni A (2019) Endoplasmic reticulum stress: a critical molecular driver of endothelial dysfunction and cardiovascular disturbances associated with diabetes. Int J Mol Sci 20(7):1658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ozawa K, Miyazaki M, Matsuhisa M, Takano K, Nakatani Y, Hatazaki M et al (2005) The endoplasmic reticuluin chaperone improves insulin resistance in type 2 diabetes. Diabetes 54

  29. Fatima K, Hussain Z, Hamid R (2021) Oxidative stress and diabetic complication: a systematic review. J Chem Biol Interfaces 11(6).

  30. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Shimomura I (2017) Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114(12):1752–1761

    Article  Google Scholar 

  31. Ashcroft FM, Rorsman P (2012) Diabetes mellitus and the β cell: the last ten years. Cell 148(6):1160–1171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shan B, Wang X, Wu Y, Xu C, Xia Z, Dai J, Liu Y (2017) The metabolic ER stress sensor IRE1α suppresses alternative activation of macrophages and impairs energy expenditure in obesity. Nat Immunol 18(5):519–529

    Article  CAS  PubMed  Google Scholar 

  33. Bronte V, Zanovello P (2005) Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 5(8):641–654

    Article  CAS  PubMed  Google Scholar 

  34. Wang N, Liang H, Zen K (2014) Molecular mechanisms that influence the macrophage M1–M2 polarization balance. Front Immunol 5:614

    Article  PubMed  PubMed Central  Google Scholar 

  35. Nguyen KD, Qiu Y, Cui X, Goh YP, Mwangi J, David T, Chawla A (2011) Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480(7375):104–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Nagai R (2009) CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nature Med 15(8):914–920

    Article  CAS  PubMed  Google Scholar 

  37. Park CS, Shastri N (2022) The role of t cells in obesity-associated inflammation and metabolic disease. Immune Netw 22(1)

  38. Kumari A, Kristensen KK, Ploug M, Winther AM (2021) The importance of lipoprotein lipase regulation in atherosclerosis. Biomedicines 9(7):782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bartlett B, Ludewick HP, Misra A, Lee S, Dwivedi G (2019) Macrophages and T cells in atherosclerosis: a translational perspective. Am J Physiol Hear Circ Physiol 317(2):H375–H386

    Article  CAS  Google Scholar 

  40. Rader DJ, Puré E (2005) Lipoproteins, macrophage function, and atherosclerosis: beyond the foam cell? Cell Metab 1(4):223–230

    Article  CAS  PubMed  Google Scholar 

  41. Xu P, Zhai Y, Wang J (2018) The role of PPAR and its cross-talk with CAR and LXR in obesity and atherosclerosisInt. J Mol Sci 19(4):1260

    Article  Google Scholar 

  42. Chinetti G, Lestavel S, Remaley A, Neve B, Torra IP, Minnich A, Staels B (2000) PPAR alpha and PPAR gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABC-1 pathway. Circulation 102(18):311–311

    Google Scholar 

  43. Maguire EM, Pearce SW, Xiao Q (2019) Foam cell formation: a new target for fighting atherosclerosis and cardiovascular disease. Vascul Pharmacol 112:54–71

    Article  CAS  PubMed  Google Scholar 

  44. Frambach SJ, de Haas R, Smeitink JA, Rongen GA, Russel FG, Schirris TJ (2020) Brothers in arms: ABCA1-and ABCG1-mediated cholesterol efflux as promising targets in cardiovascular disease treatment. Pharmacol Rev 72(1):152–190

    Article  CAS  PubMed  Google Scholar 

  45. Ouimet M, Barrett TJ, Fisher EA (2019) HDL and reverse cholesterol transport: Basic mechanisms and their roles in vascular health and disease. Circ Res 124(10):1505–1518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Valasek MA, Clarke SL, Repa JJ (2007) Fenofibrate reduces intestinal cholesterol absorption via PPARα-dependent modulation of NPC1L1 expression in mouse. J Lipid Res 48(12):2725–2735

    Article  CAS  PubMed  Google Scholar 

  47. Diskin C, Pålsson-McDermott EM (2018) Metabolic modulation in macrophage effector function. Front Immunol 9:270

    Article  PubMed  PubMed Central  Google Scholar 

  48. Poznyak AV, Wu WK, Melnichenko AA, Wetzker R, Sukhorukov V, Markin AM, Orekhov AN (2020) Signaling pathways and key genes involved in regulation of foam cell formation in atherosclerosis. Cells 9(3):584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Szablewski L (2019) Introductory chapter: adipose tissue. In Adipose Tissue-An Update. IntechOpen.

  50. Rusdiana R, Widjaja SS, Amelia R (2020) The correlation between serum vascular endothelial growth factor and lipid profile in type 2 diabetes mellitus. Open Access Maced J Med Sci 8(1B):1131–1135

    Article  Google Scholar 

  51. Diaz-Canestro C, Xu A (2021) Impact of different adipose depots on cardiovascular disease. J Cardiovasc Pharmacol 78:S30–S39

    Article  CAS  PubMed  Google Scholar 

  52. Sung HK, Doh KO, Son JE, Park JG, Bae Y, Choi S, Nagy A (2013) Adipose vascular endothelial growth factor regulates metabolic homeostasis through angiogenesis. Cell Metab 17(1):61–72

    Article  CAS  PubMed  Google Scholar 

  53. Ruiz-Ojeda FJ, Méndez-Gutiérrez A, Aguilera CM, Plaza-Díaz J (2019) Extracellular matrix remodeling of adipose tissue in obesity and metabolic diseases. Int J Mol Sci 20(19):4888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gealekman O, Guseva N, Hartigan C, Apotheker S, Gorgoglione M, Gurav K, Corvera S (2011) Depot-specific differences and insufficient subcutaneous adipose tissue angiogenesis in human obesity. Circulation 123(2):186–194

    Article  PubMed  PubMed Central  Google Scholar 

  55. Ngo DT, Farb MG, Kikuchi R, Karki S, Tiwari S, Bigornia SJ, Gokce N (2014) Antiangiogenic actions of vascular endothelial growth factor-A165b, an inhibitory isoform of vascular endothelial growth factor-A, in human obesity. Circulation 130(13):1072–1080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Fernández-Hernando C, Suárez Y (2020) ANGPTL4: a multifunctional protein involved in metabolism and vascular homeostasis. Curr Opin Hematol 27(3):206–213

    Article  PubMed  PubMed Central  Google Scholar 

  57. Kovrov O, Kristensen KK, Larsson E, Ploug M, Olivecrona G (2019) On the mechanism of angiopoietin-like protein 8 for control of lipoprotein lipase activity. J Lipid Res 60(4):783–793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ruscica M, Zimetti F, Adorni MP, Sirtori CR, Lupo MG, Ferri N (2020) Pharmacological aspects of ANGPTL3 and ANGPTL4 inhibitors: new therapeutic approaches for the treatment of atherogenic dyslipidemia. Pharmacol Res 153:104653

    Article  CAS  PubMed  Google Scholar 

  59. Dowsett L, Higgins E, Alanazi S, Alshuwayer NA, Leiper FC, Leiper J (2020) ADMA: a key player in the relationship between vascular dysfunction and inflammation in atherosclerosis. J Clin Med 9(9):3026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mosevoll KA, Johansen S, Wendelbo Ø, Nepstad I, Bruserud Ø, Reikvam H (2018) Cytokines, adhesion molecules, and matrix metalloproteases as predisposing, diagnostic, and prognostic factors in venous thrombosis. Front Med 5:147.

    Article  Google Scholar 

  61. Feijóo-Bandín S, Aragón-Herrera A, Moraña-Fernández S, Anido-Varela L, Tarazón E, Roselló-Lletí E, Lago F (2020) Adipokines and inflammation: Focus on cardiovascular diseases. Int J Mol Sci 21(20):7711

    Article  PubMed  PubMed Central  Google Scholar 

  62. Scherer PE (2006) Adipose tissue: from lipid storage compartment to endocrine organ. Diabetes 55(6):1537–1545

    Article  CAS  PubMed  Google Scholar 

  63. Cohen E, Margalit I, Shochat T, Goldberg E, Krause I (2021) Markers of chronic inflammation in overweight and obese individuals and the role of gender: a cross-sectional study of a large cohort. J Inflamm Res 14:567

    Article  PubMed  PubMed Central  Google Scholar 

  64. Marchini T, Mitre LS, Wolf D (2021) Inflammatory cell recruitment in cardiovascular disease. Front Cell Dev Biol 9:207

    Article  Google Scholar 

  65. Mohindra R, Agrawal DK, Thankam FG (2021) Altered vascular extracellular matrix in the pathogenesis of atherosclerosis. J Cardiovasc Transl Res 14(4):647–660

    Article  PubMed  Google Scholar 

  66. Wolf MP, Hunziker P (2020) Atherosclerosis: insights into vascular pathobiology and outlook to novel treatments. J Cardiovasc Transl Res 13(5):744–757

    Article  PubMed  Google Scholar 

  67. Golbidi S, Edvinsson L, Laher I (2020) Smoking and endothelial dysfunction. Curr Vasc Pharmacol 18(1):1–11

    Article  CAS  PubMed  Google Scholar 

  68. Nosalski R, McGinnigle E, Siedlinski M, Guzik TJ (2017) Novel immune mechanisms in hypertension and cardiovascular risk. Curr Cardiovasc Risk Rep 11(4):1–12

    Article  Google Scholar 

  69. Guzik TJ, Skiba DS, Touyz RM, Harrison DG (2017) The role of infiltrating immune cells in dysfunctional adipose tissue. Cardiovasc Res 113(9):1009–1023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kawai T, Autieri MV, Scalia R (2021) Adipose tissue inflammation and metabolic dysfunction in obesity. Am J Physiol Cell Physiol 320(3):C375–C391.

    Article  CAS  PubMed  Google Scholar 

  71. Gelen V, Kükürt A, Şengül E, Devecı HA (2021) Leptin and its role in oxidative stress and apoptosis: an overview. Role Obes Hum Health Disease 143

  72. Yuxiang L, Fujiu K (2020) Human resistin and cardiovascular disease. Int Heart J 61(3):421–423

    Article  PubMed  Google Scholar 

  73. Sengenès C, Miranville A, Lolmède K, Curat CA, Bouloumié A (2007) The role of endothelial cells in inflamed adipose tissue. J Intern Med 262(4):415–421

    Article  PubMed  Google Scholar 

  74. Poredoš P, Cífková R, Maier JAM, Nemcsik J, Šabovič M, Jug B, Blinc A (2022) Preclinical atherosclerosis and cardiovascular events: do we have a consensus about the role of preclinical atherosclerosis in the prediction of cardiovascular events? Atherosclerosis 348:25–35

    Article  PubMed  Google Scholar 

  75. Aroor AR, Jia G, Sowers JR (2018) Cellular mechanisms underlying obesity-induced arterial stiffness. Am J Physiol Regul Integr Comp Physiol 314(3):R387–R398

    Article  PubMed  Google Scholar 

  76. Sun K, Tordjman J, Clément K, Scherer PE (2013) Fibrosis and adipose tissue dysfunction. Cell Metab 18(4):470–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bolinder J, Kerckhoffs DA, Moberg E, Hagström-Toft E, Arner P (2000) Rates of skeletal muscle and adipose tissue glycerol release in nonobese and obese subjects. Diabetes 49(5):797–802

    Article  CAS  PubMed  Google Scholar 

  78. Petralia MC, Mazzon E, Fagone P, Basile MS, Lenzo V, Quattropani MC, Nicoletti F (2020) Pathogenic contribution of the Macrophage migration inhibitory factor family to major depressive disorder and emerging tailored therapeutic approaches. J Affect Disord 263:15–24

    Article  PubMed  Google Scholar 

  79. Wood IS, de Heredia FP, Wang B, Trayhurn P (2009) Cellular hypoxia and adipose tissue dysfunction in obesity: symposium on ‘Frontiers in Adipose Tissue Biology.’ Proc Nutr Soc 68(4):370–377

    Article  CAS  PubMed  Google Scholar 

  80. Mack I, BelAiba RS, Djordjevic T, Görlach A, Hauner H, Bader BL (2009) Functional analyses reveal the greater potency of preadipocytes compared with adipocytes as endothelial cell activator under normoxia, hypoxia, and TNFα exposure. Am J Physiol Endocrinol Metab 297(3):E735–E748

    Article  CAS  PubMed  Google Scholar 

  81. Sun, K., Park, J., Gupta, O. T., Holland, W. L., Auerbach, P., Zhang, N., ... & Scherer, P. E. (2014). Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction. Nature communications, 5(1), 1–12.

  82. Liu J, Liu Z (2019) Muscle insulin resistance and the inflamed microvasculature: fire from within. Int J Mol Sci 20(3):562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Virdis A, Colucci R, Bernardini N, Blandizzi C, Taddei S, Masi S (2019) Microvascular endothelial dysfunction in human obesity: Role of TNF-α. J Clin Endocrinol Metab 104(2):341–348

    Article  PubMed  Google Scholar 

  84. Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF (2002) Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem 277(2):1531–1537

    Article  CAS  PubMed  Google Scholar 

  85. Schmelzle K, Kane S, Gridley S, Lienhard GE, White FM (2006) Temporal dynamics of tyrosine phosphorylation in insulin signaling. Diabetes 55(8):2171–2179

    Article  CAS  PubMed  Google Scholar 

  86. Kwon H, Pessin JE (2013) Adipokines mediate inflammation and insulin resistance. Front Endocrinol 4:71

    Article  Google Scholar 

  87. Ueki K, Kondo T, Kahn CR (2004) Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol 24(12):5434–5446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. McInnes J (2013) Mitochondrial-associated metabolic disorders: foundations, pathologies and recent progress. Nutr Metab 10(1):1–13

    Article  Google Scholar 

  89. Aon MA, Bhatt N, Cortassa SC (2014) Mitochondrial and cellular mechanisms for managing lipid excess. Front Physiol 5:282

    Article  PubMed  PubMed Central  Google Scholar 

  90. Kembro JM, Aon MA, Winslow RL, O’Rourke B, Cortassa S (2013) Integrating mitochondrial energetics, redox and ROS metabolic networks: a two-compartment model. Biophys J 104(2):332–343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90(1):207–258

    Article  CAS  PubMed  Google Scholar 

  92. Jana BA, Chintamaneni PK, Krishnamurthy PT, Wadhwani A, Mohankumar SK (2019) Cytosolic lipid excess-induced mitochondrial dysfunction is the cause or effect of high fat diet-induced skeletal muscle insulin resistance: a molecular insight. Mol Biol Rep 46(1):957–963

    Article  CAS  PubMed  Google Scholar 

  93. Holland WL, Brozinick JT, Wang LP, Hawkins ED, Sargent KM, Liu Y, Summers SA (2007) Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 5(3):167–179

    Article  CAS  PubMed  Google Scholar 

  94. Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, Muoio DM (2008) Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 7(1):45–56

    Article  CAS  PubMed  Google Scholar 

  95. Fernando S, Bursill CA, Nicholls SJ, Psaltis PJ (2020) Pathophysiology of atherosclerosis. In: Mechanisms of Vascular disease. Springer, Cham, pp 19–45

  96. Freitas Lima LC, Braga VDA, Socorro Do, de França Silva M, Cruz JDC, Sousa Santos SH, de Oliveira Monteiro MM, Balarini CDM (2015) Adipokines, diabetes and atherosclerosis: an inflammatory association. Front Physiol 6:304

    Article  PubMed  PubMed Central  Google Scholar 

  97. Tabas I, Williams KJ, Borén J (2007) Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 116(16):1832–1844

    Article  CAS  PubMed  Google Scholar 

  98. Stephen SL, Freestone K, Dunn S, Twigg MW, Homer-Vanniasinkam S, Walker JH, Ponnambalam S (2010) Scavenger receptors and their potential as therapeutic targets in the treatment of cardiovascular disease. Int J Hypertens 2010.

  99. Fruchart JC, Sacks F, Hermans MP, Assmann G, Brown WV, Ceska R, Residual Risk Reduction Initiative (2008) The residual risk reduction initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol 102(10):1K-34K

    Article  PubMed  Google Scholar 

  100. Aguiar C, Alegria E, Bonadonna RC, Catapano AL, Cosentino F, Elisaf M, Ferrari R (2015) A review of the evidence on reducing macrovascular risk in patients with atherogenic dyslipidaemia: a report from an expert consensus meeting on the role of fenofibrate–statin combination therapy. Atheroscler Suppl 19:1–12

    Article  PubMed  Google Scholar 

  101. Ferrari R, Aguiar C, Alegria E, Bonadonna RC, Cosentino F, Elisaf M, Catapano AL (2016) Current practice in identifying and treating cardiovascular risk, with a focus on residual risk associated with atherogenic dyslipidaemia. Eur Heart J Suppl 18(suppl_C):C2–C12

    Article  CAS  PubMed  Google Scholar 

  102. Lau WB, Ohashi K, Wang Y, Ogawa H, Murohara T, Ma XL, Ouchi N (2017) Role of adipokines in cardiovascular disease. Circ J 81(7):920–928.

    Article  CAS  PubMed  Google Scholar 

  103. Shibata R, Ohashi K, Murohara T, Ouchi N (2014) The potential of adipokines as therapeutic agents for cardiovascular disease. Cytokine Growth Factor Rev 25(4):483–487

    Article  CAS  PubMed  Google Scholar 

  104. Mattu HS, Randeva HS (2013) Role of adipokines in cardiovascular. J Endocrinol 216:T17–T36

    Article  CAS  PubMed  Google Scholar 

  105. Dahlman I, Elsen M, Tennagels N, Korn M, Brockmann B, Sell H, Arner P (2012) Functional annotation of the human fat cell secretome. Arch Physiol Biochem 118(3):84–91

    Article  CAS  PubMed  Google Scholar 

  106. Chen G, Goeddel DV (2002) TNF-R1 signaling: a beautiful pathway. Science 296(5573):1634–1635

    Article  CAS  PubMed  Google Scholar 

  107. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Investig 112(12):1796–1808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389(6651):610–614

    Article  CAS  PubMed  Google Scholar 

  109. Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB (1995) The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Investig 95(5):2111–2119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Hivert MF, Sullivan LM, Fox CS, Nathan DM, D’Agostino RB Sr, Wilson PW, Meigs JB (2008) Associations of adiponectin, resistin, and tumor necrosis factor-α with insulin resistance. J Clin Endocrinol Metab 93(8):3165–3172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Stanley TL, Zanni MV, Johnsen S, Rasheed S, Makimura H, Lee H, Grinspoon SK (2011) TNF-α antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome. J Clin Endocrinol Metab 96(1):E146–E150

    Article  CAS  PubMed  Google Scholar 

  112. Kanety H, Feinstein R, Papa MZ, Hemi R, Karasik A (1995) Tumor Necrosis Factor α-induced Phosphorylation of Insulin Receptor Substrate-1 (IRS-1): POSSIBLE MECHANISM FOR SUPPRESSION OF INSULIN-STIMULATED TYROSINE PHOSPHORYLATION OF IRS-1 (). J Biol Chem 270(40):23780–23784

    Article  CAS  PubMed  Google Scholar 

  113. Fève B, Bastard JP (2009) The role of interleukins in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol 5(6):305–311

    Article  PubMed  Google Scholar 

  114. Xu H, Sethi JK, Hotamisligil GS (1999) Transmembrane tumor necrosis factor (TNF)-α inhibits adipocyte differentiation by selectively activating TNF receptor 1. J Biol Chem 274(37):26287–26295

    Article  CAS  PubMed  Google Scholar 

  115. Ruan H, Miles PD, Ladd CM, Ross K, Golub TR, Olefsky JM, Lodish HF (2002) Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-α: implications for insulin resistance. Diabetes 51(11):3176–3188

    Article  CAS  PubMed  Google Scholar 

  116. Hector J, Schwarzloh B, Goehring J, Strate TG, Hess UF, Deuretzbacher G, Algenstaedt P (2007) TNF-α alters visfatin and adiponectin levels in human fat. Hormone Metab Res 39(04):250–255

    Article  CAS  Google Scholar 

  117. Makki K, Froguel P, Wolowczuk I (2013) Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. Int Scholarly Res Notices 2013.

  118. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505):425–432

    Article  CAS  PubMed  Google Scholar 

  119. Adya R, Tan BK, Randeva HS (2015) Differential effects of leptin and adiponectin in endothelial angiogenesis. J Diabetes Res 2015

  120. Friedman JM (1998) Leptin, leptin receptors, and the control of body weight. Nutr Rev 56(supp_l1):S38–S46

    CAS  PubMed  Google Scholar 

  121. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P (1995) Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269(5223):546–549

    Article  CAS  PubMed  Google Scholar 

  122. Bjørbæk C, Lavery HJ, Bates SH, Olson RK, Davis SM, Flier JS, Myers MG (2000) SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985. J Biol Chem 275(51):40649–40657

    Article  Google Scholar 

  123. Mori H, Hanada R, Hanada T, Aki D, Mashima R, Nishinakamura H, Yoshimura A (2004) Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat Med 10(7):739–743

    Article  CAS  PubMed  Google Scholar 

  124. Grunfeld C, Zhao C, Fuller J, Pollack A, Moser A, Friedman J, Feingold KR (1996) Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. J Clin Investig 97(9):2152–2157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Kiguchi N, Maeda T, Kobayashi Y, Fukazawa Y, Kishioka S (2009) Leptin enhances CC-chemokine ligand expression in cultured murine macrophage. Biochem Biophys Res Commun 384(3):311–315

    Article  CAS  PubMed  Google Scholar 

  126. Faggioni R, Jones-Carson J, Reed DA, Dinarello CA, Feingold KR, Grunfeld C, Fantuzzi G (2000) Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: role of tumor necrosis factor α and IL-18. Proc Natl Acad Sci 97(5):2367–2372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kajikawa Y, Ikeda M, Takemoto S, Tomoda J, Ohmaru N, Kusachi S (2011) Association of circulating levels of leptin and adiponectin with metabolic syndrome and coronary heart disease in patients with various coronary risk factors. Int Heart J 52(1):17–22

    Article  CAS  PubMed  Google Scholar 

  128. Zeng R, Xu CH, Xu YN, Wang YL, Wang M (2014) Association of leptin levels with pathogenetic risk of coronary heart disease and stroke: a meta-analysis. Arq Bras Endocrinol Metabol 58:817–823

    Article  PubMed  Google Scholar 

  129. Fujimaki S, Kanda T, Fujita K, Tamura J, Kobayashi I (2001) The significance of measuring plasma leptin in acute myocardial infarction. J Int Med Res 29(2):108–113

    Article  CAS  PubMed  Google Scholar 

  130. Barouch LA, Berkowitz DE, Harrison RW, O’Donnell CP, Hare JM (2003) Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice. Circulation 108(6):754–759

    Article  CAS  PubMed  Google Scholar 

  131. McGaffin KR, Zou B, McTiernan CF, O’Donnell CP (2009) Leptin attenuates cardiac apoptosis after chronic ischaemic injury. Cardiovasc Res 83(2):313–324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Ceddia RB, Koistinen HA, Zierath JR, Sweeney G (2002) Analysis of paradoxical observations on the association between leptin and insulin resistance. FASEB J 16(10):1163–1176

    Article  CAS  PubMed  Google Scholar 

  133. Eder K, Baffy N, Falus A, Fulop AK (2009) The major inflammatory mediator interleukin-6 and obesity. Inflamm Res 58(11):727–736

    Article  CAS  PubMed  Google Scholar 

  134. Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Coppack SW (1997) Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-α, in vivo. J Clin Endocrinol Metab 82(12):4196–4200

    CAS  PubMed  Google Scholar 

  135. Bacchiega BC, Bacchiega AB, Usnayo MJG, Bedirian R, Singh G, Pinheiro GDRC (2017) Interleukin 6 inhibition and coronary artery disease in a High-Risk population: a prospective Community-Based clinical study. J Am Heart Assoc 6(3):e005038

    Article  PubMed  PubMed Central  Google Scholar 

  136. Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium. (2012) The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet 379(9822): 1214-1224

  137. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH (2000) Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101(15):1767–1772

    Article  CAS  PubMed  Google Scholar 

  138. Anderson DR, Poterucha JT, Mikuls TR, Duryee MJ, Garvin RP, Klassen LW, Thiele GM (2013) IL-6 and its receptors in coronary artery disease and acute myocardial infarction. Cytokine 62(3):395–400

    Article  CAS  PubMed  Google Scholar 

  139. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G (2001) Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab.

  140. Mooney RA (2007) Counterpoint: interleukin-6 does not have a beneficial role in insulin sensitivity and glucose homeostasis. J Appl Physiol 102(2):816–818

    Article  CAS  PubMed  Google Scholar 

  141. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM (2001) C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286(3):327–334

    Article  CAS  PubMed  Google Scholar 

  142. Fernandez-Real JM, Vayreda M, Richart C, Gutierrez C, Broch M, Vendrell J, Ricart W (2001) Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J Clin Endocrinol Metab 86(3):1154–1159

    Article  CAS  PubMed  Google Scholar 

  143. Carey AL, Bruce CR, Sacchetti M, Anderson MJ, Olsen DB, Saltin B, Febbraio MA (2004) Interleukin-6 and tumor necrosis factor-α are not increased in patients with type 2 diabetes: evidence that plasma interleukin-6 is related to fat mass and not insulin responsiveness. Diabetologia 47(6):1029–1037

    Article  CAS  PubMed  Google Scholar 

  144. Ohlson LO, Larsson B, Svärdsudd K, Welin L, Eriksson H, Wilhelmsen L, Tibblin G (1985) The influence of body fat distribution on the incidence of diabetes mellitus: 13.5 years of follow-up of the participants in the study of men born in 1913. Diabetes 34(10):1055–1058

    Article  CAS  PubMed  Google Scholar 

  145. Patel SD, Rajala MW, Rossetti L, Scherer PE, Shapiro L (2004) Disulfide-dependent multimeric assembly of resistin family hormones. Science 304(5674):1154–1158

    Article  CAS  PubMed  Google Scholar 

  146. Norata GD, Ongari M, Garlaschelli K, Raselli S, Grigore L, Catapano AL (2007) Plasma resistin levels correlate with determinants of the metabolic syndrome. Eur J Endocrinol 156(2):279–284

    Article  CAS  PubMed  Google Scholar 

  147. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Lazar MA (2001) The hormone resistin links obesity to diabetes. Nature 409(6818):307–312

    Article  CAS  PubMed  Google Scholar 

  148. Palanivel R, Maida A, Liu Y, Sweeney G (2006) Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin. Diabetologia 49(1):183–190

    Article  CAS  PubMed  Google Scholar 

  149. Fisher JS (2006) Potential role of the AMP-activated protein kinase in regulation of insulin action. Cellscience 2(3):68

    PubMed  PubMed Central  Google Scholar 

  150. Chen C, Jiang J, Lü JM, Chai H, Wang X, Lin PH, Yao Q (2010) Resistin decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells. Am J Physiol Heart Circ Physiol 299(1):H193–H201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Jamaluddin MS, Weakley SM, Yao Q, Chen C (2012) Resistin: functional roles and therapeutic considerations for cardiovascular disease. Br J Pharmacol 165(3):622–632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Qiu W, Chen N, Zhang Q, Zhuo L, Wang X, Wang D, Jin H (2014) Resistin increases platelet P-selectin levels via p38 MAPK signal pathway. Diab Vasc Dis Res 11(2):121–124

    Article  PubMed  Google Scholar 

  153. Adeghate E (2008) Visfatin: structure, function and relation to diabetes mellitus and other dysfunctions. Curr Med Chem 15(18):1851–1862

    Article  CAS  PubMed  Google Scholar 

  154. Auguet T, Aragonès G, Guiu-Jurado E, Berlanga A, Curriu M, Martinez S, Richart C (2016) Adipo/cytokines in atherosclerotic secretomes: increased visfatin levels in unstable carotid plaque. BMC Cardiovasc Disord 16(1):1–7

    Article  Google Scholar 

  155. Maeda N, Funahashi T, Matsuzawa Y, Shimomura I (2020) Adiponectin, a unique adipocyte-derived factor beyond hormones. Atherosclerosis 292:1–9

    Article  CAS  PubMed  Google Scholar 

  156. Nakano Y, Tobe T, Choi-Miura NH, Mazda T, Tomita M (1996) Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. J Biochem 120(4):803–812

    Article  CAS  PubMed  Google Scholar 

  157. Shapiro L, Scherer PE (1998) The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor. Curr Biol 8(6):335–340

    Article  CAS  PubMed  Google Scholar 

  158. Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T, Scherer PE (2003) Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin: implications for metabolic regulation and bioactivity. J Biol Chem 278(11):9073–9085

    Article  CAS  PubMed  Google Scholar 

  159. Wong GW, Wang J, Hug C, Tsao TS, Lodish HF (2004) A family of Acrp30/adiponectin structural and functional paralogs. Proc Natl Acad Sci 101(28):10302–10307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Whitehead JP, Richards AA, Hickman IJ, Macdonald GA, Prins JB (2006) Adiponectin–a key adipokine in the metabolic syndrome. Diabetes Obes Metab 8(3):264–280

    Article  CAS  PubMed  Google Scholar 

  161. Scherer PE (2014) Adiponectin: basic and clinical aspects. Preface. Best Pract Res Clin Endocrinol Metab 28(1):1–2

    Article  PubMed  Google Scholar 

  162. Ye R, Scherer PE (2013) Adiponectin, driver or passenger on the road to insulin sensitivity? Mol Metab 2(3):133–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Qiao L, Lee B, Kinney B, Yoo HS, Shao J (2011) Energy intake and adiponectin gene expression. Am J Physiol Endocrinol Metab 300(5):E809–E816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Kovacova Z, Vitkova M, Kovacikova M, Klimcakova E, Bajzova M, Hnevkovska Z, Polak J (2009) Secretion of adiponectin multimeric complexes from adipose tissue explants is not modified by very low calorie diet. Eur J Endocrinol 160(4):585

    Article  CAS  PubMed  Google Scholar 

  165. Wang Z, Al-Regaiey KA, Masternak MM, Bartke A (2006) Adipocytokines and lipid levels in Ames dwarf and calorie-restricted mice. J Gerontol A Biol Sci Med Sci 61(4):323–331

    Article  PubMed  Google Scholar 

  166. Dolezalova R, Lacinova Z, Dolinkova M, Kleiblova P, Haluzikova D, Housa D, Haluzik M (2007) Changes of endocrine function of adipose tissue in anorexia nervosa: comparison of circulating levels versus subcutaneous mRNA expression. Clin Endocrinol 67(5):674–678

    Article  CAS  Google Scholar 

  167. Rasouli N, Yao-Borengasser A, Miles LM, Elbein SC, Kern PA (2006) Increased plasma adiponectin in response to pioglitazone does not result from increased gene expression. Am J Physiol Endocrinol Metab 290(1):E42–E46

    Article  CAS  PubMed  Google Scholar 

  168. Cawthorn WP, Scheller EL, Learman BS, Parlee SD, Simon BR, Mori H, MacDougald OA (2014) Bone marrow adipose tissue is an endocrine organ that contributes to increased circulating adiponectin during caloric restriction. Cell Metab 20(2):368–375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Shimabukuro M, Higa N, Asahi T, Oshiro Y, Takasu N, Tagawa T, Matsuzawa Y (2003) Hypoadiponectinemia is closely linked to endothelial dysfunction in man. J Clin Endocrinol Metab 88(7):3236–3240

    Article  CAS  PubMed  Google Scholar 

  170. Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, Noda T (2002) Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 277(29):25863–25866

    Article  CAS  PubMed  Google Scholar 

  171. Yamauchi T, Hara K, Kubota N, Terauchi Y, Tobe K, Froguel P, Kadowaki T (2003) Dual roles of adiponectin/Acrp30 in vivo as an anti-diabetic and anti-atherogenic adipokine. Curr Drug Targets Immune Endocr Metab Disord 3(4):243–253

    Article  CAS  Google Scholar 

  172. Nakanishi S, Yamane K, Kamei N, Nojima H, Okubo M, Kohno N (2005) A protective effect of adiponectin against oxidative stress in Japanese Americans: the association between adiponectin or leptin and urinary isoprostane. Metabolism 54(2):194–199

    Article  CAS  PubMed  Google Scholar 

  173. Valerio A, Cardile A, Cozzi V, Bracale R, Tedesco L, Pisconti A, Nisoli E (2006) TNF-α downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents. J Clin Investig 116(10):2791–2798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, Matsuzawa Y (2000) Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-κβ signaling through a cAMP-dependent pathway. Circulation 102(11):1296–1301

    Article  CAS  PubMed  Google Scholar 

  175. Robinson K, Prins J, Venkatesh B (2011) Clinical review: adiponectin biology and its role in inflammation and critical illness. Crit Care 15(2):1–9

    Article  Google Scholar 

  176. Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama A, Okamoto Y, Matsuzawa Y (2001) Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 103(8):1057–1063

    Article  CAS  PubMed  Google Scholar 

  177. Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Matsuzawa Y (1999) Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 100(25):2473–2476

    Article  CAS  PubMed  Google Scholar 

  178. Yamaguchi N, Argueta JGM, Masuhiro Y, Kagishita M, Nonaka K, Saito T, Yamashita Y (2005) Adiponectin inhibits Toll-like receptor family-induced signaling. FEBS Lett 579(30):6821–6826

    Article  CAS  PubMed  Google Scholar 

  179. Ajuwon KM, Spurlock ME (2005) Adiponectin inhibits LPS-induced NF-κβ activation and IL-6 production and increases PPARγ2 expression in adipocytes. Am J Physiol Regul Integr Comp Physiol 288(5):R1220–R1225

    Article  CAS  PubMed  Google Scholar 

  180. Febriza A, Ridwan R, Asad S, Kasim VN, Idrus HH (2019) Adiponectin and its role in inflammatory process of obesity. Mol Cell Biomed Sci 3(2):60–66

    Article  Google Scholar 

  181. Tomizawa A, Hattori Y, Kasai K, Nakano Y (2008) Adiponectin induces NF-κβ activation that leads to suppression of cytokine-induced NF-κβ activation in vascular endothelial cells: globular adiponectin vs. high molecular weight adiponectin. Diabetes Vasc Disease Res 5(2):123–127

    Article  Google Scholar 

  182. DeFronzo RA, Tripathy D (2009) Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care 32(suppl_2):S157–S163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Zhao L, Fu Z, Liu Z (2014) Adiponectin and insulin cross talk: the microvascular connection. Trends Cardiovasc Med 24(8):319–324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Williams IM, McClatchey PM, Bracy DP, Bonner JS, Valenzuela FA, Wasserman DH (2020) Transendothelial insulin transport is impaired in skeletal muscle capillaries of obese male mice. Obesity 28(2):303–314

    Article  CAS  PubMed  Google Scholar 

  185. Clerk LH, Vincent MA, Barrett EJ, Lankford MF, Lindner JR (2007) Skeletal muscle capillary responses to insulin are abnormal in late-stage diabetes and are restored by angiogensin-converting enzyme inhibition. Am J Physiol Endocrinol Metab

  186. Horton WB, Barrett EJ (2021) Microvascular dysfunction in diabetes mellitus and cardiometabolic disease. Endocr Rev 42(1):29–55

    Article  PubMed  Google Scholar 

  187. Schmid PM, Resch M, Steege A, Fredersdorf-Hahn S, Stoelcker B, Birner C, Endemann DH (2011) Globular and full-length adiponectin induce NO-dependent vasodilation in resistance arteries of Zucker lean but not Zucker diabetic fatty rats. Am J Hypertens 24(3):270–277

    Article  CAS  PubMed  Google Scholar 

  188. Watanabe T, Watanabe-Kominato K, Takahashi Y, Kojima M, Watanabe R (2011) Adipose tissue-derived omentin-1 function and regulation. Compr Physiol 7(3):765–781

    Google Scholar 

  189. Suzuki YA, Shin K, Lönnerdal B (2001) Molecular cloning and functional expression of a human intestinal lactoferrin receptor. Biochemistry 40(51):15771–15779

    Article  CAS  PubMed  Google Scholar 

  190. Jialal I, Devaraj S, Kaur H, Adams-Huet B, Bremer AA (2013) Increased chemerin and decreased omentin-1 in both adipose tissue and plasma in nascent metabolic syndrome. J Clin Endocrinol Metab 98(3):E514–E517

    Article  CAS  PubMed  Google Scholar 

  191. Pan HY, Guo L, Li Q (2010) Changes of serum omentin-1 levels in normal subjects and in patients with impaired glucose regulation and with newly diagnosed and untreated type 2 diabetes. Diabetes Res Clin Pract 88(1):29–33

    Article  CAS  PubMed  Google Scholar 

  192. Barth S, Klein P, Horbach T, Dötsch J, Rauh M, Rascher W, Knerr I (2010) Expression of neuropeptide Y, omentin and visfatin in visceral and subcutaneous adipose tissues in humans: relation to endocrine and clinical parameters. Obes Facts 3(4):245–251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Auguet T, Quintero Y, Riesco D, Morancho B, Terra X, Crescenti A, Richart C (2011) New adipokines vaspin and omentin. Circulating levels and gene expression in adipose tissue from morbidly obese women. BMC Med Genet 12(1):1–8

    Article  Google Scholar 

  194. Greulich S, Chen WJ, Maxhera B, Rijzewijk LJ, van der Meer RW, Jonker JT, Ouwens DM (2013) Cardioprotective properties of omentin-1 in type 2 diabetes: evidence from clinical and in vitro studies. PLoS ONE 8(3):e59697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Ouwens DM, Sell H, Greulich S, Eckel J (2010) The role of epicardial and perivascular adipose tissue in the pathophysiology of cardiovascular disease. J Cell Mol Med 14(9):2223–2234

    Article  PubMed  PubMed Central  Google Scholar 

  196. Yamawaki H, Kuramoto J, Kameshima S, Usui T, Okada M, Hara Y (2011) Omentin, a novel adipocytokine inhibits TNF-induced vascular inflammation in human endothelial cells. Biochem Biophys Res Commun 408(2):339–343

    Article  CAS  PubMed  Google Scholar 

  197. Zhong X, Li X, Liu F, Tan H, Shang D (2012) Omentin inhibits TNF-α-induced expression of adhesion molecules in endothelial cells via ERK/NF-κβ pathway. Biochem Biophys Res Commun 425(2):401–406

    Article  CAS  PubMed  Google Scholar 

  198. Watanabe K, Watanabe R, Konii H, Shirai R, Sato K, Matsuyama TA, Watanabe T (2016) Counteractive effects of omentin-1 against atherogenesis. Cardiovasc Res 110(1):118–128

    Article  CAS  PubMed  Google Scholar 

  199. Tan YL, Zheng XL, Tang CK (2015) The protective functions of omentin in cardiovascular diseases. Clin Chim Acta 448:98–106

    Article  CAS  PubMed  Google Scholar 

  200. Ouchi N, Higuchi A, Ohashi K, Oshima Y, Gokce N, Shibata R, Walsh K (2010) Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity. Science 329(5990):454–457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Ehrlund A, Mejhert N, Lorente-Cebrian S, Åström G, Dahlman I, Laurencikiene J, Ryden M (2013) Characterization of the Wnt inhibitors secreted frizzled-related proteins (SFRPs) in human adipose tissue. J Clin Endocrinol Metab 98(3):E503–E508

    Article  CAS  PubMed  Google Scholar 

  202. Bhatt PM, Malgor R (2014) Wnt5a: a player in the pathogenesis of atherosclerosis and other inflammatory disorders. Atherosclerosis 237(1):155–162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Wang D, Zhang Y, Shen C (2020) Research update on the association between SFRP5, an anti-inflammatory adipokine, with obesity, type 2 diabetes mellitus and coronary heart disease. J Cell Mol Med 24(5):2730–2735

    Article  PubMed  PubMed Central  Google Scholar 

  204. Gharibi A, Yaghmaei P, Basati G, Soleimannejad K, Abbasi N (2018) Decreased levels of the anti-inflammatory adipokine, secreted frizzled-related protein 5 (sfrp5), in patients with coronary artery disease. Ann Trop Med Public Health 6(Specia):S136

    Google Scholar 

  205. Nakamura K, Sano S, Fuster JJ, Kikuchi R, Shimizu I, Ohshima K, Walsh K (2016) Secreted frizzled-related protein 5 diminishes cardiac inflammation and protects the heart from ischemia/reperfusion injury*♦. J Biol Chem 291(6):2566–2575

    Article  CAS  PubMed  Google Scholar 

  206. Kikuchi R, Nakamura K, MacLauchlan S, Ngo DTM, Shimizu I, Fuster JJ, Walsh K (2014) An antiangiogenic isoform of VEGF-A contributes to impaired vascularization in peripheral artery disease. Nat Med 20(12):1464–1471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Miyoshi T, Doi M, Usui S, Iwamoto M, Kajiya M, Takeda K, Ito H (2014) Low serum level of secreted frizzled-related protein 5, an anti-inflammatory adipokine, is associated with coronary artery disease. Atherosclerosis 233(2):454–459

    Article  CAS  PubMed  Google Scholar 

  208. Carstensen-Kirberg M, Kannenberg JM, Huth C, Meisinger C, Koenig W, Heier M, Thorand B (2017) Inverse associations between serum levels of secreted frizzled-related protein-5 (SFRP5) and multiple cardiometabolic risk factors: KORA F4 study. Cardiovasc Diabetol 16(1):1–10

    Article  Google Scholar 

  209. Cho YK, Kang YM, Lee SE, Lee YL, Seol SM, Lee WJ, Jung CH (2018) Effect of SFRP5 (secreted frizzled-related protein 5) on the WNT5A (wingless-type family member 5a)-induced endothelial dysfunction and its relevance with arterial stiffness in human subjects. Arterioscler Thromb Vasc Biol 38(6):1358–1367

    Article  CAS  PubMed  Google Scholar 

  210. Schäffler A, Buechler C (2012) CTRP family: linking immunity to metabolism. Trends Endocrinol Metab 23(4):194–204

    Article  PubMed  Google Scholar 

  211. Wang YJ, Zhao JL, Lau WB, Liu J, Guo R, Ma XL (2017) Adipose tissue-derived cytokines, CTRPs as biomarkers and therapeutic targets in metabolism and the cardiovascular system. Vessel Plus 1:202–212

    CAS  Google Scholar 

  212. Sangwung P, Petersen KF, Shulman GI, Knowles JW (2020) Mitochondrial dysfunction, insulin resistance, and potential genetic implicationspotential role of alterations in mitochondrial function in the pathogenesis of insulin resistance and type 2 diabetes. Endocrinology 161(4).

  213. Haluzik M, Colombo C, Gavrilova O, Chua S, Wolf N, Chen M, Reitman ML (2004) Genetic background (C57BL/6J versus FVB/N) strongly influences the severity of diabetes and insulin resistance in ob/ob mice. Endocrinology 145(7):3258–3264

    Article  CAS  PubMed  Google Scholar 

  214. Wong GW, Krawczyk SA, Kitidis-Mitrokostas C, Ge G, Spooner E, Hug C, Lodish HF (2009) Identification and characterization of CTRP9, a novel secreted glycoprotein, from adipose tissue that reduces serum glucose in mice and forms heterotrimers with adiponectin. FASEB J 23(1):241–258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Wong GW, Krawczyk SA, Kitidis-Mitrokostas C, Revett T, Gimeno R, Lodish HF (2008) Molecular, biochemical and functional characterizations of C1q/TNF family members: adipose-tissue-selective expression patterns, regulation by PPAR-γ agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions. Biochem J 416(2):161–177

    Article  CAS  PubMed  Google Scholar 

  216. Peterson JM, Wei Z, Wong GW (2009) CTRP8 and CTRP9B are novel proteins that hetero-oligomerize with C1q/TNF family members. Biochem Biophys Res Commun 388(2):360–365

    Article  CAS  PubMed  Google Scholar 

  217. Wei Z, Lei X, Seldin MM, Wong GW (2012) Endopeptidase cleavage generates a functionally distinct isoform of C1q/tumor necrosis factor-related protein-12 (CTRP12) with an altered oligomeric state and signaling specificity. J Biol Chem 287(43):35804–35814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Wei Z, Peterson JM, Lei X, Cebotaru L, Wolfgang MJ, Baldeviano GC, Wong GW (2012) C1q/TNF-related protein-12 (CTRP12), a novel adipokine that improves insulin sensitivity and glycemic control in mouse models of obesity and diabetes. J Biol Chem 287(13):10301–10315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Tomas E, Tsao TS, Saha AK, Murrey HE, Cheng Zhang C, Itani SI, Ruderman NB (2002) Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: Acetyl–CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci 99(25):16309–16313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP, Scherer PE (2004) Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem 279(13):12152–12162

    Article  CAS  PubMed  Google Scholar 

  221. Lasser G, Guchhait P, Ellsworth JL, Sheppard P, Lewis K, Bishop P, Fruebis J (2006) C1qTNF–related protein-1 (CTRP-1): a vascular wall protein that inhibits collagen-induced platelet aggregation by blocking VWF binding to collagen. Blood 107(2):423–430

    Article  CAS  PubMed  Google Scholar 

Download references


Authors would like to thank the Director of RIPANS for his support and cooperation.


No funding available.

Author information

Authors and Affiliations



PKR is the first author and given the main concept of the manuscript, drafting and preparation of the manuscript. Dr. JI wrote prepared the figures of the manuscript and helped preparation of the manuscript. Dr. HL made the tabulation, helped in drafting the manuscript, and scrutinized and organized the entire manuscript. All authors have read and approved the manuscript for publication to your esteemed journal.

Corresponding author

Correspondence to Probin Kr Roy.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not Applicable.

Competing interests

The authors declare no competing interest associated with this work.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Roy, P.K., Islam, J. & Lalhlenmawia, H. Prospects of potential adipokines as therapeutic agents in obesity-linked atherogenic dyslipidemia and insulin resistance. Egypt Heart J 75, 24 (2023).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: