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J Clin Endocrinol Metab. Nov 2008; 93(11 Suppl 1): S64–S73.
PMCID: PMC2585759

Adipocytokines and the Metabolic Complications of Obesity


Context: Adipose tissue is increasingly recognized as an active endocrine organ with many secretory products and part of the innate immune system. With obesity, macrophages infiltrate adipose tissue, and numerous adipocytokines are released by both macrophages and adipocytes. Adipocytokines play important roles in the pathogenesis of insulin resistance and associated metabolic complications such as dyslipidemia, hypertension, and premature heart disease.

Evidence Acquisition: Published literature was analyzed with the intent of addressing the role of the major adipose secretory proteins in human obesity, insulin resistance, and type 2 diabetes.

Evidence Synthesis: This review analyzes the characteristics of different adipocytokines, including leptin, adiponectin, pro-inflammatory cytokines, resistin, retinol binding protein 4, visfatin, and others, and their roles in the pathogenesis of insulin resistance.

Conclusions: Inflamed fat in obesity secretes an array of proteins implicated in the impairment of insulin signaling. Further studies are needed to understand the triggers that initiate inflammation in adipose tissue and the role of each adipokine in the pathogenesis of insulin resistance.

Many recent epidemiological studies have documented the rapid increase in the prevalence of obesity. According to data from the Center for Disease Control Behavioral Risk Factor Surveillance System, 22 states in the United States have an obesity [body mass index (BMI) >30 kg/m2] prevalence of over 30% in 2006, whereas only 10 yr earlier, no state had an obesity prevalence of more than 20%. Along with the increase in obesity is a parallel increase in the prevalence of type 2 diabetes, impaired glucose tolerance (1,2), and other complications of obesity, such as hypertension, sleep apnea, and arthritis. Whether or not the obesity epidemic leads to an increase in the incidence of new obesity related malignancies remains to be determined (3,4). A recent study suggested that future life expectancy may decrease for the first time due to the increase in obesity (5).

The metabolic complications of obesity, often referred to as the metabolic syndrome, consist of insulin resistance, often culminating in β-cell failure, impaired glucose tolerance and type 2 diabetes, dyslipidemia, hypertension, and premature heart disease. Abdominal obesity, ectopic lipid accumulation, hepatic steatosis, and sleep apnea can also be included in the metabolic complications of obesity (6).

This paper is intended to provide an overview of the pathogenesis of the metabolic complications of obesity, with particular emphasis on the role of inflammation and adipose tissue-derived proteins. There are many adipokines, and space limitations do not permit a thorough discussion of all of them. Therefore, this review will discuss a number of the major adipokines, and will focus on adipokines related to inflammation, and in particular adipokines that have been the subject of studies in humans, and where there are clinical implications for obesity and insulin resistance.

Obesity Is Associated with Inflammation

The role of adipose tissue in metabolic syndrome has continued to evolve with the description of numerous secretory products from adipocytes. These “adipokines” are important determinants of insulin resistance, either through a traditional (circulating) hormonal effect, or through local effects on the adipocyte.

In the mid-1990s, the expression of TNFα by adipose tissue of obese rodents and humans was first described (7,8). Subsequently, other adipose tissue-derived proteins were described, and many of these adipokines have been implicated in the pathogenesis of the chronic inflammation and insulin resistance associated with obesity. In addition to the production of pro-inflammatory cytokines that promote metabolic complications, adipose tissue is the sole source of adiponectin, which is antiinflammatory and associated with protection from atherosclerosis (9,10).

The study of adipose tissue inflammation was considerably impacted by the demonstration of resident macrophages in adipose tissue (11,12). The adipose tissue of obese rodents and humans contains increased numbers of macrophages, and once activated, macrophages secrete a host of cytokines such as TNFα, IL-6, and IL-1 (13), and the adipose tissue resident macrophages were responsible for the expression of most of the tissue TNFα and IL-6. The expression of macrophage markers in human adipose tissue was high in subjects with obesity and insulin resistance, and was also correlated with the expression of TNFα and IL-6 (12,14).

There are a number of possible mechanisms underlying the infiltration of macrophages into adipose tissue. One possibility is the elaboration of chemokines by adipocytes, which would then attract resident macrophages. Adipocytes express low levels of monocyte chemoattractant protein (MCP)-1, and increased expression is found in obese subjects (14). From an evolutionary perspective, adipose macrophages may have represented an important part of the host defense against injury or infection. On the other hand, recent studies have suggested that macrophages infiltrate adipose tissue as part of a scavenger function in response to adipocyte necrosis. Careful immunohistological studies of mouse and human adipose tissue demonstrated that most of the macrophages in adipose tissue of obese mice were surrounding dead adipocytes and formed a syncytium, often referred to as a “crown-like structure” (15). With the rapid development of obesity in both diet and genetically obese rodent models, the number of crown-like structures in adipose tissue increases rapidly, and the macrophage burden surrounding necrotic adipocytes becomes considerable (16).

If adipocyte necrosis is indeed the initiating event in the process of macrophage infiltration, there are a number of possible causes. Hypoxia has been proposed to be an inciting etiology of necrosis (17). With obesity and progressive adipocyte enlargement, the blood supply to adipocytes may be reduced (18), and the induction of adipocyte hypoxia in vitro results in the expression of a number of inflammatory cytokines (19,20,21). Indeed, an increased prevalence of insulin resistance in patients with sleep apnea independent of obesity has been reported, which is perhaps due to intermittent hypoxia, inflammation, and oxidative stress (22).

Another body of thought suggests that unbridled adipocyte expansion and triglyceride accumulation in adipose tissue are ultimately a benign phenomenon, and perhaps even beneficial to relieve lipotoxicity in liver, skeletal muscle, and other ectopic sites (23). Adipose tissue inflammation may occur when adipocyte expansion is limited, either due to impaired adipocyte development, decreased lipid synthesis, or matrix factors that prevent cell enlargement. One example of limited adipocyte development is lipodystrophy. Humans and rodents with extreme forms of lipodystrophy have little or no adipose tissue and extreme ectopic fat deposition, leading to lipotoxicity and insulin resistance (24). However, lesser degrees of lipodystrophy occur in patients with HIV lipodystrophy, who demonstrate features of the metabolic syndrome. The adipose tissue of HIV-infected patients demonstrated increased inflammation and lower levels of expression of lipin-β (25,26,27,28). Lipin is a phosphatidate phosphatase involved in lipid synthesis, and animals with lipin deficiency are lipodystrophic (29,30). In addition, lower levels of adipose lipin expression are found in non-HIV infected subjects with insulin resistance, and peroxisome proliferator activated receptor (PPAR)-γ agonists increase the expression of the β-isoform of lipin (31). Other genes involved in adipocyte differentiation or lipogenesis may also be associated with adipose tissue inflammation. Therefore, the association of obesity with insulin resistance and inflammation is well established. The concept of limited adipocyte expansion, leading to inflammation and many of the metabolic consequences of obesity, is somewhat counterintuitive, but enjoys some support in the literature. This concept clearly needs further development and clarification with future research.

Adipokines Expressed by Adipocytes


Leptin (Greek, leptos, thin), is a 167-amino acid hormone secreted largely by adipose tissue that controls food intake and energy expenditure (32). Circulating levels of leptin parallel fat cell stores, increasing with overfeeding and decreasing with starvation. The absence of leptin or a mutation in leptin receptor genes induces a massive hyperphagia and obesity in animal models (33), and humans (34,35), however, the prevalence of these mutations in obese humans is rare.

The effects of leptin are mediated by receptors, mainly located in the central nervous system, and in other tissues, including adipocytes and endothelial cells. Leptin receptor belongs to the class I family of cytokine receptors, and it engages both the signal transducer and activator of transcription-3 (STAT3) pathway and the insulin receptor substrate phosphoinositide-3 kinase pathway, among others (36). It has been shown that STAT3 is essential for mediating food intake, liver glucose production, and gonadotropin secretion (36), however, the control of adipose tissue metabolism by leptin is STAT3 independent (37). Recently, Buettner et al. (37) showed that the infusion of leptin in hypothalamus led to the suppression of lipogenesis in adipose tissue through activation of the phosphoinositide-3 kinase pathway, sympathic nervous system, and the engagement of adipose tissue endocannabinoid system.

Other potential physiological roles for leptin have been described. Leptin modulates the T-cell immune response, stimulates proliferation of T-helper cells, and increases production of pro-inflammatory cytokines by regulating different immune cells (38,39). Leptin is also important in regulating the reproductive system and the onset of puberty, and leptin deficiency is associated with hypogonadism (40).

The increased risk of cardiovascular disease with obesity makes adipokines, including leptin, an attractive instigator of atherosclerosis. In a large prospective study, leptin was independently associated with an increased risk of coronary artery disease (41). However, the question whether leptin directly causes atherosclerosis in obese individuals is still unresolved. In in vitro or animal studies, different atherogenic properties, including increased oxidative stress, impairment of vasorelaxation, and increased thrombosis, have been described for leptin (42,43).

Potential use of leptin as a drug

Treatment with recombinant human leptin reverses hyperphagia, obesity, hypogonadism, and impaired T-cell-mediated immunity associated with congenital leptin deficiency (44,45). In addition, leptin replacement is a very promising therapeutic approach for the management of the complications of lipodystrophy (46). In contrast, leptin treatment for the reversal of typical obesity and obesity related metabolic disorders has not proven to be successful (47). Obese individuals, for unknown reasons, become resistant to the satiety and weight-reducing effect of leptin. A recent study reported a synergistic effect for weight loss with leptin and amylin coadministration in diet-induced obese rats by restoring hypothalamic sensitivity to leptin (48). If confirmed in clinical research studies, the restoration of leptin sensitivity might change the neurohormonal approaches to obesity pharmacotherapy.


Adiponectin is a 30-kDa protein secreted from adipocytes (9), and its circulating levels are decreased in obesity induced insulin resistance (49,50). Paradoxically, in rare cases of severe insulin resistance with proximal defect in insulin action, elevated levels of adiponectin have been reported (51). Mice lacking adiponectin have reduced insulin sensitivity (52,53,54); in contrast, adiponectin overexpression in ob/ob mice, confers dramatic metabolic improvements (23).

Once adiponectin is synthesized, it undergoes several posttranslational modifications, including hydroxylation and glycosylation (55), and some of these modifications are necessary for its bioactivity (56). Circulating adiponectin is found in several different isoforms, including trimer, low-molecular weight (-hexamers), and high-molecular weight (HMW) (18mers) forms (57,58). Different adiponectin oligomers hold distinct biological functions. Most insulin-sensitizing effects of adiponectin have been linked to the HMW isoform, whereas the central effects of adiponectin have been contributed to hexamer and trimer isoforms (55).

The distribution of adiponectin oligomers in the circulation is primarily controlled at the level of secretion from adipocytes. Molecular chaperones in the endoplasmic reticulum (ER), including ER protein of 44 kDa and ER oxidoreductase 1-Lα, play an important role in the secretion of adiponectin (55,63).

Several studies have linked hypoadiponectinemia to diabetes (50), hypertension (59), atherosclerosis, and endothelial dysfunction (60). More recent studies have shown that the HMW oligomer is inversely associated with the risk for diabetes independent of total adiponectin (61), and the HMW oligomer is responsible for the association of adiponectin with traits of metabolic syndrome (62,63).

Adiponectin inserts its effects through two transmembrane receptors (AdipoR1 and AdipoR2) that are ubiquitously expressed. AdipoR1 is predominantly expressed in skeletal muscle with a preference for binding to globular adiponectin, whereas AdipoR2 is most abundant in the liver with a preference for binding to full-length adiponectin (64). Adiponectin improves insulin sensitivity by increasing energy expenditure and fatty acid oxidation through activation of AMP-activated protein kinase (AMPK), and by increasing the expression of PPARα target genes such as CD36, acyl-coenzyme oxidase, and uncoupling protein 2 (60). Alternatively, adiponectin may lead to an improved metabolic profile by the expansion of sc adipose tissue with decreased levels of macrophage infiltration (23), similar to the actions of PPARγ agonists. Thiazolidinediones (TZDs) are known to increase circulating levels of adiponectin, mostly the HMW form, by 2- to 3-fold (65,66,67), and improve insulin resistance by diversion of fat from ectopic sites to sc adipose tissue (68). Interestingly, insulin-sensitizing effects of TZDs are significantly diminished in the absence of adiponectin (54), suggesting an important role of adiponectin in reduction of lipotoxicity and inflammation associated with obesity.

Adiponectin has also had vasculoprotective effects mediated via an increase in endothelial nitric oxide production, or modulation of expression of adhesion molecules and scavenger receptors (60,69).

In addition to peripheral actions, it has been suggested that adiponectin has central effects in the regulation of energy homeostasis (70). Adiponectin was present in cerebrospinal fluid largely in the form of trimer and hexamer, in contrast to the distribution of adiponectin in serum, which consists of higher molecular masses (71). It has been proposed that adiponectin increases food intake by enhancing hypothalamic AMPK activity in fasting conditions (72).


Resistin is a 12-kDa peptide that was originally discovered as a result of examining differential gene expression of mouse adipose tissue after TZD treatment (73). Resistin is part of a gene family of “Resistin-like molecules,” and is increased along with PPARγ during the differentiation of 3T3-L1 adipocytes (74). Resistin was decreased by TZD treatment of mice and was increased in insulin-resistant mice. Furthermore, treatment with antiresistin antibody improved insulin sensitivity and glucose transport in mice and mouse adipocytes, respectively (73). Additional studies in mice suggest that an important site of action of resistin is on hepatic glucose production (75). Although these data in mice are exciting, the role of resistin in human insulin resistance is less clear. Resistin is expressed by adipocytes in mice but is expressed by the macrophages of humans (76). A number of studies have examined plasma resistin levels or adipose resistin expression, and have found variable associations with insulin resistance (77,78,79,80). A recent large study involving the Framingham offspring cohort found a significant relationship between insulin resistance and resistin, however, this relationship was considerably weaker than the relationship with adiponectin, and was lost after adjustment for BMI (81). Resistin decreases after TZD treatment of humans, although resistin was also decreased by metformin treatment (65,82). Therefore, resistin is clearly an important adipokine that likely plays a role in the development of insulin resistance; however, it appears to be quantitatively less important in humans than other adipokines.

Retinol binding protein 4 (RBP4)

One interesting rodent model of insulin resistance is the adipose tissue-specific glucose transporter 4 (Glut4) knockout mouse (83), in which the defect in adipose tissue glucose transport yielded peripheral insulin resistance, apparently due to a circulating factor. RBP4 was identified as a highly expressed circulating adipokine in this model and caused insulin resistance when overexpressed or injected into mice (84). Since that time, a number of human studies have been performed that examined RBP4 protein levels in circulation and/or its gene expression in adipose tissue in subjects with varying degrees of obesity, insulin resistance, or type 2 diabetes. Some papers demonstrated a positive association between RBP4 and insulin resistance or obesity (84,85,86,87,88,89,90,91,92,93,94), sometimes with strikingly strong correlations, whereas others have not found such a relationship (95,96,97,98,99,100). One study found no relationship between RBP4 and insulin sensitivity in older subjects, but a weak relationship in young subjects, suggesting an age-related difference (101). Another study found no significant relationship between RBP4 and insulin sensitivity, but RBP4 was associated with adipose tissue macrophage markers, suggesting a possible role of RBP4 in inflammation (95). The response to TZDs has been examined in fewer studies, and again the response was inconsistent. If RBP4 is associated with insulin resistance, one would expect a decrease after treatment with rosi- or pioglitazone. Such a response was found in Glut4 knockout mice (84) and in some human studies (90,91,102,103). However, in other studies, human subjects treated with TZDs demonstrated no change or an increase in RBP4 mRNA (94,95), and the addition of pioglitazone to adipocytes in vitro also resulted in increased RBP4 mRNA (95). RBP4 circulates bound to transthyretin, which decreases RBP4 renal clearance, and transthyretin plasma levels were increased 4-fold in ob/ob mice compared with lean mice or diet-induced obese mice (104). Although RBP4-transthyretin binding may be important physiologically, this area needs further study. Thus, the data are currently conflicting on the role of RBP4 in insulin resistance and the metabolic complications of obesity. Because of the association with Glut4, RBP4 is presumed to play a role in fuel sensing in the adipocyte, but in other respects, a possible mechanism for causing insulin resistance is not clear.


Visfatin is expressed in many cells and tissues, and was previously identified as a protein involved in B-cell maturation (pre-B colony enhancing factor) (105,106). More recently, visfatin was described to be a highly expressed protein with insulin-like functions, and was predominantly found in visceral adipose tissue, from which the name visfatin was derived (107). Injection of visfatin in mice lowered blood glucose, and mice with a mutation in visfatin had higher glucose levels.

Although these initial studies were promising, subsequent studies of visfatin in humans have generally not confirmed the initial study, which was, in part, retracted (108). A subsequent study did not confirm the insulin mimetic action of visfatin but instead demonstrated that visfatin has nicotinamide adenine dinucleotide (NAD) biosynthetic activity, which is essential for B-cell function (109). In human studies, a positive correlation between visceral adipose tissue visfatin gene expression and BMI was noted, along with a negative correlation between BMI and sc fat visfatin (110,111), suggesting that visfatin regulation in these different depots is different, and adipose depot ratios are highly dependent on the obesity of the subjects. No difference in visfatin expression between fat depots of humans was noted (110,111), and visfatin was expressed predominantly by nonmacrophage cells in the adipose tissue stroma (111). Plasma visfatin was positively associated with BMI in one study (110), but not in others (111,112). Variable results were obtained regarding the relationship between visfatin and diabetes or insulin resistance (111,112,113,114), and visfatin was not responsive to PPARγ agonists and was not correlated with macrophage markers (111). Therefore, there are a number of inconsistencies among the different studies of visfatin, and the role of this adipokine in obesity and insulin resistance is not clear.

Inflammatory Cytokines Produced by Macrophages

Obesity is characterized by increased fat mass frequently associated with chronic inflammation. Yet, the mechanisms triggering the inflammatory pathway in obesity are to be determined, and discussed previously. An increased number of macrophages resident in human adipose tissue has been reported in obesity (14) that may contribute to the inflammatory process by secreting pro-inflammatory cytokines such as TNFα, IL6, and MCP-1. In addition to increased infiltration of macrophages in adipose tissue, obesity is associated with changes in the phenotype of macrophages from alternatively activated toward a more classical and pro-inflammatory cell (115) as the source of pro-inflammatory mediators. Inactivation of the nuclear factor-κB pathway, which induces inflammatory mediators, has led to the protection against insulin resistance (116).


Of the pro-inflammatory cytokines, TNFα is well described to disturb insulin signaling. Mice lacking TNFα or TNFα receptors are resistant to the development of obesity induced insulin resistance (117,118). In adipose tissue, TNFα is mostly secreted by macrophages in the stromal vascular fraction. Circulating TNFα and adipose tissue TNFα gene expression are increased in insulin resistance (119), and acute infusion of TNFα inhibited insulin-induced glucose uptake in healthy subjects (120). Neutralization of TNFα in rodents has improved insulin resistance (7), whereas attempts to neutralize TNFα in humans to improve insulin resistance have generally not been successful (121), although more recent studies have shown slight improvement in insulin resistance with TNFα inhibition (122,123,124). Limited effects of TNFα blockade on insulin resistance could be explained by the paracrine actions of TNFα. Further investigations on the mechanisms involved in TNFα overexpression associated with obesity and molecular signals underlying TNFα-induced metabolic dysregulation are warranted.


IL-6 is another cytokine similar to TNFα that is overexpressed in the adipose tissue of obesity (119). The role of IL-6 in metabolic changes associated with obesity is unclear. There are some reports of IL-6 causing impaired insulin signaling in the liver and adipocytes by inducing ubiquitin-mediated degradation of insulin receptor substrate through suppressor of cytokine signaling (SOCS) 1 and 3 (125,126). However, effects of IL-6 on insulin sensitivity in skeletal muscle is controversial (126). Exercise that is associated with increased insulin action in skeletal muscle increases circulating IL-6 levels dramatically (127), suggesting possible antiinflammatory roles for IL-6 in skeletal muscle. The data on the increased onset of obesity and diabetes in mice lacking IL-6 are conflicting (128,129).


As discussed previously, infiltration of macrophages into adipose tissue is an important contributor of the increased inflammatory process in obesity. Adipocytes secrete various chemoattractants that draw monocytes from circulation into adipose tissue. MCP-1, also known as chemokine (C-C motif) ligand 2 (CCL-2), is one the chemoattractants that plays an important role in the recruitment of macrophages. Moreover, obesity is associated with increased plasma levels of MCP-1 and overexpression in adipose tissue (14,130). Mice lacking MCP-1 receptor (CCR-2) have decreased adipose tissue macrophage infiltration and improved metabolic function (12). Similarly, it has been demonstrated that mice lacking MCP-1 have reduced adipose tissue macrophage infiltration (131), however, a more recent study did not confirm this finding (132). This suggests that there are other candidates that might play a role in the recruitment of macrophages into the adipose tissue, such as macrophage inflammatory protein-1α (11) or osteopontin (133,134). Osteopontin is an extracellular matrix protein that promotes monocyte chemotaxis, and the lack of osteopontin in mice caused improved insulin sensitivity and decreased macrophage infiltration into adipose tissue (134).

Adipokines Involved with Thrombosis: Thrombospondin (TSP) and Plasminogen Activator Inhibitor 1 (PAI-1)

PAI-1 is elevated in subjects with metabolic complications of obesity, and is expressed in the stromal fraction of adipose tissue, including endothelial cells (135,136,137,138,139). PAI-1 inhibits both tissue-type plasminogen activator and urokinase-type plasminogen activator through its serine protease inhibitor function, and this inhibition of fibrinolysis may contribute to a pro-thrombotic state (140).

PAI-1 gene expression is controlled by TGF-β, which combines with phosphorylated SMAD and binds to the PAI-1 promoter (141). Another important link in PAI-1 activation was the recent demonstration of TSP1 expression in adipocytes (142). TSP1 is expressed by many tissues, and has many different activities, including inhibition of angiogenesis, cell proliferation, and wound healing (143,144). TSP1 is a major activator of TGF-β (145), and PAI-1 activation by TSP1 has been described (146) (Fig. 11).

Figure 1
Role of TSP1, TGF-β, and PAI-1 in adipose tissue. TSP1 is expressed by adipose tissue, and activates TGF-β, which in turn activates PAI-1, which is a procoagulant. TGF-β is also activated by high glucose and angiotensin II. TSP1 ...

A recent study demonstrated TSP1 expression largely by adipocytes compared with the stromal vascular fraction of adipose tissue, suggesting that TSP1 is a true adipokine (142). TSP1 expression was increased in obese, insulin-resistant subjects, was associated with plasma PAI-1 levels, and was positively associated with adipose tissue macrophage markers. In addition, TSP1 expression was decreased by treatment of subjects or adipocytes with the PPARγ agonist, pioglitazone. TSP1 has chemotactic properties (143) that provide a link between TSP1 and macrophage-mediated adipocyte inflammation. In addition, adipocyte-macrophage coculture experiments demonstrated TSP1 gene and protein up-regulation by both cells, suggesting a feed-forward inflammatory mechanism in adipose tissue (142). TSP1 may be an important component of inflammation and coagulation in the metabolic complications of obesity.


Adipose tissue was once recognized simply as an inert storage organ, but now is appreciated increasingly as an endocrine organ and part of an innate immune system. Factors secreted from adipose tissue contribute considerably to the regulation of metabolism and inflammatory responses. The adipose tissue of insulin-sensitive humans secretes adiponectin abundantly, which is associated with a favorable metabolic condition. However, with adiposity, adiponectin secretion decreases significantly, and multiple adipocyte-derived factors induce activation and infiltration of macrophage into adipose tissue. Activated macrophages secrete cytokines that can contribute to more macrophage infiltration. As shown in Fig. 22,, inflamed fat in obesity secretes an array of proteins implicated in the impairment of insulin signaling. In addition, in a hypothetical model, inflamed fat releases more free fatty acids that contribute to fat accumulation in ectopic sites, including liver and muscle. Increased lipid content in liver and muscle has been associated with insulin resistance. PPARγ ligands, such as TZDs, improve insulin resistance through multiple potential mechanisms. PPARγ agonists enhance adipogenesis, increase adiponectin, and exert antiinflammatory effects on macrophages resident in adipose tissue. Future studies are needed to focus on the factors initiating the inflammatory process in adipose tissue and the regulation of adipocyte secretory products.

Figure 2
Changes in adipose tissue, liver, and muscle with obesity and insulin resistance. The adipose tissue of lean subjects contains few macrophages, and secretes relatively high levels of adiponectin, and low levels of inflammatory cytokines. β-Oxidation ...


This work was supported by Merit Review Grant from the Veterans Administration (to N.R.), and DK71277 and DK080327 from the National Institutes of Health (to P.A.K.).

Disclosure Statement: P.A.K. and N.R. have received honoraria for speaking from Takeda Pharmaceuticals.

Abbreviations: AMPK, AMP-activated protein kinase; BMI, body mass index; ER, endoplasmic reticulum; Glut4, glucose transporter 4; HMM, high-molecular mass; MCP, monocyte chemoattractant protein; PAI-1, plasminogen activator inhibitor 1; PPAR, peroxisome proliferator activated receptor; RBP4, retinol binding protein 4; STAT3, signal transducer and activator of transcription-3; TSP, thrombospondin; TZD, thiazolidinedione.


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