Adipocytokines and the Metabolic Complications of Obesity
Neda Rasouli and
Philip A. Kern
The Central Arkansas Veterans Healthcare System (N.R.), and the Department of Medicine, Division of Endocrinology, University of Arkansas for Medical Sciences (N.R., P.A.K.), Little Rock, Arkansas 72205
Address all correspondence and requests for reprints to: Philip A. Kern, M.D., Slot 718, University of Arkansas for Medical Sciences, 4301 Markham Street, Little Rock, Arkansas 72205. E-mail: KernPhilipA{at}uams.edu.
Context: Adipose tissue is increasingly recognized as an activeendocrine organ with many secretory products and part of theinnate immune system. With obesity, macrophages infiltrate adiposetissue, and numerous adipocytokines are released by both macrophagesand adipocytes. Adipocytokines play important roles in the pathogenesisof insulin resistance and associated metabolic complicationssuch as dyslipidemia, hypertension, and premature heart disease.
Evidence Acquisition: Published literature was analyzed withthe intent of addressing the role of the major adipose secretoryproteins in human obesity, insulin resistance, and type 2 diabetes.
Evidence Synthesis: This review analyzes the characteristicsof different adipocytokines, including leptin, adiponectin,pro-inflammatory cytokines, resistin, retinol binding protein4, visfatin, and others, and their roles in the pathogenesisof insulin resistance.
Conclusions: Inflamed fat in obesity secretes an array of proteinsimplicated in the impairment of insulin signaling. Further studiesare needed to understand the triggers that initiate inflammationin adipose tissue and the role of each adipokine in the pathogenesisof insulin resistance.
Many recent epidemiological studies have documented the rapidincrease in the prevalence of obesity. According to data fromthe Center for Disease Control Behavioral Risk Factor SurveillanceSystem, 22 states in the United States have an obesity [bodymass index (BMI) >30 kg/m2] prevalence of over 30% in 2006,whereas only 10 yr earlier, no state had an obesity prevalenceof more than 20%. Along with the increase in obesity is a parallelincrease in the prevalence of type 2 diabetes, impaired glucosetolerance (1, 2), and other complications of obesity, such ashypertension, sleep apnea, and arthritis. Whether or not theobesity epidemic leads to an increase in the incidence of newobesity related malignancies remains to be determined (3, 4).A recent study suggested that future life expectancy may decreasefor the first time due to the increase in obesity (5).
The metabolic complications of obesity, often referred to asthe metabolic syndrome, consist of insulin resistance, oftenculminating in β-cell failure, impaired glucose toleranceand type 2 diabetes, dyslipidemia, hypertension, and prematureheart disease. Abdominal obesity, ectopic lipid accumulation,hepatic steatosis, and sleep apnea can also be included in themetabolic complications of obesity (6).
This paper is intended to provide an overview of the pathogenesisof the metabolic complications of obesity, with particular emphasison the role of inflammation and adipose tissue-derived proteins.There are many adipokines, and space limitations do not permita thorough discussion of all of them. Therefore, this reviewwill discuss a number of the major adipokines, and will focuson adipokines related to inflammation, and in particular adipokinesthat have been the subject of studies in humans, and where thereare clinical implications for obesity and insulin resistance.
The role of adipose tissue in metabolic syndrome has continuedto evolve with the description of numerous secretory productsfrom adipocytes. These "adipokines" are important determinantsof insulin resistance, either through a traditional (circulating)hormonal effect, or through local effects on the adipocyte.
In the mid-1990s, the expression of TNF by adipose tissue ofobese rodents and humans was first described (7, 8). Subsequently,other adipose tissue-derived proteins were described, and manyof these adipokines have been implicated in the pathogenesisof the chronic inflammation and insulin resistance associatedwith obesity. In addition to the production of pro-inflammatorycytokines that promote metabolic complications, adipose tissueis the sole source of adiponectin, which is antiinflammatoryand associated with protection from atherosclerosis (9, 10).
The study of adipose tissue inflammation was considerably impactedby the demonstration of resident macrophages in adipose tissue(11, 12). The adipose tissue of obese rodents and humans containsincreased numbers of macrophages, and once activated, macrophagessecrete a host of cytokines such as TNF, IL-6, and IL-1 (13),and the adipose tissue resident macrophages were responsiblefor the expression of most of the tissue TNF and IL-6. The expressionof macrophage markers in human adipose tissue was high in subjectswith obesity and insulin resistance, and was also correlatedwith the expression of TNF and IL-6 (12, 14).
There are a number of possible mechanisms underlying the infiltrationof macrophages into adipose tissue. One possibility is the elaborationof chemokines by adipocytes, which would then attract residentmacrophages. Adipocytes express low levels of monocyte chemoattractantprotein (MCP)-1, and increased expression is found in obesesubjects (14). From an evolutionary perspective, adipose macrophagesmay have represented an important part of the host defense againstinjury or infection. On the other hand, recent studies havesuggested that macrophages infiltrate adipose tissue as partof a scavenger function in response to adipocyte necrosis. Carefulimmunohistological studies of mouse and human adipose tissuedemonstrated that most of the macrophages in adipose tissueof obese mice were surrounding dead adipocytes and formed asyncytium, often referred to as a "crown-like structure" (15).With the rapid development of obesity in both diet and geneticallyobese rodent models, the number of crown-like structures inadipose tissue increases rapidly, and the macrophage burdensurrounding necrotic adipocytes becomes considerable (16).
If adipocyte necrosis is indeed the initiating event in theprocess of macrophage infiltration, there are a number of possiblecauses. Hypoxia has been proposed to be an inciting etiologyof necrosis (17). With obesity and progressive adipocyte enlargement,the blood supply to adipocytes may be reduced (18), and theinduction of adipocyte hypoxia in vitro results in the expressionof a number of inflammatory cytokines (19, 20, 21). Indeed,an increased prevalence of insulin resistance in patients withsleep apnea independent of obesity has been reported, whichis perhaps due to intermittent hypoxia, inflammation, and oxidativestress (22).
Another body of thought suggests that unbridled adipocyte expansionand triglyceride accumulation in adipose tissue are ultimatelya benign phenomenon, and perhaps even beneficial to relievelipotoxicity in liver, skeletal muscle, and other ectopic sites(23). Adipose tissue inflammation may occur when adipocyte expansionis limited, either due to impaired adipocyte development, decreasedlipid synthesis, or matrix factors that prevent cell enlargement.One example of limited adipocyte development is lipodystrophy.Humans and rodents with extreme forms of lipodystrophy havelittle 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 adiposetissue of HIV-infected patients demonstrated increased inflammationand lower levels of expression of lipin-β (25, 26, 27,28). Lipin is a phosphatidate phosphatase involved in lipidsynthesis, and animals with lipin deficiency are lipodystrophic(29, 30). In addition, lower levels of adipose lipin expressionare found in non-HIV infected subjects with insulin resistance,and peroxisome proliferator activated receptor (PPAR)- agonistsincrease the expression of the β-isoform of lipin (31).Other genes involved in adipocyte differentiation or lipogenesismay also be associated with adipose tissue inflammation. Therefore,the association of obesity with insulin resistance and inflammationis well established. The concept of limited adipocyte expansion,leading to inflammation and many of the metabolic consequencesof obesity, is somewhat counterintuitive, but enjoys some supportin the literature. This concept clearly needs further developmentand clarification with future research.
Leptin (Greek, leptos, thin), is a 167-amino acid hormone secretedlargely by adipose tissue that controls food intake and energyexpenditure (32). Circulating levels of leptin parallel fatcell stores, increasing with overfeeding and decreasing withstarvation. The absence of leptin or a mutation in leptin receptorgenes induces a massive hyperphagia and obesity in animal models(33), and humans (34, 35), however, the prevalence of thesemutations in obese humans is rare.
The effects of leptin are mediated by receptors, mainly locatedin the central nervous system, and in other tissues, includingadipocytes and endothelial cells. Leptin receptor belongs tothe class I family of cytokine receptors, and it engages boththe signal transducer and activator of transcription-3 (STAT3)pathway and the insulin receptor substrate phosphoinositide-3kinase pathway, among others (36). It has been shown that STAT3is essential for mediating food intake, liver glucose production,and gonadotropin secretion (36), however, the control of adiposetissue metabolism by leptin is STAT3 independent (37). Recently,Buettner et al. (37) showed that the infusion of leptin in hypothalamusled to the suppression of lipogenesis in adipose tissue throughactivation of the phosphoinositide-3 kinase pathway, sympathicnervous system, and the engagement of adipose tissue endocannabinoidsystem.
Other potential physiological roles for leptin have been described.Leptin modulates the T-cell immune response, stimulates proliferationof T-helper cells, and increases production of pro-inflammatorycytokines by regulating different immune cells (38, 39). Leptinis also important in regulating the reproductive system andthe onset of puberty, and leptin deficiency is associated withhypogonadism (40).
The increased risk of cardiovascular disease with obesity makesadipokines, including leptin, an attractive instigator of atherosclerosis.In a large prospective study, leptin was independently associatedwith an increased risk of coronary artery disease (41). However,the question whether leptin directly causes atherosclerosisin obese individuals is still unresolved. In in vitro or animalstudies, different atherogenic properties, including increasedoxidative stress, impairment of vasorelaxation, and increasedthrombosis, 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 immunityassociated with congenital leptin deficiency (44, 45). In addition,leptin replacement is a very promising therapeutic approachfor the management of the complications of lipodystrophy (46).In contrast, leptin treatment for the reversal of typical obesityand obesity related metabolic disorders has not proven to besuccessful (47). Obese individuals, for unknown reasons, becomeresistant to the satiety and weight-reducing effect of leptin.A recent study reported a synergistic effect for weight losswith leptin and amylin coadministration in diet-induced obeserats by restoring hypothalamic sensitivity to leptin (48). Ifconfirmed in clinical research studies, the restoration of leptinsensitivity might change the neurohormonal approaches to obesitypharmacotherapy.
Adiponectin
Adiponectin is a 30-kDa protein secreted from adipocytes (9),and its circulating levels are decreased in obesity inducedinsulin resistance (49, 50). Paradoxically, in rare cases ofsevere insulin resistance with proximal defect in insulin action,elevated levels of adiponectin have been reported (51). Micelacking 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 posttranslationalmodifications, including hydroxylation and glycosylation (55),and some of these modifications are necessary for its bioactivity(56). Circulating adiponectin is found in several differentisoforms, including trimer, low-molecular weight (-hexamers),and high-molecular weight (HMW) (18mers) forms (57, 58). Differentadiponectin oligomers hold distinct biological functions. Mostinsulin-sensitizing effects of adiponectin have been linkedto the HMW isoform, whereas the central effects of adiponectinhave been contributed to hexamer and trimer isoforms (55).
The distribution of adiponectin oligomers in the circulationis primarily controlled at the level of secretion from adipocytes.Molecular chaperones in the endoplasmic reticulum (ER), includingER protein of 44 kDa and ER oxidoreductase 1-L, play an importantrole 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 isinversely associated with the risk for diabetes independentof total adiponectin (61), and the HMW oligomer is responsiblefor the association of adiponectin with traits of metabolicsyndrome (62, 63).
Adiponectin inserts its effects through two transmembrane receptors(AdipoR1 and AdipoR2) that are ubiquitously expressed. AdipoR1is predominantly expressed in skeletal muscle with a preferencefor binding to globular adiponectin, whereas AdipoR2 is mostabundant in the liver with a preference for binding to full-lengthadiponectin (64). Adiponectin improves insulin sensitivity byincreasing energy expenditure and fatty acid oxidation throughactivation of AMP-activated protein kinase (AMPK), and by increasingthe expression of PPAR target genes such as CD36, acyl-coenzymeoxidase, and uncoupling protein 2 (60). Alternatively, adiponectinmay lead to an improved metabolic profile by the expansion ofsc adipose tissue with decreased levels of macrophage infiltration(23), similar to the actions of PPAR agonists. Thiazolidinediones(TZDs) are known to increase circulating levels of adiponectin,mostly the HMW form, by 2- to 3-fold (65, 66, 67), and improveinsulin resistance by diversion of fat from ectopic sites tosc adipose tissue (68). Interestingly, insulin-sensitizing effectsof TZDs are significantly diminished in the absence of adiponectin(54), suggesting an important role of adiponectin in reductionof lipotoxicity and inflammation associated with obesity.
Adiponectin has also had vasculoprotective effects mediatedvia an increase in endothelial nitric oxide production, or modulationof expression of adhesion molecules and scavenger receptors(60, 69).
In addition to peripheral actions, it has been suggested thatadiponectin has central effects in the regulation of energyhomeostasis (70). Adiponectin was present in cerebrospinal fluidlargely in the form of trimer and hexamer, in contrast to thedistribution of adiponectin in serum, which consists of highermolecular masses (71). It has been proposed that adiponectinincreases food intake by enhancing hypothalamic AMPK activityin fasting conditions (72).
Resistin
Resistin is a 12-kDa peptide that was originally discoveredas a result of examining differential gene expression of mouseadipose tissue after TZD treatment (73). Resistin is part ofa gene family of "Resistin-like molecules," and is increasedalong with PPAR during the differentiation of 3T3-L1 adipocytes(74). Resistin was decreased by TZD treatment of mice and wasincreased in insulin-resistant mice. Furthermore, treatmentwith antiresistin antibody improved insulin sensitivity andglucose transport in mice and mouse adipocytes, respectively(73). Additional studies in mice suggest that an important siteof action of resistin is on hepatic glucose production (75).Although these data in mice are exciting, the role of resistinin human insulin resistance is less clear. Resistin is expressedby adipocytes in mice but is expressed by the macrophages ofhumans (76). A number of studies have examined plasma resistinlevels or adipose resistin expression, and have found variableassociations with insulin resistance (77, 78, 79, 80). A recentlarge study involving the Framingham offspring cohort founda significant relationship between insulin resistance and resistin,however, this relationship was considerably weaker than therelationship with adiponectin, and was lost after adjustmentfor 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 adipokinethat likely plays a role in the development of insulin resistance;however, it appears to be quantitatively less important in humansthan other adipokines.
Retinol binding protein 4 (RBP4)
One interesting rodent model of insulin resistance is the adiposetissue-specific glucose transporter 4 (Glut4) knockout mouse(83), in which the defect in adipose tissue glucose transportyielded peripheral insulin resistance, apparently due to a circulatingfactor. RBP4 was identified as a highly expressed circulatingadipokine in this model and caused insulin resistance when overexpressedor injected into mice (84). Since that time, a number of humanstudies have been performed that examined RBP4 protein levelsin circulation and/or its gene expression in adipose tissuein subjects with varying degrees of obesity, insulin resistance,or type 2 diabetes. Some papers demonstrated a positive associationbetween RBP4 and insulin resistance or obesity (84, 85, 86,87, 88, 89, 90, 91, 92, 93, 94), sometimes with strikingly strongcorrelations, whereas others have not found such a relationship(95, 96, 97, 98, 99, 100). One study found no relationship betweenRBP4 and insulin sensitivity in older subjects, but a weak relationshipin young subjects, suggesting an age-related difference (101).Another study found no significant relationship between RBP4and insulin sensitivity, but RBP4 was associated with adiposetissue macrophage markers, suggesting a possible role of RBP4in inflammation (95). The response to TZDs has been examinedin fewer studies, and again the response was inconsistent. IfRBP4 is associated with insulin resistance, one would expecta decrease after treatment with rosi- or pioglitazone. Sucha response was found in Glut4 knockout mice (84) and in somehuman studies (90, 91, 102, 103). However, in other studies,human subjects treated with TZDs demonstrated no change or anincrease in RBP4 mRNA (94, 95), and the addition of pioglitazoneto adipocytes in vitro also resulted in increased RBP4 mRNA(95). RBP4 circulates bound to transthyretin, which decreasesRBP4 renal clearance, and transthyretin plasma levels were increased4-fold in ob/ob mice compared with lean mice or diet-inducedobese mice (104). Although RBP4-transthyretin binding may beimportant physiologically, this area needs further study. Thus,the data are currently conflicting on the role of RBP4 in insulinresistance and the metabolic complications of obesity. Becauseof the association with Glut4, RBP4 is presumed to play a rolein fuel sensing in the adipocyte, but in other respects, a possiblemechanism for causing insulin resistance is not clear.
Visfatin
Visfatin is expressed in many cells and tissues, and was previouslyidentified as a protein involved in B-cell maturation (pre-Bcolony enhancing factor) (105, 106). More recently, visfatinwas described to be a highly expressed protein with insulin-likefunctions, and was predominantly found in visceral adipose tissue,from which the name visfatin was derived (107). Injection ofvisfatin in mice lowered blood glucose, and mice with a mutationin visfatin had higher glucose levels.
Although these initial studies were promising, subsequent studiesof visfatin in humans have generally not confirmed the initialstudy, which was, in part, retracted (108). A subsequent studydid not confirm the insulin mimetic action of visfatin but insteaddemonstrated that visfatin has nicotinamide adenine dinucleotide(NAD) biosynthetic activity, which is essential for B-cell function(109). In human studies, a positive correlation between visceraladipose tissue visfatin gene expression and BMI was noted, alongwith a negative correlation between BMI and sc fat visfatin(110, 111), suggesting that visfatin regulation in these differentdepots is different, and adipose depot ratios are highly dependenton the obesity of the subjects. No difference in visfatin expressionbetween fat depots of humans was noted (110, 111), and visfatinwas expressed predominantly by nonmacrophage cells in the adiposetissue stroma (111). Plasma visfatin was positively associatedwith BMI in one study (110), but not in others (111, 112). Variableresults were obtained regarding the relationship between visfatinand diabetes or insulin resistance (111, 112, 113, 114), andvisfatin was not responsive to PPAR agonists and was not correlatedwith macrophage markers (111). Therefore, there are a numberof inconsistencies among the different studies of visfatin,and the role of this adipokine in obesity and insulin resistanceis not clear.
Obesity is characterized by increased fat mass frequently associatedwith chronic inflammation. Yet, the mechanisms triggering theinflammatory pathway in obesity are to be determined, and discussedpreviously. An increased number of macrophages resident in humanadipose tissue has been reported in obesity (14) that may contributeto the inflammatory process by secreting pro-inflammatory cytokinessuch as TNF, IL6, and MCP-1. In addition to increased infiltrationof macrophages in adipose tissue, obesity is associated withchanges in the phenotype of macrophages from alternatively activatedtoward a more classical and pro-inflammatory cell (115) as thesource of pro-inflammatory mediators. Inactivation of the nuclearfactor-B pathway, which induces inflammatory mediators, hasled to the protection against insulin resistance (116).
TNF
Of the pro-inflammatory cytokines, TNF is well described todisturb insulin signaling. Mice lacking TNF or TNF receptorsare resistant to the development of obesity induced insulinresistance (117, 118). In adipose tissue, TNF is mostly secretedby macrophages in the stromal vascular fraction. CirculatingTNF and adipose tissue TNF gene expression are increased ininsulin resistance (119), and acute infusion of TNF inhibitedinsulin-induced glucose uptake in healthy subjects (120). Neutralizationof TNF in rodents has improved insulin resistance (7), whereasattempts to neutralize TNF in humans to improve insulin resistancehave generally not been successful (121), although more recentstudies have shown slight improvement in insulin resistancewith TNF inhibition (122, 123, 124). Limited effects of TNFblockade on insulin resistance could be explained by the paracrineactions of TNF. Further investigations on the mechanisms involvedin TNF overexpression associated with obesity and molecularsignals underlying TNF-induced metabolic dysregulation are warranted.
IL-6
IL-6 is another cytokine similar to TNF that is overexpressedin the adipose tissue of obesity (119). The role of IL-6 inmetabolic changes associated with obesity is unclear. Thereare some reports of IL-6 causing impaired insulin signalingin the liver and adipocytes by inducing ubiquitin-mediated degradationof insulin receptor substrate through suppressor of cytokinesignaling (SOCS) 1 and 3 (125, 126). However, effects of IL-6on insulin sensitivity in skeletal muscle is controversial (126).Exercise that is associated with increased insulin action inskeletal muscle increases circulating IL-6 levels dramatically(127), suggesting possible antiinflammatory roles for IL-6 inskeletal muscle. The data on the increased onset of obesityand diabetes in mice lacking IL-6 are conflicting (128, 129).
MCPs
As discussed previously, infiltration of macrophages into adiposetissue is an important contributor of the increased inflammatoryprocess in obesity. Adipocytes secrete various chemoattractantsthat draw monocytes from circulation into adipose tissue. MCP-1,also known as chemokine (C-C motif) ligand 2 (CCL-2), is onethe chemoattractants that plays an important role in the recruitmentof macrophages. Moreover, obesity is associated with increasedplasma levels of MCP-1 and overexpression in adipose tissue(14, 130). Mice lacking MCP-1 receptor (CCR-2) have decreasedadipose tissue macrophage infiltration and improved metabolicfunction (12). Similarly, it has been demonstrated that micelacking 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 mightplay a role in the recruitment of macrophages into the adiposetissue, such as macrophage inflammatory protein-1 (11) or osteopontin(133, 134). Osteopontin is an extracellular matrix protein thatpromotes monocyte chemotaxis, and the lack of osteopontin inmice caused improved insulin sensitivity and decreased macrophageinfiltration 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 ofobesity, and is expressed in the stromal fraction of adiposetissue, including endothelial cells (135, 136, 137, 138, 139).PAI-1 inhibits both tissue-type plasminogen activator and urokinase-typeplasminogen activator through its serine protease inhibitorfunction, and this inhibition of fibrinolysis may contributeto a pro-thrombotic state (140).
PAI-1 gene expression is controlled by TGF-β, which combineswith phosphorylated SMAD and binds to the PAI-1 promoter (141).Another important link in PAI-1 activation was the recent demonstrationof TSP1 expression in adipocytes (142). TSP1 is expressed bymany tissues, and has many different activities, including inhibitionof angiogenesis, cell proliferation, and wound healing (143,144). TSP1 is a major activator of TGF-β (145), and PAI-1activation by TSP1 has been described (146) (Fig. 1).
FIG. 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 expression is inhibited by PPAR agonists, which may explain some of the beneficial effects of these drugs.
A recent study demonstrated TSP1 expression largely by adipocytescompared with the stromal vascular fraction of adipose tissue,suggesting that TSP1 is a true adipokine (142). TSP1 expressionwas increased in obese, insulin-resistant subjects, was associatedwith plasma PAI-1 levels, and was positively associated withadipose tissue macrophage markers. In addition, TSP1 expressionwas decreased by treatment of subjects or adipocytes with thePPAR agonist, pioglitazone. TSP1 has chemotactic properties(143) that provide a link between TSP1 and macrophage-mediatedadipocyte inflammation. In addition, adipocyte-macrophage cocultureexperiments demonstrated TSP1 gene and protein up-regulationby both cells, suggesting a feed-forward inflammatory mechanismin adipose tissue (142). TSP1 may be an important componentof inflammation and coagulation in the metabolic complicationsof obesity.
Adipose tissue was once recognized simply as an inert storageorgan, but now is appreciated increasingly as an endocrine organand part of an innate immune system. Factors secreted from adiposetissue contribute considerably to the regulation of metabolismand inflammatory responses. The adipose tissue of insulin-sensitivehumans secretes adiponectin abundantly, which is associatedwith a favorable metabolic condition. However, with adiposity,adiponectin secretion decreases significantly, and multipleadipocyte-derived factors induce activation and infiltrationof macrophage into adipose tissue. Activated macrophages secretecytokines that can contribute to more macrophage infiltration.As shown in Fig. 2, inflamed fat in obesity secretes an arrayof proteins implicated in the impairment of insulin signaling.In addition, in a hypothetical model, inflamed fat releasesmore free fatty acids that contribute to fat accumulation inectopic sites, including liver and muscle. Increased lipid contentin liver and muscle has been associated with insulin resistance.PPAR ligands, such as TZDs, improve insulin resistance throughmultiple potential mechanisms. PPAR agonists enhance adipogenesis,increase adiponectin, and exert antiinflammatory effects onmacrophages resident in adipose tissue. Future studies are neededto focus on the factors initiating the inflammatory processin adipose tissue and the regulation of adipocyte secretoryproducts.
FIG. 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 of lipids in muscle is high, and there is little ectopic fat in the muscle and liver. With obesity and insulin resistance, adipose tissue contains many macrophages, and the tissue secretes high levels of many adipokines, and low levels of adiponectin. This adipose tissue may be limited in its lipid storage capacity, and this feature, along with the pro-inflammatory state, promotes ectopic lipid accumulation. The adipose tissue in some subjects can be characterized as expandable, meaning the tissue can accommodate more lipid. This may result from treatment with a TZD. Such adipose tissue may be less inflamed, and because this adipose tissue can accumulate more lipid, there is less ectopic fat.
Footnotes
This work was supported by Merit Review Grant from the VeteransAdministration (to N.R.), and DK71277 and DK080327 from theNational Institutes of Health (to P.A.K.).
Disclosure Statement: P.A.K. and N.R. have received honorariafor speaking from Takeda Pharmaceuticals.
Abbreviations: AMPK, AMP-activated protein kinase; BMI, bodymass index; ER, endoplasmic reticulum; Glut4, glucose transporter4; HMM, high-molecular mass; MCP, monocyte chemoattractant protein;PAI-1, plasminogen activator inhibitor 1; PPAR, peroxisome proliferatoractivated receptor; RBP4, retinol binding protein 4; STAT3,signal transducer and activator of transcription-3; TSP, thrombospondin;TZD, thiazolidinedione.
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, 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-
B pathway, which induces inflammatory mediators, has led to the protection against insulin resistance (116). 
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. 
, 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. PPAR
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