Adipokines%20%20Therapeutic%20Targets%20for%20Metabolic%20Syndrome

Current Drug Targets, 2005, 6, 525-5295251389-4501/05 $50.00+.00© 2005 Bentham Science Publishers Ltd.Adipokines: Therapeutic Targets for Metabolic SyndromeKunihisa Kobayashi * and Toyoshi InoguchiDepartment of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1Maidashi, Higashi-ku, Fukuoka 812-8582, JapanAbstract: For a long time it has been known that obesity (adiposity) is linked to insulin resistance. Recently, manyinvestigators have reported that adipocytes secrete a variety of bioactive molecules, termed adipokines (adipocytokines),including TNF α, IL-6, leptin, adiponectin, resistin and so on. These adipokines play pivotal roles in energy homeostasisby affecting insulin sensitivity, glucose and lipid metabolisms, food intake, the coagulation system and inflammation. Thisreview provides a summary of these adipose tissue-secreting biomolecules and discusses their feasibilities as drug targetsfor the treatment of metabolic syndrome.INTRODUCTIONAtherosclerotic cardiovascular disease is still the leadingcause of death in industrialized countries. The clustering ofrisk factors for atherosclerosis, known as metabolic synd-rome, has been showing a steady but remarkable increaseover recent years. Obesity is not only an independent riskfactor for atherosclerosis, but also contributes to theincreased incidences of other risk factors, such as diabetes,dyslipidemia, hypertension and hypercoagulability. Adiposetissues, especially the visceral adipose tissues, have beenwidely recognized as endocrine and paracrine organs thatsecrete many bioactive molecules, termed adipokines(adipocytokines), which influence metabolic processes suchas insulin resistance, glucose and lipid metabolisms, foodintake and inflammation. These adipokines, including TNF α,IL-6, resistin, leptin, adiponectin, visfatin and so on, are nowconsidered to represent one of the strongest molecular linksbetween obesity and atherosclerosis. This review summar-izes recent reports on adipokines and discusses their feasi-bilities as possible therapeutic targets.TUMOR NECROSIS FACTOR α (TNF α)TNF α [1] was recognized as the first cytokine that couldinduce insulin resistance. TNF α is upregulated in whiteadipose tissue (WAT) in obese animal models, includingob/ob mice, db/db mice and fa/fa rats [2]. In humans, theTNF α mRNA and protein levels in adipose tissues arepositively correlated with the percent body fat. In vitrostudies revealed that TNF α induces impaired insulinsignaling through serine phosphorylation of insulin receptorsubstrate 1 (IRS-1) [3,4], and also down-regulates the insulinreceptor, IRS-1 and glucose transporter-4 [5]. Insulin resis-tance in fa/fa rats was ameliorated by an anti-TNF α antibody[2]. TNF α-depleted mice showed significantly improvedinsulin sensitivity in both diet-induced obesity and ob/obobesity model mice [6]. The effects of thiazolidinediones on *Address correspondence to this author at the Department of Medicine andBioregulatory Science, Graduate School of Medical Sciences, KyushuUniversity, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Tel:+81-92-642-5284; Fax: +81-92-642-5287;E-mail: nihisak@intmed3.med.kyushu-u.ac.jpTNF α expression are controversial, since troglitazone suppressed TNF α mRNA expression in adipose tissues in Zucker rats in vivo [7], while rosiglitazone (BRL 49653) had no effect on TNF α secretion by human adipocytes in vitro [8]. Two groups investigating the involvement of free fatty acids in TNF α secretion reported that β-adrenergic agonist-mediated lipolysis stimulated TNF α secretion in humans [9],and that aP2-deficient mice did not express TNF α in their adipose tissues [10]. Taken together, thiazolidinediones and beta-adrenergic stimulation may be potential ways to regulate this adipokine.PLASMINOGEN ACTIVATOR INHIBITOR-1 (PAI-1)PAI-1 [11] inhibits plasminogen activator, thereby lead-ing to impaired fibrinolytic activity and thrombus formation.Hence, it may play an important role in the increased incidence of cardiovascular diseases in obese individuals.Visceral fat deposition causes enhancement of both PAI-1mRNA expression in adipose tissue and its plasma protein level. Stromal cells and preadipocytes, which are more abundant in visceral fat than in subcutaneous fat, produce PAI-1 protein in human adipose tissue [12]. PAI-1 also has roles in other biological processes, such as cell migration and angiogenesis. However, the effect of PAI-1 on adipocyte growth has been controversial. Although PAI-1 overexpres-sion in WAT reduced the WAT mass in mice on a high-fat diet [13], PAI-1 gene disruption in ob/ob mice reduced adiposity [14]. Further investigations are necessary to deter-mine the feasibility of PAI-1 as a therapeutic target.INTERLEUKIN-6 (IL-6)Adipose tissues represent a major source of IL-6, since they secrete 10-30% of the circulating IL-6 [15]. The plasma levels of IL-6 are elevated in obesity and insulin resistance [16]. Furthermore, the adipose tissue IL-6 content is nega-tively correlated with insulin-mediated glucose uptake [17].Recently, it was reported that IL-6 impairs insulin signaling through the induction of suppressor of cytokine signaling-3,which subsequently inhibits insulin-induced insulin receptor autophosphorylation and IRS-1 binding to the insulin recep-tor [18]. Interestingly, intracerebroventricular IL-6 treatment decreased body fat in rats [19], while IL-6-depleted mice526 Current Drug Targets, 2005, Vol. 6, No. 4Kobayashi and Inoguchishowed mature-onset obesity with impaired glucose tolerance [20].RESISTINResistin was identified as a thiazolidinedione-down-regulated gene by subtractive screening of mRNAs from 3T3-L1 adipocytes [21]. The same gene was independently discovered as FIZZ3 [22] and ADSF [23]. Its expression is upregulated in diet-induced obesity as well as in genetic models of obesity and insulin resistance, and it impaired insulin action and glucose tolerance in normal mice [21]. Although resistin antagonized the insulin effect on glucose uptake in differentiated 3T3-L1 adipocytes [21] and skeletal muscle L6 cells [24,25], suggesting that it is a direct link between obesity and diabetes: a few studies have reported the opposite observations, namely that resistin expression was significantly decreased in the WAT of several different obesity models compared with their lean counterparts [26], and its expression level was increased by thiazolidinediones [26,27]. Another group reported that resistin enhanced glucose production in the liver by reducing insulin-mediated suppression of gluconeogenesis and increasing glycogeno-lysis in vivo, suggesting that it blunts insulin action in the liver [28-30]. Recently, Banerjee et al. [31] reported the phenotype of mice lacking resistin. In these mice, the fasting blood glucose level was lower than that in wild-type controls due to reduced hepatic glucose production, suggesting a physiological role for resistin in maintaining glucose homeo-stasis in mice. In addition, they reported that phosphorylation of AMP-activated protein kinase was abrogated in the liver of these mice, implying that this kinase may be an important regulator of resistin signaling as well as the signaling of other adipokines, such as adiponectin [32] and leptin [32,33].To understand the role of resistin in lipoprotein metabol-ism in mice, we induced resistin protein overexpression in C57BL/6 mice using an adenovirus containing mouse resistin cDNA (AdmRes) [34]. Although the fasting plasma glucose levels did not differ between AdmRes-treated mice and controls, the basal insulin concentration was signifi-cantly elevated in AdmRes-treated mice. In addition, the glucose-lowering effect of insulin was impaired in AdmRes-treated mice, as evaluated by insulin tolerance tests. Further-more, the total cholesterol and triglyceride concentrations were significantly higher, while the high-density lipoprotein cholesterol level was significantly lower. Lipoprotein analysis revealed that low-density lipoprotein was markedly increased in AdmRes-treated mice compared to controls.In addition, in vivo Triton WR-1339 studies showed evi-dence of enhanced very low-density lipoprotein production in AdmRes-treated mice. The expressions of genes involved in lipoprotein metabolism, such as the LDL receptor and ApoA-I in the liver, were decreased. These results suggest that resistin overexpression induces dyslipidemia in mice, which is also commonly seen in insulin resistance, partially through enhanced secretion of lipoproteins. These observa-tions regarding the properties of resistin in rodents may not be readily applicable to humans. Although some studies have reported that resistin has a positive link with obesity and insulin resistance in humans [35-37], its role in human insulin resistance remains controversial, partly because human resistin is abundantly expressed in circulating mononuclear cells that are involved in the inflammation process [38]. Verma et al. [39] revealed that resistin protein promotes human saphenous vein endothelial cell activation by promoting endothelin-1 release, and also up regulates VCAM-1 and MCP-1 and down regulates TRAF-3, an inhi-bitor of the CD40 ligand. These data suggest that human resistin protein may induce arteriosclerosis through an inflammatory process, rather than through insulin resistance. Further investigations are required to determine the physiol-ogical role of resistin in humans.LEPTINLeptin was originally cloned as the protein product of the ob gene, which is mutated in obese ob/ob mice [40]. Administration of recombinant leptin to ob/ob mice induced reductions in their food intake, adipose tissue mass and body weight [41], through modulation of orexigenic and anorexi-genic peptides in the hypothalamus. The leptin receptor is expressed ubiquitously and belongs to the cytokine class I receptor family. db/db mice, which have a leptin receptor mutation [42], show severe insulin resistance and diabetic obese properties. The leptin receptor has several isoforms [43] (Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd and Ob-Re) derived by alternative splicing. Ob-Rb is a long form with an intra-cellular signaling domain [44]. Leptin reduces fat deposits in non-adipose tissues, thereby ameliorating insulin resistance [45,46]. This insulin sensitizing effect is mediated by activation of AMP-activated protein kinase, which induces acetyl-CoA carboxylase inhibition, thereby leading to fatty acid oxidation [33]. However, increased plasma levels of leptin in obese individuals imply the existence of leptin resistance. In fact, leptin administration has little effect on normal obese subjects. Patients with lipodystrophy, includ-ing lipoatrophic diabetes, have little adipose tissue and a trace amount of plasma leptin, and also show hypertrigly-ceridemia, fatty liver and severe insulin resistance. Leptin administration ameliorates these conditions. ADIPONECTINAdiponectin, also referred to as 30 kDa adipocyte complement-related protein (acrp30) [47], gelatin-binding protein-28 (GBP28) [48] and Adipo Q [49], is an adipose-specific secretory factor that is encoded by the gene, adipose most abundant gene transcript-1 (apM1) [50]. Its average plasma level in humans is very high [51,52] at 5-10 µg/ml and it exists in a variety of structures from trimers to multi-mers.Adiponectin was reported to have possible anti-athero-genic properties in early epidemiological studies, since its plasma concentrations were found to be decreased in obese individuals [51], and in patients with type 2 diabetes mellitus [52], essential hypertension [53] and coronary heart disease [54,55]. In vivo studies revealed increased neointimal thickening after arterial injury in adiponectin-deficient mice [56,57], which was attenuated by adenovirus-mediated supplementation with adiponectin [56]. Furthermore, an adenovirus-induced increase in plasma adiponectin reduced atherosclerosis in apolipoprotein E-deficient mice, and adiponectin was co-localized with lipid-laden macrophagesAdipokines Current Drug Targets, 2005, Vol. 6, No. 4 527at atherosclerotic lesions [58]. Several studies have reported possible underlying mechanisms for the anti-atherogenic effects of adiponectin, namely that adiponectin suppresses adhesion molecule expressions in endothelial cells [54], cholesteryl ester accumulation in macrophages [59] and smooth muscle cell proliferation [60].Okamoto et al. [61] reported that adiponectin adhered rapidly to the subendothelial space of injured vascular walls and suggested that it had vascular protective role. We also showed that adiponectin inhibited the binding of apolipo-protein B100-containing lipoproteins to vascular proteogly-cans as an initial event in atherogenesis. According to the response to retention hypothesis of atherogenesis, two processes considered to be central to the development of atherosclerosis are the retention of lipoproteins by binding to proteoglycans in the arterial wall, and subsequent modifica-tion of these retained lipoproteins by processes such as oxidation [62]. It is possible that inhibition of LDL binding to biglycan could suppress the initiation and development of atherosclerosis. Our results showed that both types of adiponectin bound to biglycan, and that full-length adiponec-tin was associated with LDL. These results suggest that adiponectin competitively inhibits LDL binding to biglycan through masking the binding sites of apolipoprotein B and/or through weakening the electric charge difference between apolipoprotein B and biglycan.In 2001, two groups [63,64] independently reported that adiponectin increased insulin sensitivity through decreasing the triglyceride contents in muscle and liver and decreasing the hepatic glucose output. Adiponectin-deficient mice [65] showed moderate insulin resistance on a normal diet and severe insulin resistance on a high-fat/high-sucrose diet.Moreover, adenoviral supplementation of adiponectin reversed insulin resistance in knockout and wild-type mice. This effect of adiponectin on insulin action is mediated by an increase in fatty acid oxidation in skeletal muscle [32] and a decrease in glucose production in the liver, partly through the activation of AMP-activated protein kinase [32,66]. Two receptors for adiponectin were recently reported as AdipoR1 and AdipoR2, and these are predominantly expressed in the muscle and liver, respectively. For application of adiponectin to clinical use, the adiponectin signaling pathway needs to be clarified.VISFATINVisfatin [67] is the most recently reported adipokine and is more highly expressed in visceral fat tissues than in subcutaneous fat tissues. The same protein had already been identified as pre-B cell colony-enhancing factor. Visfatin shows insulin-mimetic effects in vitro and in vivo. Further-more, adenovirus-mediated high expression of visfatin reduced the plasma levels of glucose and insulin in mice, while heterozygous knockout mice showed higher plasma glucose levels and impaired glucose tolerance. Visfatin induced tyrosine phosphorylation of insulin signaling-related molecules and showed an additive effect with insulin. Interestingly, competitive inhibition assays revealed that unlabeled insulin displaced radiolabeled insulin binding to the insulin receptor, whereas unlabeled visfatin did not, and vice versa. These results indicate that visfatin binds to the insulin receptor and activates insulin signaling in a different manner from insulin. Visfatin may represent a promising new target for further elucidating insulin action and develop-ing new therapies for diabetes mellitus.Figure528 Current Drug Targets, 2005, Vol. 6, No. 4Kobayashi and InoguchiCONCLUDING REMARKSWhite adipose tissues are considered to be one of the largest endocrine organs in the body. 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