The mechanisms linking adiposopathy to type 2 diabetes

Abstract

Obesity is defined as excessive accumulation of body fat in proportion to body size. When obesity occurs, the functions of adipose tissue may be deregulated, which is termed as adiposopathy. Adiposopathy is an independent risk factor for many diseases, including diabetes and cardiovascular diseases. In overweight or obese subjects with adiposopathy, hyperlipidemia exerts lipotoxicity in pancreatic islet and liver and induces pancreatic β cell dysfunction and liver insulin resistance, which are the decisive factors causing type 2 diabetes. Moreover, adipokines have been shown to play important roles in the regulation of glucose homeostasis. When adiposopathy occurs, abnormal changes in the serum adipokine profile correlate with the development and progression of pancreatic β cell dysfunction and insulin resistance in peripheral tissue. The current paper briefly discusses the latest findings regarding the effects of adiposopathy-related lipotoxicity and cytokine toxicity on the development of type 2 diabetes.

Keywords

obesity / adiposopathy / lipotoxicity / adipokines / diabetes

References

[1] Yang W, Lu J, Weng J, Jia W, Ji L, Xiao J, Shan Z, Liu J, Tian H, Ji Q, Zhu D, Ge J, Lin L, Chen L, Guo X, Zhao Z, Li Q, Zhou Z, Shan G, He J; the China National Diabetes and Metabolic Disorders Study Group. Prevalence of diabetes among men and women in China. N Engl J Med2010; 362(12): 1090–1101

[2] Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care1994; 17(9): 961–969

[3] Bays H, Blonde L, Rosenson R. Adiposopathy: how do diet, exercise and weight loss drug therapies improve metabolic disease in overweight patients? Expert Rev Cardiovasc Ther2006; 4(6): 871–895

[4] Bays HE. Adiposopathy, diabetes mellitus, and primary prevention of atherosclerotic coronary artery disease: treating “sick fat” through improving fat function with antidiabetes therapies. Am J Cardiol2012; 110(9 Suppl): 4B–12B

[5] Dixon JB, O’Brien PE, Playfair J, Chapman L, Schachter LM, Skinner S, Proietto J, Bailey M, Anderson M. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA2008; 299(3): 316–323

[6] Wilkinson P, French R, Kane R, Lachowycz K, Stephenson J, Grundy C, Jacklin P, Kingori P, Stevens M, Wellings K. Teenage conceptions, abortions, and births in England, 1994-2003, and the national teenage pregnancy strategy. Lancet2006; 368(9550): 1879–1886

[7] Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance: unravelling the mechanism. Lancet2010; 375(9733): 2267–2277

[8] Boden G. Obesity, insulin resistance and free fatty acids. Curr Opin Endocrinol Diabetes Obes2011; 18(2): 139–143

[9] Lois K, Kumar S. Obesity and diabetes. Endocrinol Nutr2009; 56(Suppl 4): 38–42

[10] Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature1994; 372(6505): 425–432

[11] Zhuang XF, Zhao MM, Weng CL, Sun NL. Adipocytokines: a bridge connecting obesity and insulin resistance. Med Hypotheses2009; 73(6): 981–985

[12] Matsuzawa Y. Adiponectin: a key player in obesity related disorders. Curr Pharm Des2010; 16(17): 1896–1901

[13] Miyazaki Y, DeFronzo RA. Rosiglitazone and pioglitazone similarly improve insulin sensitivity and secretion, glucose tolerance and adipocytokines in type 2 diabetic patients. Diabetes Obes Metab2008; 10(12): 1204–1211

[14] Kashyap S, Belfort R, Gastaldelli A, Pratipanawatr T, Berria R, Pratipanawatr W, Bajaj M, Mandarino L, DeFronzo R, Cusi K. A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes2003; 52(10): 2461–2474

[15] Alquier T, Peyot ML, Latour MG, Kebede M, Sorensen CM, Gesta S, Ronald Kahn C, Smith RD, Jetton TL, Metz TO, Prentki M, Poitout V. Deletion of GPR40 impairs glucose-induced insulin secretion in vivo in mice without affecting intracellular fuel metabolism in islets. Diabetes2009; 58(11): 2607–2615

[16] Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci USA2001; 98(13): 7522–7527

[17] Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest1996; 97(12): 2859–2865

[18] Storgaard H, Jensen CB, Vaag AA, Vølund A, Madsbad S. Insulin secretion after short- and long-term low-grade free fatty acid infusion in men with increased risk of developing type 2 diabetes. Metabolism2003; 52(7): 885–894

[19] Boden G, Homko C, Mozzoli M, Showe LC, Nichols C, Cheung P. Thiazolidinediones upregulate fatty acid uptake and oxidation in adipose tissue of diabetic patients. Diabetes2005; 54(3): 880–885

[20] Shimabukuro M, Zhou YT, Lee Y, Unger RH. Troglitazone lowers islet fat and restores β cell function of Zucker diabetic fatty rats. J Biol Chem1998; 273(6): 3547–3550

[21] Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron R, Kim JK, Cushman SW, Cooney GJ, Atcheson B, White MF, Kraegen EW, Shulman GI. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem2002; 277(52): 50230–50236

[22] Turban S, Hajduch E. Protein kinase C isoforms: mediators of reactive lipid metabolites in the development of insulin resistance. FEBS Lett2011; 585(2): 269–274

[23] Nowotny B, Zahiragic L, Krog D, Nowotny PJ, Herder C, Carstensen M, Yoshimura T, Szendroedi J, Phielix E, Schadewaldt P, Schloot NC, Shulman GI, Roden M. Mechanisms underlying the onset of oral lipid-induced skeletal muscle insulin resistance in humans. Diabetes2013; 62(7): 2240–2248

[24] Boden G, She P, Mozzoli M, Cheung P, Gumireddy K, Reddy P, Xiang X, Luo Z, Ruderman N. Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-kB pathway in rat liver. Diabetes2005; 54(12): 3458–3465

[25] Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-kB. Nat Med2005; 11(2): 183–190

[26] Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M. IKK-β links inflammation to obesity-induced insulin resistance. Nat Med2005; 11(2): 191–198

[27] Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature2002; 420(6913): 333–336

[28] Lebrun P, Van Obberghen E. SOCS proteins causing trouble in insulin action. Acta Physiol (Oxf)2008; 192(1): 29–36

[29] Reyna SM, Ghosh S, Tantiwong P, Meka CS, Eagan P, Jenkinson CP, Cersosimo E, Defronzo RA, Coletta DK, Sriwijitkamol A, Musi N. Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. Diabetes2008; 57(10): 2595–2602

[30] Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest2004; 114(12): 1752–1761

[31] Jiao P, Ma J, Feng B, Zhang H, Diehl JA, Chin YE, Yan W, Xu H. FFA-induced adipocyte inflammation and insulin resistance: involvement of ER stress and IKKβ pathways. Obesity (Silver Spring)2011; 19(3): 483–491

[32] Nakamura S, Takamura T, Matsuzawa-Nagata N, Takayama H, Misu H, Noda H, Nabemoto S, Kurita S, Ota T, Ando H, Miyamoto K, Kaneko S. Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria. J Biol Chem2009; 284(22): 14809–14818

[33] Yang C, Aye CC, Li X, Diaz Ramos A, Zorzano A, Mora S. Mitochondrial dysfunction in insulin resistance: differential contributions of chronic insulin and saturated fatty acid exposure in muscle cells. Biosci Rep2012; 32(5): 465–478

[34] Barazzoni R, Zanetti M, Gortan Cappellari G, Semolic A, Boschelle M, Codarin E, Pirulli A, Cattin L, Guarnieri G. Fatty acids acutely enhance insulin-induced oxidative stress and cause insulin resistance by increasing mitochondrial reactive oxygen species (ROS) generation and nuclear factor-κB inhibitor (IκB)-nuclear factor-κB (NFκB) activation in rat muscle, in the absence of mitochondrial dysfunction. Diabetologia2012; 55(3): 773–782

[35] Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R, Fukusumi S, Ogi K, Hosoya M, Tanaka Y, Uejima H, Tanaka H, Maruyama M, Satoh R, Okubo S, Kizawa H, Komatsu H, Matsumura F, Noguchi Y, Shinohara T, Hinuma S, Fujisawa Y, Fujino M. Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40. Nature2003; 422(6928): 173–176

[36] Steneberg P, Rubins N, Bartoov-Shifman R, Walker MD, Edlund H. The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse. Cell Metab2005; 1(4): 245–258

[37] Shimabukuro M, Zhou YT, Levi M, Unger RH. Fatty acid-induced β cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci USA1998; 95(5): 2498–2502

[38] Obeid LM, Linardic CM, Karolak LA, Hannun YA. Programmed cell death induced by ceramide. Science1993; 259(5102): 1769–1771

[39] Laybutt DR, Preston AM, Akerfeldt MC, Kench JG, Busch AK, Biankin AV, Biden TJ. Endoplasmic reticulum stress contributes to β cell apoptosis in type 2 diabetes. Diabetologia2007; 50(4): 752–763

[40] Huang CJ, Lin CY, Haataja L, Gurlo T, Butler AE, Rizza RA, Butler PC. High expression rates of human islet amyloid polypeptide induce endoplasmic reticulum stress mediated β-cell apoptosis, a characteristic of humans with type 2 but not type 1 diabetes. Diabetes2007; 56(8): 2016–2027

[41] Kharroubi I, Ladrière L, Cardozo AK, Dogusan Z, Cnop M, Eizirik DL. Free fatty acids and cytokines induce pancreatic β-cell apoptosis by different mechanisms: role of nuclear factor-kB and endoplasmic reticulum stress. Endocrinology2004; 145(11): 5087–5096

[42] Yuan H, Zhang X, Huang X, Lu Y, Tang W, Man Y, Wang S, Xi J, Li J. NADPH oxidase 2-derived reactive oxygen species mediate FFAs-induced dysfunction and apoptosis of β-cells via JNK, p38 MAPK and p53 pathways. PLoS ONE2010; 5(12): e15726

[43] Martinez SC, Tanabe K, Cras-Méneur C, Abumrad NA, Bernal-Mizrachi E, Permutt MA. Inhibition of Foxo1 protects pancreatic islet β-cells against fatty acid and endoplasmic reticulum stress-induced apoptosis. Diabetes2008; 57(4): 846–859

[44] Misaki Y, Miyauchi R, Mochizuki K, Takabe S, Shimada M, Ichikawa Y, Goda T. Plasma interleukin-1β concentrations are closely associated with fasting blood glucose levels in healthy and preclinical middle-aged nonoverweight and overweight Japanese men. Metabolism2010; 59(10): 1465–1471

[45] Wang C, Guan Y, Yang J. Cytokines in the progression of pancreatic β-cell dysfunction. Int J Endocrinol2010; 2010: 515136

[46] Giannoukakis N, Rudert WA, Ghivizzani SC, Gambotto A, Ricordi C, Trucco M, Robbins PD. Adenoviral gene transfer of the interleukin-1 receptor antagonist protein to human islets prevents IL-1β-induced β-cell impairment and activation of islet cell apoptosis in vitro. Diabetes1999; 48(9): 1730–1736

[47] Papaccio G, Graziano A, D’Aquino R, Valiante S, Naro F. A biphasic role of nuclear transcription factor (NF)-kB in the islet β-cell apoptosis induced by interleukin (IL)-1β. J Cell Physiol2005; 204(1): 124–130

[48] Osborn O, Brownell SE, Sanchez-Alavez M, Salomon D, Gram H, Bartfai T. Treatment with an interleukin 1 β antibody improves glycemic control in diet-induced obesity. Cytokine2008; 44(1): 141–148

[49] Larsen CM, Faulenbach M, Vaag A, Vølund A, Ehses JA, Seifert B, Mandrup-Poulsen T, Donath MY. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med2007; 356(15): 1517–1526

[50] Kieffer TJ, Heller RS, Habener JF. Leptin receptors expressed on pancreatic β-cells. Biochem Biophys Res Commun1996; 224(2): 522–527

[51] Harvey J, McKenna F, Herson PS, Spanswick D, Ashford ML. Leptin activates ATP-sensitive potassium channels in the rat insulin-secreting cell line, CRI-G1. J Physiol1997; 504(Pt 3): 527–535

[52] Zhao AZ, Bornfeldt KE, Beavo JA. Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. J Clin Invest1998; 102(5): 869–873

[53] Laubner K, Kieffer TJ, Lam NT, Niu X, Jakob F, Seufert J. Inhibition of preproinsulin gene expression by leptin induction of suppressor of cytokine signaling 3 in pancreatic β-cells. Diabetes2005; 54(12): 3410–3417

[54] Morioka T, Asilmaz E, Hu J, Dishinger JF, Kurpad AJ, Elias CF, Li H, Elmquist JK, Kennedy RT, Kulkarni RN. Disruption of leptin receptor expression in the pancreas directly affects β cell growth and function in mice. J Clin Invest2007; 117(10): 2860–2868

[55] Huypens PR. Leptin and adiponectin regulate compensatory β cell growth in accordance to overweight. Med Hypotheses2007; 68(5): 1134–1137

[56] Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol2006; 7(2): 85–96

[57] Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes. Nature2001; 409(6818): 307–312

[58] Minn AH, Patterson NB, Pack S, Hoffmann SC, Gavrilova O, Vinson C, Harlan DM, Shalev A. Resistin is expressed in pancreatic islets. Biochem Biophys Res Commun2003; 310(2): 641–645

[59] Brown JE, Onyango DJ, Dunmore SJ. Resistin down-regulates insulin receptor expression, and modulates cell viability in rodent pancreatic β-cells. FEBS Lett2007; 581(17): 3273–3276

[60] Gao CL, Zhao DY, Qiu J, Zhang CM, Ji CB, Chen XH, Liu F, Guo XR. Resistin induces rat insulinoma cell RINm5F apoptosis. Mol Biol Rep 2009; 36(7): 1703–1708

[61] Nakata M, Okada T, Ozawa K, Yada T. Resistin induces insulin resistance in pancreatic islets to impair glucose-induced insulin release. Biochem Biophys Res Commun2007; 353(4): 1046–1051

[62] Yang J, Zhang D, Li J, Zhang X, Fan F, Guan Y. Role of PPARg in renoprotection in type 2 diabetes: molecular mechanisms and therapeutic potential. Clin Sci (Lond)2009; 116(1): 17–26

[63] Kriketos AD, Gan SK, Poynten AM, Furler SM, Chisholm DJ, Campbell LV. Exercise increases adiponectin levels and insulin sensitivity in humans. Diabetes Care2004; 27(2): 629–630

[64] Winzer C, Wagner O, Festa A, Schneider B, Roden M, Bancher-Todesca D, Pacini G, Funahashi T, Kautzky-Willer A. Plasma adiponectin, insulin sensitivity, and subclinical inflammation in women with prior gestational diabetes mellitus. Diabetes Care2004; 27(7): 1721–1727

[65] Kharroubi I, Rasschaert J, Eizirik DL, Cnop M. Expression of adiponectin receptors in pancreatic β cells. Biochem Biophys Res Commun2003; 312(4): 1118–1122

[66] Liu Y, Michael MD, Kash S, Bensch WR, Monia BP, Murray SF, Otto KA, Syed SK, Bhanot S, Sloop KW, Sullivan JM, Reifel-Miller A. Deficiency of adiponectin receptor 2 reduces diet-induced insulin resistance but promotes type 2 diabetes. Endocrinology2007; 148(2): 683–692

[67] Jung TW, Lee MW, Lee YJ, Kim SM, Lee KT, Whang WK, Cheon HJ, Jeong YT, Chung KW, Cho JM, Kim H, Jung TW. Regulation of adiponectin receptor 2 expression via PPAR-α in NIT-1 cells. Endocr J2009; 56(3): 377–382

[68] Rakatzi I, Mueller H, Ritzeler O, Tennagels N, Eckel J. Adiponectin counteracts cytokine- and fatty acid-induced apoptosis in the pancreatic β-cell line INS-1. Diabetologia2004; 47(2): 249–258

[69] Lin P, Chen L, Li D, Liu J, Yang N, Sun Y, Xu Y, Fu Y, Hou X. Adiponectin reduces glucotoxicity-induced apoptosis of INS-1 rat insulin-secreting cells on a microfluidic chip. Tohoku J Exp Med2009; 217(1): 59–65

[70] Brown JE, Conner AC, Digby JE, Ward KL, Ramanjaneya M, Randeva HS, Dunmore SJ. Regulation of β-cell viability and gene expression by distinct agonist fragments of adiponectin. Peptides2010; 31(5): 944–949

[71] Staiger K, Stefan N, Staiger H, Brendel MD, Brandhorst D, Bretzel RG, Machicao F, Kellerer M, Stumvoll M, Fritsche A, Häring HU. Adiponectin is functionally active in human islets but does not affect insulin secretory function or β-cell lipoapoptosis. J Clin Endocrinol Metab2005; 90(12): 6707–6713

[72] Revollo JR, Körner A, Mills KF, Satoh A, Wang T, Garten A, Dasgupta B, Sasaki Y, Wolberger C, Townsend RR, Milbrandt J, Kiess W, Imai S. Nampt/PBEF/Visfatin regulates insulin secretion in β cells as a systemic NAD biosynthetic enzyme. Cell Metab2007; 6(5): 363–375

[73] Brown JE, Onyango DJ, Ramanjaneya M, Conner AC, Patel ST, Dunmore SJ, Randeva HS. Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic β-cells. J Mol Endocrinol2010; 44(3): 171–178

[74] Spinnler R, Gorski T, Stolz K, Schuster S, Garten A, Beck-Sickinger AG, Engelse MA, de Koning EJ, Körner A, Kiess W, Maedler K. The adipocytokine Nampt and its product NMN have no effect on β-cell survival but potentiate glucose stimulated insulin secretion. PLoS ONE2013; 8(1): e54106

[75] Cheng Q, Dong W, Qian L, Wu J, Peng Y. Visfatin inhibits apoptosis of pancreatic β-cell line, MIN6, via the mitogen-activated protein kinase/phosphoinositide 3-kinase pathway. J Mol Endocrinol2011; 47(1): 13–21

[76] Takahashi M, Okimura Y, Iguchi G, Nishizawa H, Yamamoto M, Suda K, Kitazawa R, Fujimoto W, Takahashi K, Zolotaryov FN, Hong KS, Kiyonari H, Abe T, Kaji H, Kitazawa S, Kasuga M, Chihara K, Takahashi Y. Chemerin regulates β-cell function in mice. Sci Rep2011;1:123

[77] Borst SE, Conover CF. High-fat diet induces increased tissue expression of TNF-α. Life Sci2005; 77(17): 2156–2165

[78] Aygun AD, Gungor S, Ustundag B, Gurgoze MK, Sen Y. Proinflammatory cytokines and leptin are increased in serum of prepubertal obese children. Mediators Inflamm2005; 2005(3): 180–183

[79] Ehses JA, Lacraz G, Giroix MH, Schmidlin F, Coulaud J, Kassis N, Irminger JC, Kergoat M, Portha B, Homo-Delarche F, Donath MY. IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat. Proc Natl Acad Sci USA2009; 106(33): 13998–14003

[80] Nov O, Kohl A, Lewis EC, Bashan N, Dvir I, Ben-Shlomo S, Fishman S, Wueest S, Konrad D, Rudich A. Interleukin-1β may mediate insulin resistance in liver-derived cells in response to adipocyte inflammation. Endocrinology2010; 151(9): 4247–4256

[81] Boisclair YR, Wang J, Shi J, Hurst KR, Ooi GT. Role of the suppressor of cytokine signaling-3 in mediating the inhibitory effects of interleukin-1β on the growth hormone-dependent transcription of the acid-labile subunit gene in liver cells. J Biol Chem2000; 275(6): 3841–3847

[82] Ling PR, Bistrian BR, Mendez B, Istfan NW. Effects of systemic infusions of endotoxin, tumor necrosis factor, and interleukin-1 on glucose metabolism in the rat: relationship to endogenous glucose production and peripheral tissue glucose uptake. Metabolism1994; 43(3): 279–284

[83] Szanto I, Kahn CR. Selective interaction between leptin and insulin signaling pathways in a hepatic cell line. Proc Natl Acad Sci USA2000; 97(5): 2355–2360

[84] Himeno K, Seike M, Fukuchi S, Masaki T, Kakuma T, Sakata T, Yoshimatsu H. Heterozygosity for leptin receptor (fa) accelerates hepatic triglyceride accumulation without hyperphagia in Zucker rats. Obes Res Clin Pract2009; 3(1): 29–34

[85] Leonardo ES, Bassoli BK, Cassolla P, Borba-Murad GR, Bazotte RB, De Souza HM. Leptin inhibits glycogen catabolism but does not modify acutely the suppressive effect of insulin on glucose production and glycogenolysis stimulated by 8-Br-cAMP in rat liver perfused in situ. Pharmacol Res2009; 59(3): 176–182

[86] Huang W, Dedousis N, Bhatt BA, O’Doherty RM. Impaired activation of phosphatidylinositol 3-kinase by leptin is a novel mechanism of hepatic leptin resistance in diet-induced obesity. J Biol Chem2004; 279(21): 21695–21700

[87] Benomar Y, Wetzler S, Larue-Achagiotis C, Djiane J, Tomé D, Taouis M. In vivo leptin infusion impairs insulin and leptin signalling in liver and hypothalamus. Mol Cell Endocrinol2005; 242(1–2): 59–66

[88] Vilà L, Roglans N, Alegret M, Sánchez RM, Vázquez-Carrera M, Laguna JC. Suppressor of cytokine signaling-3 (SOCS-3) and a deficit of serine/threonine (Ser/Thr) phosphoproteins involved in leptin transduction mediate the effect of fructose on rat liver lipid metabolism. Hepatology2008; 48(5): 1506–1516

[89] Dekker MJ, Su Q, Baker C, Rutledge AC, Adeli K. Fructose: a highly lipogenic nutrient implicated in insulin resistance, hepatic steatosis, and the metabolic syndrome. Am J Physiol Endocrinol Metab2010; 299(5): E685–E694

[90] Hennige AM, Stefan N, Kapp K, Lehmann R, Weigert C, Beck A, Moeschel K, Mushack J, Schleicher E, Häring HU. Leptin down-regulates insulin action through phosphorylation of serine-318 in insulin receptor substrate 1. FASEB J2006; 20(8): 1206–1208

[91] Eguchi M, Gillis LC, Liu Y, Lyakho vs ky N, Du M, McDermott JC, Sweeney G. Regulation of SOCS-3 expression by leptin and its co-localization with insulin receptor in rat skeletal muscle cells. Mol Cell Endocrinol2007; 267(1–2): 38–45

[92] Liu F, Yang T, Wang B, Zhang M, Gu N, Qiu J, Fan HQ, Zhang CM, Fei L, Pan XQ, Guo M, Chen RH, Guo XR. Resistin induces insulin resistance, but does not affect glucose output in rat-derived hepatocytes. Acta Pharmacol Sin2008; 29(1): 98–104

[93] Yang Y, Xiao M, Mao Y, Li H, Zhao S, Gu Y, Wang R, Yu J, Zhang X, Irwin DM, Niu G, Tan H. Resistin and insulin resistance in hepatocytes: resistin disturbs glycogen metabolism at the protein level. Biomed Pharmacother2009; 63(5): 366–374

[94] Luo Z, Zhang Y, Li F, He J, Ding H, Yan L, Cheng H. Resistin induces insulin resistance by both AMPK-dependent and AMPK-independent mechanisms in HepG2 cells. Endocrine2009; 36(1): 60–69

[95] Steppan CM, Wang J, Whiteman EL, Birnbaum MJ, Lazar MA. Activation of SOCS-3 by resistin. Mol Cell Biol2005; 25(4): 1569–1575

[96] Sheng CH, Di J, Jin Y, Zhang YC, Wu M, Sun Y, Zhang GZ. Resistin is expressed in human hepatocytes and induces insulin resistance. Endocrine2008; 33(2): 135–143

[97] Szalowska E, Elferink MG, Hoek A, Groothuis GM, Vonk RJ. Resistin is more abundant in liver than adipose tissue and is not up-regulated by lipopolysaccharide. J Clin Endocrinol Metab2009; 94(8): 3051–3057

[98] Li FP, Li ZZ, Zhang M, Yan L, Fu ZZ. Effects of resistin on skeletal glucose metabolism. Front Med China2010; 4(3): 329–335

[99] Palanivel R, Maida A, Liu Y, Sweeney G. Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin. Diabetologia2006; 49(1): 183–190

[100] Kaser S, Moschen A, Cayon A, Kaser A, Crespo J, Pons-Romero F, Ebenbichler CF, Patsch JR, Tilg H. Adiponectin and its receptors in non-alcoholic steatohepatitis. Gut2005; 54(1): 117–121

[101] Nawrocki AR, Rajala MW, Tomas E, Pajvani UB, Saha AK, Trumbauer ME, Pang Z, Chen AS, Ruderman NB, Chen H, Rossetti L, Scherer PE. Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor g agonists. J Biol Chem2006; 281(5): 2654–2660

[102] Nan MH, Park JS, Myung CS. Construction of adiponectin-encoding plasmid DNA and gene therapy of non-obese type 2 diabetes mellitus. J Drug Target2010; 18(1): 67–77

[103] Shen Z, Liang X, Rogers CQ, Rideout D, You M. Involvement of adiponectin-SIRT1-AMPK signaling in the protective action of rosiglitazone against alcoholic fatty liver in mice. Am J Physiol Gastrointest Liver Physiol 2010; 298(3): G364–G374

[104] Asano T, Watanabe K, Kubota N, Gunji T, Omata M, Kadowaki T, Ohnishi S. Adiponectin knockout mice on high fat diet develop fibrosing steatohepatitis. J Gastroenterol Hepatol2009; 24(10): 1669–1676

[105] Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med2002; 8(11): 1288–1295

[106] Lin E, Phillips LS, Ziegler TR, Schmotzer B, Wu K, Gu LH, Khaitan L, Lynch SA, Torres WE, Smith CD, Gletsu-Miller N. Increases in adiponectin predict improved liver, but not peripheral, insulin sensitivity in severely obese women during weight loss. Diabetes2007; 56(3): 735–742

[107] Sun X, Han R, Wang Z, Chen Y. Regulation of adiponectin receptors in hepatocytes by the peroxisome proliferator-activated receptor-g agonist rosiglitazone. Diabetologia2006; 49(6): 1303–1310

[108] Sattar AA, Sattar R. Insulin-regulated expression of adiponectin receptors in muscle and fat cells. Cell Biol Int2012; 36(12): 1293–1297

[109] Choudhary S, Sinha S, Zhao Y, Banerjee S, Sathyanarayana P, Shahani S, Sherman V, Tilton RG, Bajaj M. NF-κB-inducing kinase (NIK) mediates skeletal muscle insulin resistance: blockade by adiponectin. Endocrinology2011; 152(10): 3622–3627

[110] Vu V, Bui P, Eguchi M, Xu A, Sweeney G. Globular adiponectin induces LKB1/AMPK-dependent glucose uptake via actin cytoskeleton remodeling. J Mol Endocrinol2013; 51(1): 155–165

[111] Gaddipati R, Sasikala M, Padaki N, Mukherjee RM, Sekaran A, Jayaraj-Mansard M, Rabella P, Rao-Guduru V, Reddy-Duvvuru N. Visceral adipose tissue visfatin in nonalcoholic fatty liver disease. Ann Hepatol2010; 9(3): 266–270

[112] Skop V, Kontrová K, Zídek V, Pravenec M, Kazdová L, Mikulík K, Sajdok J, Zídková J. Autocrine effects of visfatin on hepatocyte sensitivity to insulin action. Physiol Res2010; 59(4): 615–618

[113] Sun Q, Li L, Li R, Yang M, Liu H, Nowicki MJ, Zong H, Xu J, Yang G. Overexpression of visfatin/PBEF/Nampt alters whole-body insulin sensitivity and lipid profile in rats. Ann Med2009; 41(4): 311–320

[114] Romanowska A, Lebensztejn DM. Evaluation of serum visfatin concentrations in children with nonalcoholic fatty liver disease. Pol Merkuriusz Lek2010; 28: 459–461 (in Polish)

[115] Costford SR, Bajpeyi S, Pasarica M, Albarado DC, Thomas SC, Xie H, Church TS, Jubrias SA, Conley KE, Smith SR. Skeletal muscle NAMPT is induced by exercise in humans. Am J Physiol Endocrinol Metab2010; 298(1): E117–E126

[116] Sell H, Divoux A, Poitou C, Basdevant A, Bouillot JL, Bedossa P, Tordjman J, Eckel J, Clément K. Chemerin correlates with markers for fatty liver in morbidly obese patients and strongly decreases after weight loss induced by bariatric surgery. J Clin Endocrinol Metab2010; 95(6): 2892–2896

[117] Ernst MC, Issa M, Goralski KB, Sinal CJ. Chemerin exacerbates glucose intolerance in mouse models of obesity and diabetes. Endocrinology2010; 151(5): 1998–2007

[118] Ouwens DM, Bekaert M, Lapauw B, Van Nieuwenhove Y, Lehr S, Hartwig S, Calders P, Kaufman JM, Sell H, Eckel J, Ruige JB. Chemerin as biomarker for insulin sensitivity in males without typical characteristics of metabolic syndrome. Arch Physiol Biochem2012; 118(3): 135–138

[119] Becker M, Rabe K, Lebherz C, Zugwurst J, Göke B, Parhofer KG, Lehrke M, Broedl UC. Expression of human chemerin induces insulin resistance in the skeletal muscle but does not affect weight, lipid levels, and atherosclerosis in LDL receptor knockout mice on high-fat diet. Diabetes2010; 59(11): 2898–2903

[120] Lau CH, Muniandy S. Novel adiponectin-resistin (AR) and insulin resistance (IRAR) indexes are useful integrated diagnostic biomarkers for insulin resistance, type 2 diabetes and metabolic syndrome: a case control study. Cardiovasc Diabetol2011; 10(1): 8

[121] Pagano C, Dorigo A, Nisoli E, Tonello C, Calcagno A, Tami V, Granzotto M, Carruba MO, Federspil G, Vettor R. Role of insulin and free fatty acids in the regulation of ob gene expression and plasma leptin in normal rats. Obes Res2004; 12(12): 2062– 2069

[122] Haugen F, Zahid N, Dalen KT, Hollung K, Nebb HI, Drevon CA. Resistin expression in 3T3-L1 adipocytes is reduced by arachidonic acid. J Lipid Res2005; 46(1): 143–153

[123] Gu N, Guo XR, Ni YH, Liu F, Fei L, Chen RH. Overexpression of resistin affect 3T3-L1 adipocyte lipid metabolism. Chin J Med Genet ( Zhonghua Yi Xue Yi Chuan Xue Za Zhi)2007; 24(3): 251–255 (in Chinese)

[124] Kukla M, Mazur W, Buldak RJ, Zwirska-Korczala K. Potential role of leptin, adiponectin and three novel adipokines—visfatin, chemerin and vaspin—in chronic hepatitis. Mol Med2011; 17(11–12): 1397–1410

[125] López-Bermejo A, Chico-Julià B, Fernàndez-Balsells M, Recasens M, Esteve E, Casamitjana R, Ricart W, Fernández-Real JM. Serum visfatin increases with progressive β-cell deterioration. Diabetes2006; 55(10): 2871–2875

[126] Choi YJ, Choi SE, Ha ES, Kang Y, Han SJ, Kim DJ, Lee KW, Kim HJ. Involvement of visfatin in palmitate-induced upregulation of inflammatory cytokines in hepatocytes. Metabolism2011; 60(12): 1781–1789

[127] Kover K, Tong PY, Watkins D, Clements M, Stehno-Bittel L, Novikova L, Bittel D, Kibiryeva N, Stuhlsatz J, Yan Y, Ye SQ, Moore WV. Expression and regulation of nampt in human islets. PLoS ONE2013; 8(3): e58767

[128] Song SH, Fukui K, Nakajima K, Kozakai T, Sasaki S, Roh SG, Katoh K. Cloning, expression analysis, and regulatory mechanisms of bovine chemerin and chemerin receptor. Domest Anim Endocrinol2010; 39(2): 97–105

Acknowledgements

This study was supported by grants from the Ministry of Science and Technology (Grant Nos. 2012CB517504, 2013CB945202, and 2010CB517504), the Natural Science Foundation of China (Grant Nos. 81170791, 81030003, 81100398, and 81270943). This study was also supported by a grant from Beijing Natural Science Foundation (Grant No. 7122107).

We appreciate the editing by T. Guan.

Compliance with ethics guidelines

Jichun Yang, Jihong Kang, and Youfei Guan declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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2014 Higher Education Press and Springer-Verlag Berlin Heidelberg