Exp Clin Endocrinol Diabetes 2005; 113(2): 67-79
DOI: 10.1055/s-2004-830555
Review

J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Adipocytokines: Fat-Derived Humoral Mediators of Metabolic Homeostasis

H. Staiger1 , H.-U. Häring1
  • 1Department of Endocrinology, Metabolism, and Pathobiochemistry, Medical Clinic Tübingen, Eberhard-Karls-University, Tübingen, Germany
Further Information

Publication History

Received: June 21, 2004 First decision: July 21, 2004

Accepted: September 9, 2004

Publication Date:
17 March 2005 (online)

Abstract

The metabolic syndrome currently reaches epidemic proportions in the Western industrialized world. Its hallmarks obesity, type 2 diabetes mellitus, and atherosclerosis are closely associated, and we are just beginning to understand the reasons for this relationship: adipose tissue-derived proteohormones (adipocytokines), under normal weight conditions, guarantee homeostasis of glucose and lipid metabolism, but their dysregulated production in the obese state promotes insulin resistance, inflammation, as well as atherosclerotic events. This review will focus on the current understanding of the adipocytokines' molecular role in metabolism and metabolic disease.

References

  • 1 Ahren B, Havel P J. Leptin inhibits insulin secretion induced by cellular cAMP in a pancreatic B cell line (INS-1 cells).  Am J Physiol. 1999;  277 R959-R966
  • 2 Arita Y, Kihara S, Ouchi N, Maeda K, Kuriyama H, Okamoto Y, Kumada M, Hotta K, Nishida M, Takahashi M, Nakamura T, Shimomura I, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell.  Circulation. 2002;  105 2893-2898
  • 3 Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.  Biochem Biophys Res Commun. 1999;  257 79-83
  • 4 Ashworth C J, Hoggard N, Thomas L, Mercer J G, Wallace J M, Lea R G. Placental leptin.  Rev Reprod. 2000;  5 18-24
  • 5 Banks W A, Kastin A J, Huang W, Jaspan J P, Maness L M. Leptin enters the brain by a saturable system independent of insulin.  Peptides. 1996;  17 305-311
  • 6 Bastard J P, Maachi M, Van Nhieu J T, Jardel C, Bruckert E, Grimaldi A, Robert J J, Capeau J, Hainque B. Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro.  J Clin Endocrinol Metab. 2002;  87 2084-2089
  • 7 Bays H, Mandarino L, DeFronzo R A. Mechanisms of endocrine disease. Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach.  J Clin Endocrinol Metab. 2004;  89 463-478
  • 8 Berg A H, Combs T P, Du X, Brownlee M, Scherer P E. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action.  Nat Med. 2001;  7 947-952
  • 9 Berti L, Gammeltoft S. Leptin stimulates glucose uptake in C2C12 muscle cells by activation of ERK2.  Mol Cell Endocrinol. 1999;  157 121-130
  • 10 Berti L, Kellerer M, Capp E, Häring H U. Leptin stimulates glucose transport and glycogen synthesis in C2C12 myotubes: evidence for a PI3-kinase mediated effect.  Diabetologia. 1997;  40 606-609
  • 11 Blum W F, Englaro P, Hanitsch S, Juul A, Hertel N T, Muller J, Skakkebaek N E, Heiman M L, Birkett M, Attanasio A M, Kiess W, Rascher W. Plasma leptin levels in healthy children and adolescents: dependence on body mass index, fat mass, gender, pubertal stage, and testosterone.  J Clin Endocrinol Metab. 1997;  82 2904-2910
  • 12 Bjorbaek C, Elmquist J K, Franz J D, Shoelson S E, Flier J S. Identification of SOCS-3 as a potential mediator of central leptin resistance.  Mol Cell. 1998;  1 619-625
  • 13 Boden G, Chen X, Mozzoli M, Ryan I. Effect of fasting on serum leptin in normal human subjects.  J Clin Endocrinol Metab. 1996;  81 3419-3423
  • 14 Bogan J S, Lodish H F. Two compartments for insulin-stimulated exocytosis in 3T3-L1 adipocytes defined by endogenous ACRP30 and GLUT4.  J Cell Biol. 1999;  146 609-620
  • 15 Bouloumie A, Drexler H C, Lafontan M, Busse R. Leptin, the product of Ob gene, promotes angiogenesis.  Circ Res. 1998;  83 1059-1066
  • 16 Brakenhielm E, Veitonmaki N, Cao R, Kihara S, Matsuzawa Y, Zhivotovsky B, Funahashi T, Cao Y. Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis.  Proc Natl Acad Sci USA. 2004;  101 2476-2481
  • 17 Bruun J M, Lihn A S, Verdich C, Pedersen S B, Toubro S, Astrup A, Richelsen B. Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans.  Am J Physiol Endocrinol Metab. 2003;  285 E527-E533
  • 18 Campfield L A, Smith F J, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks.  Science. 1995;  269 546-549
  • 19 Caro J F, Sinha M K, Kolaczynski J W, Zhang P L, Considine R V. Leptin: the tale of an obesity gene.  Diabetes. 1996;  45 1455-1461
  • 20 Casabiell X, Pineiro V, Tome M A, Peino R, Dieguez C, Casanueva F F. Presence of leptin in colostrum and/or breast milk from lactating mothers: a potential role in the regulation of neonatal food intake.  J Clin Endocrinol Metab. 1997;  82 4270-4273
  • 21 Chehab F F, Lim M E, Lu R H. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin.  Nat Genet. 1996;  12 318-320
  • 22 Chen H, Montagnani M, Funahashi T, Shimomura I, Quon M J. Adiponectin stimulates production of nitric oxide in vascular endothelial cells.  J Biol Chem. 2003;  278 45021-45026
  • 23 Cioffi J A, Shafer A W, Zupancic T J, Smith-Gbur J, Mikhail A, Platika D, Snodgrass H R. Novel B219/OB receptor isoforms: possible role of leptin in hematopoiesis and reproduction.  Nat Med. 1996;  2 585-589
  • 24 Cnop M, Havel P J, Utzschneider K M, Carr D B, Sinha M K, Boyko E J, Retzlaff B M, Knopp R H, Brunzell J D, Kahn S E. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex.  Diabetologia. 2003;  46 459-469
  • 25 Coleman D L. Effects of parabiosis of obese with diabetes and normal mice.  Diabetologia. 1973;  9 294-298
  • 26 Coleman D L, Hummel K P. Effects of parabiosis of normal with genetically diabetic mice.  Am J Physiol. 1969;  217 1298-1304
  • 27 Combs T P, Berg A H, Obici S, Scherer P E, Rossetti L. Endogenous glucose production is inhibited by the adipose-derived protein acrp30.  J Clin Invest. 2001;  108 1875-1881
  • 28 Combs T P, Wagner J A, Berger J, Doebber T, Wang W J, Zhang B B, Tanen M, Berg A H, O'Rahilly S, Savage D B, Chatterjee K, Weiss S, Larson P J, Gottesdiener K M, Gertz B J, Charron M J, Scherer P E, Moller D E. Induction of adipocyte complement-related protein of 30 kilodaltons by PPARγ agonists: a potential mechanism of insulin sensitization.  Endocrinology. 2002;  143 998-1007
  • 29 Considine R V, Sinha M K, Heiman M L, Kriauciunas A, Stephens T W, Nyce M R, Ohannesian J P, Marco C C, McKee L J, Bauer T L, Caro J F. Serum immunoreactive leptin concentrations in normal weight and obese humans.  N Engl J Med. 1996;  334 292-295
  • 30 Couillard C, Mauriège P, Imbeault P, Prud'homme D, Nadeau A, Tremblay A, Bouchard C, Després J P. Hyperleptinemia is more closely associated with adipose cell hypertrophy than with adipose tissue hyperplasia.  Int J Obes. 2000;  24 782-788
  • 31 Dal Maso L, Augustin L SA, Karalis A, Talamini R, Franceschi S, Trichopoulos D, Mantzoros C S, La Vecchia C. Circulating adiponectin and endometrial cancer risk.  J Clin Endocrinol Metab. 2004;  89 1160-1163
  • 32 Delporte M L, Funahashi T, Takahashi M, Matsuzawa Y, Brichard S M. Pre- and post-translational negative effect of β-adrenoceptor agonists on adiponectin secretion: in vitro and in vivo studies.  Biochem J. 2002;  367 677-685
  • 33 De Vos P, Saladin R, Auwerx J, Staels B. Induction of ob gene expression by corticosteroids is accompanied by body weight loss and reduced food intake.  J Biol Chem. 1995;  270 15958-15961
  • 34 Donahoo W T, Jensen D R, Yost T J, Eckel R H. Isoproterenol and somatostatin decrease plasma leptin in humans; a novel mechanism regulating leptin secretion.  J Clin Endocrinol Metab. 1997;  82 4139-4143
  • 35 Ducy P, Amling M, Takeda S, Priemel M, Schilling A F, Beil F T, Shen J, Vinson C, Rueger J M, Karsenty G. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass.  Cell. 2000;  100 195-207
  • 36 Elmquist J K, Elias C F, Saper C B. From lesions to leptin: hypothalamic control of food intake and body weight.  Neuron. 1999;  22 221-232
  • 37 Emilsson V, Liu Y, Cawthorne M A, Morton N M, Devenport M. Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion.  Diabetes. 1997;  46 313-316
  • 38 Engeli S, Feldpausch M, Gorzelniak K, Hartwig F, Heintze U, Janke J, Mohlig M, Pfeiffer A F, Luft F C, Sharma A M. Association between adiponectin and mediators of inflammation in obese women.  Diabetes. 2003;  52 942-947
  • 39 Farooqi I S, Jebb S A, Langmack G, Lawrence E, Cheetham C H, Prentice A M, Hughes I A, McCamish M A, O'Rahilly S. Effects of recombinant leptin therapy in a child with congenital leptin deficiency.  N Engl J Med. 1999;  341 879-884
  • 40 Fasshauer M, Klein J, Lossner U, Paschke R. Interleukin (IL)-6 mRNA expression is stimulated by insulin, isoproterenol, tumour necrosis factor alpha, growth hormone, and IL-6 in 3T3-L1 adipocytes.  Horm Metab Res. 2003 a;  35 147-152
  • 41 Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes.  Biochem Biophys Res Commun. 2002;  290 1084-1089
  • 42 Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Adiponectin gene expression is inhibited by β-adrenergic stimulation via protein kinase A in 3T3-L1 adipocytes.  FEBS Lett. 2001;  507 142-146
  • 43 Fasshauer M, Kralisch S, Klier M, Lossner U, Blüher M, Klein J, Paschke R. Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-L1 adipocytes.  Biochem Biophys Res Commun. 2003 b;  301 1045-1050
  • 44 Febbraio M A, Pedersen B K. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles.  FASEB J. 2002;  16 1335-1347
  • 45 Fernández-Real J M, Broch M, Vendrell J, Gutiérrez C, Casamitjana R, Pugeat M, Richart C, Ricart W. Interleukin-6 gene polymorphism and insulin sensitivity.  Diabetes. 2000 a;  49 517-520
  • 46 Fernández-Real J M, Broch M, Vendrell J, Richart C, Ricart W. Interleukin-6 gene polymorphism and lipid abnormalities in healthy subjects.  J Clin Endocrinol Metab. 2000 b;  85 1334-1339
  • 223 Fernández-Real J M, Castro A, Vazquez G, Casamitjana R, López-Bermejo A, Penarroja G, Ricart W. Adiponectin is associated with vascular function independent of insulin sensitivity.  Diabetes Care. 2004;  27 739-745
  • 47 Flier J S, Maratos-Flier E. Obesity and the hypothalamus: novel peptides for new pathways.  Cell. 1998;  92 437-440
  • 48 Fried S K, Bunkin D A, Greenberg A S. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid.  J Clin Endocrinol Metab. 1998;  83 847-850
  • 49 Fruebis J, Tsao T S, Javorschi S, Ebbets-Reed D, Erickson M RS, Yen F T, Bihain B E, Lodish H F. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidaton in muscle and causes weight loss in mice.  Proc Natl Acad Sci USA. 2001;  98 2005-2010
  • 50 Frühbeck G. Pivotal role of nitric oxide in the control of blood pressure following leptin administration.  Diabetes. 1999;  48 903-908
  • 51 Frühbeck G, Aguado M, Martínez J A. In vitro lipolytic effect of leptin on mouse adipocytes: evidence for a possible autocrine/paracrine role of leptin.  Biochem Biophys Res Commun. 1997;  240 590-594
  • 52 Fu M, Gong D W, Damcott C, Sabra M, Yang R, Pollin T I, Tanner K, Ott S, McLenithan J C, Fried S, O'Connell J R, Mitchell B D, Shuldiner A R. Systematic analysis of omentin 1 and omentin 2 on 1 q23 as candidate genes for type 2 diabetes in the old order Amish.  Diabetes. 2004;  53 (Suppl 2) A59
  • 53 Fukui Y, Motojima K. Expression of resistin in the adipose tissue is modulated by various factors including peroxisome proliferator-activated receptor alpha.  Diabetes Obes Metab. 2002;  4 342-345
  • 54 Fumeron F, Aubert R, Siddiq A, Betoulle D, Péan F, Hadjadj S, Tichet J, Wilpart E, Chesnier M C, Balkau B, Froguel P, Marre M. Adiponectin gene polymorphisms and adiponectin levels are independently associated with the development of hyperglycemia during a 3-year period. The Epidemiologic Data on the Insulin Resistance Syndrome (DESIR) prospective study.  Diabetes. 2004;  53 1150-1157
  • 55 Gabriely I, Ma X H, Yang X M, Atzmon G, Rajala M W, Berg A H, Scherer P E, Rossetti L, Barzilai N. Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process?.  Diabetes. 2002;  51 2951-2958
  • 56 Gainsford T, Willson T A, Metcalf D, Handman E, Mcfarlane C, Ng A, Nicola N A, Alexander W S, Hilton D J. Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells.  Proc Natl Acad Sci USA. 1996;  93 14564-14568
  • 57 Giacobino J P. Role of β3-adrenoceptor in the control of leptin expression.  Horm Metab Res. 1996;  28 633-637
  • 58 Greenberg A S, Nordan R P, McIntosh J, Calvo J P, Scow R O, Jablons D. Interleukin 6 reduces lipoprotein lipase activity in adipose tissue of mice in vivo and in 3T3-L1 adipocytes: a possible role for interleukin 6 in cancer cachexia.  Cancer Res. 1992;  52 4113-4116
  • 59 Halaas J L, Boozer C, Blair-West J, Fidahusein N, Denton D A, Friedman J M. Physiological response to long-term peripheral and central leptin infusion in lean and obese mice.  Proc Natl Acad Sci USA. 1998;  94 8878-8883
  • 60 Halaas J L, Gajiwala K S, Maffei M, Cohen S L, Chait B T, Robinowitz D, Lollone R L, Burley S K, Friedman J M. Weight-reducing effects of the plasma protein encoded by the obese gene.  Science. 1995;  269 543-546
  • 61 Halleux C M, Takahashi M, Delporte M L, Detry R, Funahashi T, Matsuzawa Y, Brichard S M. Secretion of adiponectin and regulation of apM1 gene expression in human visceral adipose tissue.  Biochem Biophys Res Commun. 2001;  288 1102-1107
  • 62 Hamilton B S, Paglia D, Kwan A YM, Dietel M. Increased obese mRNA expression in omental fat cells from massively obese humans.  Nat Med. 1995;  1 953-956
  • 63 Hara K, Boutin P, Mori Y, Tobe K, Dina C, Yasuda K, Yamauchi T, Otabe S, Okada T, Eto K, Kadowaki H, Hagura R, Akanuma Y, Yazaki Y, Nagai R, Taniyama M, Matsubara K, Yoda M, Nakano Y, Kimura S, Tomita M, Ito C, Froguel P, Kadowaki T. Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population.  Diabetes. 2002;  51 536-540
  • 64 Hattori Y, Suzuki M, Hattori S, Kasai K. Globular adiponectin upregulates nitric oxide production in vascular endothelial cells.  Diabetologia. 2003;  46 1543-1549
  • 65 Hauner H, Bender M, Haastert B, Hube F. Plasma concentrations of TNF-α and its soluble receptors in obese subjects.  Int J Obes. 1998;  22 1239-1243
  • 66 Hervey G R. The effects of lesions in the hypothalamus in parabiotic rats.  J Physiol. 1958;  145 336-352
  • 67 Hoggard M, Hunter L, Duncan J S, Williams L M, Trayhurn P, Mercer J G. Leptin and leptin receptor mRNA and protein expression in the murine fetus and placenta.  Proc Natl Acad Sci USA. 1997;  94 11073-11078
  • 68 Holcomb I N, Kabakoff R C, Chan B, Baker T W, Gurney A, Henzel W, Nelson C, Lowman H B, Wright B D, Skelton N J, Frantz G D, Tumas D B, Peale Jr F V, Shelton D L, Hébert C C. FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family.  EMBO J. 2000;  19 4046-4055
  • 69 Hotamisligil G S, Arner P, Caro J F, Atkinson R L, Spiegelman B M. Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance.  J Clin Invest. 1995;  95 2409-2415
  • 70 Hotamisligil G S, Johnson R S, Distel R J, Ellis R, Papaioannou V E, Spiegelman B M. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein.  Science. 1996 a;  274 1377-1379
  • 71 Hotamisligil G S, Murray D L, Choy L N, Spiegelman B M. Tumor necrosis factor α inhibits signaling from the insulin receptor.  Proc Natl Acad Sci USA. 1994;  91 4854-4858
  • 72 Hotamisligil G S, Peraldi P, Budavari A, Ellis R, White M F, Spiegelman B M. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α- and obesity-induced insulin resistance.  Science. 1996 b;  271 665-668
  • 73 Hotamisligil G S, Shargill N S, Spiegelman B M. Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance.  Science. 1993;  259 87-91
  • 74 Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients.  Arterioscler Thromb Vasc Biol. 2000;  20 1595-1599
  • 75 Hotta K, Funahashi T, Bodkin N L, Ortmeyer H K, Arita Y, Hansen B C, Matsuzawa Y. Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in Rhesus monkeys.  Diabetes. 2001;  50 1126-1133
  • 76 Hu E, Liang P, Spiegelman B M. AdipoQ is a novel adipose-specific gene dysregulated in obesity.  J Biol Chem. 1996;  271 10697-10703
  • 77 Hube F, Birgel M, Lee Y M, Hauner H. Expression pattern of tumour necrosis factor receptors in subcutaneous and omental human adipose tissue: role of obesity and non-insulin-dependent diabetes mellitus.  Eur J Clin Invest. 1999;  29 672-678
  • 78 Hube F, Lietz U, Igel M, Jensen P B, Tornqvist H, Joost H G, Hauner H. Difference in leptin mRNA levels between omental and subcutaneous abdominal adipose tissue from obese humans.  Horm Metab Res. 1996;  28 690-693
  • 79 Iwashima Y, Katsuya T, Ishikawa K, Ouchi N, Ohishi M, Sugimoto K, Fu Y, Motone M, Yamamoto K, Matsuo A, Ohashi K, Kihara S, Funahashi T, Rakugi H, Matsuzawa Y, Ogihara T. Hypoadiponectinemia is an independent risk factor for hypertension.  Hypertension. 2004;  43 1318-1323
  • 80 Janik J E, Curtis E D, Considine R V, Rager H C, Powers G C, Alvord W G. Smith JW 2nd . Interleukin 1 alpha increases serum leptin concentrations in humans.  J Clin Endocrinol Metab. 1997;  82 3084-3086
  • 81 Janke J, Engeli S, Gorzelniak K, Luft F C, Sharma A M. Resistin gene expression in human adipocytes is not related to insulin resistance.  Obes Res. 2002;  10 1-5
  • 82 Juan C C, Au L C, Fang V S, Kang S F, Ko Y H, Kuo S F, Hsu Y P, Kwok C F, Ho L T. Suppressed gene expression of adipocyte resistin in an insulin-resistant rat model probably by elevated free fatty acids.  Biochem Biophys Res Commun. 2001;  289 1328-1333
  • 83 Kamohara S, Burcelin R, Halaas J L, Friedman J M, Charron M J. Acute stimulation of glucose metabolism in mice by leptin treatment.  Nature. 1997;  389 374-377
  • 84 Kanemaki T, Kitade H, Kaibori M, Sakitani K, Hiramatsu Y, Kamiyama Y, Ito S, Okumura T. Interleukin 1 beta and interleukin 6, but not tumor necrosis factor alpha, inhibit insulin-stimulated glycogen synthesis in rat hepatocytes.  Hepatology. 1998;  27 1296-1303
  • 85 Kanety H, Feinstein R, Papa M Z, Hemi R, Karasik A. Tumor necrosis factor α-induced phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1.  J Biol Chem. 1995;  270 23780-23784
  • 86 Kappes A, Löffler G. Influences of ionomycin, dibutyryl-cycloAMP and tumour necrosis factor-alpha on intracellular amount and secretion of apM1 in differentiating primary human preadipocytes.  Horm Metab Res. 2000;  32 548-554
  • 87 Kellerer M, Koch M, Metzinger E, Mushack J, Capp E, Häring H U. Leptin activates PI-3 kinase in C2C12 myotubes via janus kinase-2 (JAK-2) and insulin receptor substrate-2 (IRS-2) dependent pathways.  Diabetologia. 1997;  40 1358-1362
  • 88 Kellerer M, Rett K, Renn W, Groop L, Häring H U. Circulating TNF-alpha and leptin levels in offspring of NIDDM patients do not correlate to individual insulin sensitivity.  Horm Metab Res. 1996;  28 737-743
  • 89 Kennedy G C. The role of depot fat in the hypothalamic control of food intake in the rat.  Proc R Soc London Ser B. 1953;  140 578-596
  • 90 Kern P A, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance.  Am J Physiol Endocrinol Metab. 2001;  280 E745-E751
  • 91 Kern P A, Saghizadeh M, Ong J M, Bosch R J, Deem R, Simsolo R B. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase.  J Clin Invest. 1995;  95 2111-2119
  • 92 Kieffer T, Scott-Heller R, Leech C A, Holz G, Habener J F. Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic b-cells.  Diabetes. 1997;  46 1087-1093
  • 93 Kim H J, Higashimori T, Park S Y, Choi H, Dong J, Kim Y J, Noh H L, Cho Y R, Cline G, Kim Y B, Kim J K. Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo.  Diabetes. 2004;  53 1060-1067
  • 94 Kim K H, Lee K, Moon Y S, Sul H S. A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation.  J Biol Chem. 2001;  276 11252-11256
  • 95 Kolaczynski J W, Considine R V, Ohannesian J P, Marco C, Opentanova I, Nyce M R, Myint M, Caro J F. Responses of leptin to short-term fasting and refeeding in humans: a link with ketogenesis but no ketones themselves.  Diabetes. 1996;  45 1511-1515
  • 96 Kristensen P, Judge M E, Thim L, Ribel U, Christjansen K N, Wulff B S, Clausen J T, Jensen P B, Madsen O D, Vrang N, Larsen P J, Hastrup S. Hypothalamic CART is a new anorectic peptide regulated by leptin.  Nature. 1998;  393 72-76
  • 97 Kubaszek A, Pihlajamäki J, Punnonen K, Karhapää P, Vauhkonen I, Laakso M. The C-174 G promoter polymorphism of the IL-6 gene affects energy expenditure and insulin sensitivity.  Diabetes. 2003;  52 558-561
  • 98 Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, Eto K, Yamashita T, Kamon J, Satoh H, Yano W, Nagai R, Kimura S, Kadowaki T, Noda T. Disruption of adiponectin causes insulin resistance and neointimal formation.  J Biol Chem. 2002;  277 25863-25866
  • 99 Kulkarni R N, Whang Z L, Wang R M, Hurley J D, Smith D M, Ghatei M A, Withers D J, Gardiner J V, Bailey C J, Bloom S R. Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice.  J Clin Invest. 1997;  100 2729-2736
  • 100 Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N, Arita Y, Okamoto Y, Shimomura I, Hiraoka H, Nakamura T, Funahashi T, Matsuzawa Y. Association of hypoadiponectinemia with coronary artery disease in men.  Arterioscler Thromb Vasc Biol. 2003;  23 85-89
  • 101 Lee G H, Proenca R, Montez J M, Carroll K, Darvishzadeh J G, Lee J I, Friedman J M. Abnormal splicing of the leptin receptor in diabetic mice.  Nature. 1996;  379 632-635
  • 102 Le Lay S, Boucher J, Rey A, Castan-Laurell I, Krief S, Ferre P, Valet P, Dugail I. Decreased resistin expression in mice with different sensitivities to a high-fat diet.  Biochem Biophys Res Commun. 2001;  289 564-567
  • 103 Levy J R, Davenport B, Clore J N, Stevens W. Lipid metabolism and resistin gene expression in insulin-resistant Fischer 344 rats.  Am J Physiol Endocrinol Metab. 2002;  282 E626-E633
  • 104 Lihn A S, Jessen N, Pedersen S B, Lund S, Richelsen B. AICAR stimulates adiponectin and inhibits cytokines in adipose tissue.  Biochem Biophys Res Commun. 2004;  316 853-858
  • 105 Liu L S, Spelleken M, Röhrig K, Hauner H, Eckel J. Tumor necrosis factor (TNF)-alpha acutely inhibits insulin signaling in human adipocytes. Implication of the p80 TNF receptor.  Diabetes. 1998;  47 515-522
  • 106 Liu Y L, Emilsson V, Cawthorne M A. Leptin inhibits glycogen synthesis in the isolated soleus muscle of obese (ob/ob) mice.  FEBS Lett. 1997;  411 351-355
  • 107 Lonnqvist F, Arner P, Nordfors L, Schalling M. Overexpression of the obese (ob) gene in adipose tissue of human obese subjects.  Nat Med. 1995;  1 950-953
  • 108 Lord G M, Matarese G, Howard J K, Baker R J, Bloom S R, Lechler R I. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression.  Nature. 1998;  394 897-901
  • 109 Lyngsø D, Simonsen L, Bülow J. Metabolic effects of interleukin-6 in human splanchnic and adipose tissue.  J Physiol. 2002;  543. 1 379-386
  • 110 Machinal F, Dieudonne M N, Leneveu M C, Pecquery R, Giudicelli Y. In vivo and in vitro ob gene expression and leptin secretion in rat adipocytes: evidence for a regional specific regulation by sex steroid hormones.  Endocrinology. 1999;  140 1567-1574
  • 111 Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant gene transcript 1).  Biochem Biophys Res Commun. 1996;  221 286-289
  • 112 Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, Furuyama N, Kondo H, Takahashi M, Arita Y, Komuro R, Ouchi N, Kihara S, Tochino Y, Okutomi K, Horie M, Takeda S, Aoyama T, Funahashi T, Matsuzawa Y. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30.  Nat Med. 2002;  8 731-737
  • 113 Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T, Shimomura I, Matsuzawa Y. PPARγ ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein.  Diabetes. 2001;  50 2094-2099
  • 114 Maffei M J, Halaas J, Ravussin E, Pratley R E, Lee G H, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, Kern P A, Friedman J M. Leptin levels in human and rodents: measurement of plasma leptin and ob mRNA in obese and weight-reduced subjects.  Nat Med. 1995;  1 1155-1161
  • 115 Mantzoros C S, Petridou E, Dessypris N, Chavelas C, Dalamaga M, Alexe D M, Papadiamantis Y, Markopoulos C, Spanos E, Chrousos G, Trichopoulos D. Adiponectin and breast cancer risk.  J Clin Endocrinol Metab. 2004;  89 1102-1107
  • 116 Mantzoros C S, Qu D, Frederich R C, Susulic V S, Lowell B B, Maratos-Flier E, Flier J S. Activation of β3 adrenergic receptors suppresses leptin expression and mediates a leptin-independent inhibition of food intake in mice.  Diabetes. 1996;  45 909-914
  • 117 Masuzaki H, Ogava Y, Sagawa N, Hosoda K, Matsumoto T, Mise H, Nishimura H, Yoshimasa Y, Tanaka I, Mori T, Nakao K. Non-adipose tissue production of leptin; leptin as a novel placenta-derived hormone in humans.  Nat Med. 1997;  3 1029-1033
  • 118 Matsuda M, Shimomura I, Sata M, Arita Y, Nishida M, Maeda N, Kumada M, Okamoto Y, Nagaretani H, Nishizawa H, Kishida K, Komuro R, Ouchi N, Kihara S, Nagai R, Funahashi T, Matsuzawa Y. Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis.  J Biol Chem. 2002;  277 37487-37491
  • 119 May L T, Torcia G, Cozzolino F, Ray A, Tatter S B, Santhanam U, Sehgal P B, Stern D. Interleukin-6 gene expression in human endothelial cells: RNA start sites, multiple IL-6 proteins and inhibition of proliferation.  Biochem Biophys Res Commun. 1989;  159 991-998
  • 120 McCall J L, Tuckey J A, Parry B R. Serum tumour necrosis factor α and insulin resistance in gastrointestinal cancer.  Br J Surg. 1992;  79 1361-1363
  • 121 McCarty M F. Interleukin-6 as a central mediator of cardiovascular risk associated with chronic inflammation, smoking, diabetes, and visceral obesity: down-regulation with essential fatty acids, ethanol and pentoxifylline.  Med Hypotheses. 1999;  52 465-477
  • 122 Menzaghi C, Ercolino T, Di Paola R, Berg A H, Warram J H, Scherer P E, Trischitta V, Doria A. A haplotype at the adiponectin locus is associated with obesity and other features of the insulin resistance syndrome.  Diabetes. 2002;  51 2306-2312
  • 123 Minokoshi Y, Kim Y B, Peroni O D, Fryer L G, Muller C, Carling D, Kahn B B. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase.  Nature. 2002;  415 339-343
  • 124 Miyazaki Y, Pipek R, Mandarino L J, DeFronzo R A. Tumor necrosis factor α and insulin resistance in obese type 2 diabetic patients.  Int J Obes. 2003;  27 88-94
  • 125 Mohamed-Ali V, Flower L, Sethi J, Hotamisligil G, Gray R, Humphries S E, York D A, Pinkney J. Beta-adrenergic regulation of IL-6 release from adipose tissue: in vivo and in vitro studies.  J Clin Endocrinol Metab. 2001;  86 5864-5869
  • 126 Mohamed-Ali V, Goodrick S, Rawesh A, Katz D R, Miles J M, Yudkin J S, Klein S, Coppack S W. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-α, in vivo.  J Clin Endocrinol Metab. 1997;  82 4196-4200
  • 127 Montague C T, Farooqui S, Whitehead J P, Soos M A, Rau H, Wareham N J, Sewter C P, Digby J E, Mohammed S N, Hurst J A, Cheetham C H, Earley A R, Barnett A H, Prins J B, O'Rahilly S. Congenital leptin deficiency is associated with severe early-onset obesity in humans.  Nature. 1997 a;  387 903-908
  • 128 Montague C T, Prins J B, Sanders L, Digby J E, O'Rahilly S. Depot- and sex-specific differences in human leptin mRNA expression: implications for the control of regional fat distribution.  Diabetes. 1997 b;  46 342-347
  • 129 Morin C L, Eckel R H, Marcel T, Pagliassotti M J. High fat diets elevate tissue-derived tumor necrosis factor-α activity.  Endocrinology. 1997;  138 4665-4671
  • 130 Müller G, Ertl J, Gerl M, Preibisch G. Leptin impairs metabolic actions of insulin in isolated rat adipocytes.  J Biol Chem. 1997;  272 10585-10593
  • 131 Muoio D M, Dohm G L, Fiedorek F T, Tapscott E B, Coleman R A. Leptin directly alters lipid partitioning in skeletal muscle.  Diabetes. 1997;  46 1360-1363
  • 132 Nakano Y, Tobe T, Choi-Miura N H, Mazda T, Tomita M. Isolation and characterization of GBP28, a novel gelatin-binding protein.  J Biochem (Tokyo). 1996;  120 803-812
  • 133 Nishizawa H, Shimomura I, Kishida K, Maeda N, Kuriyama H, Nagaretani H, Matsuda M, Kondo H, Furuyama N, Kihara S, Nakamura T, Tochino Y, Funahashi T, Matsuzawa Y. Androgens decrease plasma adiponectin, an insulin-sensitizing adipocyte-derived protein.  Diabetes. 2002;  51 2734-2741
  • 134 Lindsay R S, Funahashi T, Hanson R L, Matsuzawa Y, Tanaka S, Tataranni P A, Knowler W C, Krakoff J. Adiponectin and development of type 2 diabetes in the Pima Indian population.  Lancet. 2002;  360 57-58
  • 135 Matsubara M, Maruoka S, Katayose S. Decreased plasma adiponectin concentrations in women with dyslipidemia.  J Clin Endocrinol Metab. 2002;  87 2764-2769
  • 136 Miyoshi Y, Funahashi T, Kihara S, Taguchi T, Tamaki Y, Matsuzawa Y, Noguchi S. Association of serum adiponectin levels with breast cancer risk.  Clin Cancer Res. 2003;  9 5699-5704
  • 137 Moore G B, Chapman H, Holder J C, Lister C A, Piercy V, Smith S A, Clapham J C. Differential regulation of adipocytokine mRNAs by rosiglitazone in db/db mice.  Biochem Biophys Res Commun. 2001;  286 735-741
  • 138 Nagaev I, Smith U. Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle.  Biochem Biophys Res Commun. 2001;  285 561-564
  • 139 Nonogaki K, Fuller G M, Fuentes N L, Moser A H, Staprans I, Grunfeld C. Interleukin-6 stimulates hepatic triglyceride secretion in rats.  Endocrinology. 1995;  136 2143-2149
  • 140 Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R. Effects of an engineered human anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM.  Diabetes. 1996;  45 881-885
  • 141 Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M, Ohashi K, Sakai N, Shimomura I, Kobayashi H, Terasaka N, Inaba T, Funahashi T, Matsuzawa Y. Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice.  Circulation. 2002;  106 2767-2770
  • 142 Oral E A, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner A J, DePaoli A M, Reitman M L, Taylor S I, Gorden P, Garg A. Leptin-replacement therapy for lipodystrophy.  N Engl J Med. 2002;  346 570-578
  • 143 Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Hotta K, Nishida M, Takahashi M, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y. Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin.  Circulation. 1999;  100 2473-2476
  • 144 Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama A, Okamoto Y, Ishigami M, Kuriyama H, Kishida K, Nishizawa H, Hotta K, Muraguchi M, Ohmoto Y, Yamashita S, Funahashi T, Matsuzawa Y. Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages.  Circulation. 2001;  103 1057-1063
  • 145 Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, Hotta K, Nishida M, Takahashi M, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y. Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-κB signaling through a cAMP-dependent pathway.  Circulation. 2000;  102 1296-1301
  • 146 Ouchi N, Kihara S, Funahashi T, Nakamura T, Nishida M, Kumada M, Okamoto Y, Ohashi K, Nagaretani H, Kishida K, Nishizawa H, Maeda N, Kobayashi H, Hiraoka H, Matsuzawa Y. Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue.  Circulation. 2003;  107 671-674
  • 147 Path G, Bornstein S R, Gurniak M, Chrousos G P, Scherbaum W A, Hauner H. Human breast adipocytes express interleukin-6 (IL-6) and its receptor system: increased IL-6 production by beta-adrenergic activation and effects of IL-6 on adipocyte function.  J Clin Endocrinol Metab. 2001;  86 2281-2288
  • 148 Paz K, Hemi R, LeRoith D, Karasik A, Elhanany E, Kanety H, Zick Y. A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation.  J Biol Chem. 1997;  272 29911-29918
  • 149 Pelleymounter M, Cullen M, Baker M, Hecht R, Winters D, Boone T, Collins F. Effects of the obese gene product on body weight regulation in ob/ob mice.  Science. 1995;  269 540-543
  • 150 Petersen K F, Oral E A, Dufour S, Befroy D, Ariyan C, Yu C, Cline G W, DePaoli A M, Taylor S I, Gorden P, Shulman G I. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy.  J Clin Invest. 2002;  109 1345-1350
  • 151 Pfeiffer A, Janot J, Möhlig M, Ristow M, Rochlitz H, Busch K, Schatz H, Schifferdecker E. Circulating tumor necrosis factor α is elevated in male but not in female patients with type II diabetes mellitus.  Horm Metab Res. 1997;  29 111-114
  • 152 Pickup J C, Chusney G D, Thomas S M, Burt D. Plasma interleukin-6, tumour necrosis factor α and blood cytokine production in type 2 diabetes.  Life Sci. 2000;  67 291-300
  • 153 Poitout V, Rouault C, Guerre-Millo M, Briaud I, Reach G. Inhibition of insulin secretion by leptin in normal rodent islets of Langerhans.  Endocrinology. 1998;  139 822-826
  • 154 Pradhan A D, Manson J E, Rifai N, Buring J E, Ridker P M. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus.  JAMA. 2001;  286 327-334
  • 155 Prentki M, Joly E, El-Assaad W, Roduit R. Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes.  Diabetes. 2002;  51 (Suppl 3) S405-S413
  • 156 Prins J B, Niesler C U, Winterford C M, Bright N A, Siddle K, O'Rahilly S, Walker N I, Cameron D P. Tumor necrosis factor-alpha induces apoptosis of human adipose cells.  Diabetes. 1997;  46 1939-1944
  • 157 Qi Y, Takahashi N, Hileman S M, Patel H R, Berg A H, Pajvani U B, Scherer P E, Ahima R S. Adiponectin acts in the brain to decrease body weight.  Nat Med. 2004;  10 524-529
  • 158 Qian H, Hausman D B, Compton M M, Martin R J, Della-Fera M A, Hartzell D L, Baile C A. TNFalpha induces and insulin inhibits caspase 3-dependent adipocyte apoptosis.  Biochem Biophys Res Commun. 2001;  284 1176-1183
  • 159 Rajala M W, Lin Y, Ranalletta M, Yang X M, Qian H, Gingerich R, Barzilai N, Scherer P E. Cell type-specific expression and coregulation of murine resistin and resistin-like molecule-alpha in adipose tissue.  Mol Endocrinol. 2002;  16 1920-1930
  • 160 Rajala M W, Obici S, Scherer P E, Rossetti L. Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production.  J Clin Invest. 2003;  111 225-230
  • 161 Ranganathan S, Ciaraldi T P, Henry R R, Mudaliar S, Kern P A. Lack of effect of leptin on glucose transport, lipoprotein lipase, and insulin action in adipose and muscle cells.  Endocrinology. 1998;  139 2509-2513
  • 162 Ravussin E, Smith S R. Increased fat intake, impaired fat oxidation, and failure of fat cell proliferation result in ectopic fat storage, insulin resistance, and type 2 diabetes mellitus.  Ann NY Acad Sci. 2002;  967 363-378
  • 163 Rentsch J, Chiesi M. Regulation of ob gene mRNA levels in cultured adipocytes.  FEBS Lett. 1996;  379 55-59
  • 164 Rössner S. Obesity: the disease of the twenty-first century.  Int J Obes. 2002;  26 (Suppl 4) S2-S4
  • 165 Ryden M, Dicker A, Van Harmelen, Hauner H, Brunnberg M, Perbeck L, Lonnqvist F, Arner P. Mapping of early signaling events in tumor necrosis factor-α-mediated lipolysis in human fat cells.  J Biol Chem. 2002;  277 1085-1091
  • 166 Saladin R, De Vos P, Guerre-Millo M, Leturque A, Girard J, Staels B, Auwerx J. Transient increase in obese gene expression after food intake or insulin administration.  Nature. 1995;  377 527-529
  • 167 Sarraf P, Frederich R C, Turner E M, Ma G, Jaskowiak N T. Rivet DJ 3rd . Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia.  J Exp Med. 1997;  185 171-175
  • 168 Savage D B, Sewter C P, Klenk E S, Segal D G, Vidal-Puig A, Considine R V, O'Rahilly S. Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma actions in humans.  Diabetes. 2001;  50 2199-2202
  • 169 Scherer P E, Williams S, Fogliano M, Baldini G, Lodish H F. A novel serum protein similar to C1q, produced exclusively in adipocytes.  J Biol Chem. 1995;  270 26746-26749
  • 170 Senn J J, Klover P J, Nowak I A, Mooney R A. Interleukin-6 induces cellular insulin resistance in hepatocytes.  Diabetes. 2002;  51 3391-3399
  • 171 Seuffert J, Kieffer T J, Leech C A, Holz G G, Moritz W, Ricordi C, Habener J F. Leptin suppression of insulin secretion and gene expression in human pancreatic islets: implications for the development of adipogenic diabetes mellitus.  J Clin Endocrinol Metab. 1999;  84 670-676
  • 172 Shalaby M R, Waage A, Espevik T. Cytokine regulation of interleukin 6 production by human endothelial cells.  Cell Immunol. 1989;  121 372-382
  • 173 Shibata R, Ouchi N, Kihara S, Sato K, Funahashi T, Walsh K. Adiponectin stimulates angiogenesis in response to tissue ischemia through stimulation of AMP-activated protein kinase signaling.  J Biol Chem. 2004;  279 28670-28674
  • 174 Shimabukuro M, Koyama K, Chen G, Wang M Y, Trieu F, Lee Y, Newgard C B, Unger R H. Direct antidiabetic effect of leptin through triglyceride depletion of tissues.  Proc Natl Acad Sci USA. 1997;  94 4637-4641
  • 175 Sierra-Honigmann M R, Nath A K, Murakami C, García-Cardeña G, Papapetropoulos A, Sessa W C, Madge L A, Schechner J S, Schwabb M B, Polverini P J, Flores-Riveros J R. Biological action of leptin as an angiogenic factor.  Science. 1998;  281 1683-1686
  • 176 Sivitz W I. Lipotoxicity and glucotoxicity in type 2 diabetes. Effects on development and progression.  Postgrad Med. 2001;  109 55-59 63-64
  • 177 Slieker L J, Sloop K W, Surface P L, Kriauciunas A, LaQuier F, Manetta J, Blue-Valleskey J, Stephens T W. Regulation of expression of ob mRNA and protein by glucocorticoids and cAMP.  J Biol Chem. 1996;  271 5301-5304
  • 178 Staiger H, Tschritter O, Machann J, Thamer C, Fritsche A, Maerker E, Schick F, Häring H U, Stumvoll M. Relationship of serum adiponectin and leptin concentrations with body fat distribution in humans.  Obes Res. 2003;  11 368-372
  • 179 Steensberg A, Fischer C P, Sacchetti M, Keller C, Osada T, Schjerling P, van Hall G, Febbraio M A, Pedersen B K. Acute interleukin-6 administration does not impair muscle glucose uptake or whole-body glucose disposal in healthy humans.  J Physiol. 2003;  548. 2 631-638
  • 180 Stefan N, Vozarova B, Funahashi T, Matsuzawa Y, Weyer C, Lindsay R S, Youngren J F, Havel P J, Pratley R E, Bogardus C, Tataranni P A. Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans.  Diabetes. 2002;  51 1884-1888
  • 181 Stephens J M, Lee J, Pilch P F. Tumor necrosis factor-α-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction.  J Biol Chem. 1997;  272 971-976
  • 182 Stephens J M, Pekala P H. Transcriptional repression of Glut-4 and C/EBP genes in 3T3-L1 adipocytes by tumor necrosis factor alpha.  J Biol Chem. 1992;  266 21839-21845
  • 183 Stouthard J M, Romijn J A, Van der Poll T, Endert E, Klein S, Bakker P J, Veenhof C H, Sauerwein H P. Endocrinologic and metabolic effects of interleukin-6 in humans.  Am J Physiol. 1995;  268 E813-E819
  • 184 Steppan C M, Bailey S T, Bhat S, Brown E J, Banerjee R R, Wright C M, Patel H R, Ahima R S, Lazar M A. The hormone resistin links obesity to diabetes.  Nature. 2001 a;  409 307-312
  • 185 Steppan C M, Brown E J, Wright C M, Bhat S, Banerjee R R, Dai C Y, Enders G H, Silberg D G, Wen X, Wu G D, Lazar M A. A family of tissue-specific resistin-like molecules.  Proc Natl Acad Sci USA. 2001 b;  98 502-506
  • 186 Stumvoll M, Tschritter O, Fritsche A, Staiger H, Renn W, Weisser M, Machicao F, Häring H. Association of the T-G polymorphism in adiponectin (exon 2) with obesity and insulin sensitivity.  Diabetes. 2002;  51 37-41
  • 187 Tan K CB, Xu A, Chow W S, Lam M CW, Ai V HG, Tam S CF, Lam K SL. Hypoadiponectinemia is associated with impaired endothelium-dependent vasodilation.  J Clin Endocrinol Metab. 2004;  89 765-769
  • 188 Tartaglia L A, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards G J, Campfield L A, Clark F T, Deeds J, Muir C, Sanker S, Moriarty A, Moore K J, Smutko J S, Mays G G, Woolf E A, Monroe C A, Tepper R I. Identification and expression cloning of a leptin receptor, OB-R.  Cell. 1995;  83 1263-1271
  • 189 Thompson D, Wolf A M. The medical-care cost burden of obesity.  Obes Rev. 2001;  2 189-197
  • 190 Tomas E, Tsao T S, Saha A K, Murrey H E, Zhang C C, Itani S I, Lodish H F, Ruderman N B. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation.  Proc Natl Acad Sci USA. 2002;  99 16309-16313
  • 191 Torti F M, Dieckmann B, Beutler B, Cerami A, Ringold G M. A macrophage factor inhibits adipocyte gene expresssion: an in vitro model of cachexia.  Science. 1985;  229 867-869
  • 192 Tschritter O, Fritsche A, Thamer C, Haap M, Shirkavand F, Rahe S, Staiger H, Maerker E, Häring H, Stumvoll M. Plasma adiponectin concentrations predict insulin sensitivity of both glucose and lipid metabolism.  Diabetes. 2003;  52 239-243
  • 193 Tsigos C, Papanicolaou D A, Kyrou I, Defensor R, Mitsiadis C S, Chrousos G P. Dose-dependent effects of recombinant human interleukin-6 on glucose regulation.  J Clin Endocrinol Metab. 1997;  82 4167-4170
  • 194 Unger R H. Weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome.  Endocrinology. 2003;  144 5159-5165
  • 195 Uysal K T, Wiesbrock S M, Marino M W, Hotamisligil G S. Protection from obesity-induced insulin resistance in mice lacking TNF-α function.  Nature. 1997;  389 610-614
  • 196 Van der Poll T, Romijn J A, Endert E, Borm J J, Buller H R, Sauerwein H P. Tumour necrosis factor mimics the metabolic response to acute infection in healthy humans.  Am J Physiol. 1991;  261 E457-E465
  • 197 Van Harmelen, Reynisdottir S, Eriksson P, Thorne A, Hoffstedt J, Lonnqvist F, Arner P. Leptin secretion from subcutaneous and visceral adipose tissue in women.  Diabetes. 1998;  47 913-917
  • 198 Van Heek M, Compton D S, France C F, Tedesco R P, Fawzi A B, Graziano M P, Sybertz E J, Strader C D, Davis Jr H R. Diet-induced obese mice develop peripheral, but not central, resistance to leptin.  J Clin Invest. 1997;  99 385-390
  • 199 Van Snick J. Interleukin 6: an over-view.  Annu Rev Immunol. 1990;  8 253-278
  • 200 Vasseur F, Helbecque N, Dina C, Lobbens S, Delannoy V, Gaget S, Boutin P, Vaxillaire M, Leprêtre F, Dupont S, Hara K, Clément K, Bihain B, Kadowaki T, Froguel P. Single-nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians.  Hum Mol Genet. 2002;  11 2607-2614
  • 201 Vgontzas A N, Papanicolaou D A, Bixler E O, Kales A, Tyson K, Chrousos G P. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity.  J Clin Endocrinol Metab. 1997;  82 1313-1316
  • 202 Vicennati V, Vottero A, Friedman C, Papanicolaou D A. Hormonal regulation of interleukin-6 production in human adipocytes.  Int J Obes. 2002;  26 905-911
  • 203 Warne J P. Tumour necrosis factor α: a key regulator of adipose tissue mass.  J Endocrinol. 2003;  177 351-355
  • 204 Way J M, Gorgun C Z, Tong Q, Uysal K T, Brown K K, Harrington W W, Oliver Jr W R, Willson T M, Kliewer S A, Hotamisligil G S. Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists.  J Biol Chem. 2001;  276 25 651-25 653
  • 205 Weigert C, Brodbeck K, Staiger H, Kausch C, Machicao F, Häring H U, Schleicher E D. Palmitate, but not unsaturated fatty acids, induces the expression of interleukin-6 in human myotubes through proteasome-dependent activation of nuclear factor-κB.  J Biol Chem. 2004;  279 23942-23952
  • 206 Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley R E, Tataranni P A. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia.  J Clin Endocrinol Metab. 2001;  86 1930-1935
  • 207 Wu-Peng X S, Chua Jr S C, Okada N, Liu S M, Nicolson M, Leibel R L. Phenotype of the obese Koletsky (f) rat due to Tyr763Stop mutation in the extracellular domain of the leptin receptor (Lepr): evidence for deficient plasma-to-CSF transport of leptin in both the Zucker and Koletsky obese rat.  Diabetes. 1997;  46 513-518
  • 208 Xing H, Northrop J P, Grove J R, Kilpatrick K E, Su J L, Ringold G M. TNF alpha-mediated inhibition and reversal of adipocyte differentiation is accompanied by suppressed expression of PPAR gamma without effects on Pref-1 expression.  Endocrinology. 1997;  138 2776-2783
  • 209 Xu H, Hirosumi J, Uysal K T, Guler A D, Hotamisligil G S. Exclusive action of transmembrane TNF alpha in adipose tissue leads to reduced adipose mass and local but not systemic insulin resistance.  Endocrinology. 2002;  143 1502-1511
  • 210 Xu H, Sethi J K, Hotamisligil G S. Transmembrane tumor necrosis factor (TNF)-alpha inhibits adipocyte differentiation by selectively activating TNF receptor 1.  J Biol Chem. 1999;  274 26287-26295
  • 211 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 B B, Kadowaki T. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase.  Nat Med. 2002;  8 1-8
  • 212 Yamauchi T, Kamon J, Waki H, Imai Y, Shimozawa N, Hioki K, Uchida S, Ito Y, Takakuwa K, Matsui J, Takata M, Eto K, Terauchi Y, Komeda K, Tsunoda M, Murakami K, Ohnishi Y, Naitoh T, Yamamura K, Ueyama Y, Froguel P, Kimura S, Nagai R, Kadowaki T. Globular adiponectin protected ob/ob mice from diabetes and apoE-deficient mice from atherosclerosis.  J Biol Chem. 2003;  278 2462-2468
  • 213 Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman M L, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity.  Nat Med. 2001;  7 941-946
  • 214 Yang R, Xu A, Pray J, Hu H, Jadhao S, Hansen B, Shuldiner A, McLenithan J, Gong D. Cloning of omentin, a new adipocytokine from omental fat tissue in humans.  Diabetes. 2003;  52 (Suppl 1) A1
  • 215 Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner A J, Tomiyama Y, Matsuzawa Y. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages.  Blood. 2000;  96 1723-1732
  • 216 Yudkin J S, Kumari M, Humphries S E, Mohamed-Ali V. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?.  Atherosclerosis. 2000;  148 209-214
  • 217 Zhang H H, Halbleib M, Ahmad F, Manganiello V C, Greenberg A S. Tumor necrosis factor-alpha stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP.  Diabetes. 2002 a;  51 2029-2035
  • 218 Zhang H H, Kumar S, Barnett A H, Eggo M C. Dexamethasone inhibits tumor necrosis factor-alpha-induced apoptosis and interleukin-1 beta release in human subcutaneous adipocytes and preadipocytes.  J Clin Endocrinol Metab. 2001;  86 2817-2825
  • 219 Zhang Y, Matheny M, Zolotukhin S, Tumer M, Scarpace J P. Regulation of adiponectin and leptin gene expression in white and brown adipose tissue: influence of beta3-adrenergic agonists, retinoic acid, leptin and fasting.  Biochim Biophys Acta. 2002 b;  1584 115-122
  • 220 Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman J M. Positional cloning of the mouse obese gene and its human homologue.  Nature. 1994;  372 425-432
  • 221 Zhao A Z, Shinohara M M, Huang D, Shimizu M, Eldar-Finkelman H, Krebs E G, Beavo J A, Bornfeldt. Leptin induces insulin-like signaling that antagonises cAMP elevation by glucagon in hepatocytes.  J Biol Chem. 2000;  275 11348-11354
  • 222 Zinman B, Hanley A J, Harris S B, Kwan J, Fantus I G. Circulating tumor necrosis factor-α concentrations in a native Canadian population with high rates of type 2 diabetes mellitus.  J Clin Endocrinol Metab. 1999;  84 272-278

Prof. Dr. med. Hans-Ulrich Häring

Department of Internal Medicine IV, Medical Clinic Tübingen

Otfried-Müller-Straße 10

72076 Tübingen

Germany

Phone: + 4970712982735

Fax: + 49 70 71 29 27 84

Email: hans-ulrich.haering@med.uni-tuebingen.de

    >