Adipose tissue as an endocrine organ

Obesity is characterized by increased storage of fatty acids in an expanded adipose tissue mass and is closely associated with the development of insulin resistance in peripheral tissues such as skeletal muscle and the liver. In addition to being the largest source of fuel in the body, adipose tissue and resident macrophages are also the source of a number of secreted proteins. Cloning of the obese gene and the identification of its product, leptin, was one of the first discoveries of an adipocyte-derived signaling molecule and established an important role for adipose tissue as an endocrine organ. Since then, leptin has been found to have a profound role in the regulation of whole-body metabolism by stimulating energy expenditure, inhibiting food intake and restoring euglycemia, however, in most cases of obesity leptin resistance limits its biological efficacy. In contrast to leptin, adiponectin secretion is often diminished in obesity. Adiponectin acts to increase insulin sensitivity, fatty acid oxidation, as well as energy expenditure and reduces the production of glucose by the liver. Resistin and retinol binding protein-4 are less well described. Their expression levels are positively correlated with adiposity and they are both implicated in the development of insulin resistance. More recently it has been acknowledged that macrophages are an important part of the secretory function of adipose tissue and the main source of inflammatory cyokines, such as TNFalpha and IL-6. An increase in circulating levels of these macrophage-derived factors in obesity leads to a chronic low-grade inflammatory state that has been linked to the development of insulin resistance and diabetes. These proteins commonly known as adipokines are central to the dynamic control of energy metabolism, communicating the nutrient status of the organism with the tissues responsible for controlling both energy intake and expenditure as well as insulin sensitivity.

[1]  B. Kennedy,et al.  Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. , 2002, Developmental cell.

[2]  Philipp E. Scherer,et al.  Disulfide-Dependent Multimeric Assembly of Resistin Family Hormones , 2004, Science.

[3]  R. Ahima,et al.  Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting. , 2004, Diabetes.

[4]  J. Ohannesian,et al.  Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects. , 1996, The Journal of clinical investigation.

[5]  T Nakamura,et al.  Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. , 1999, Circulation.

[6]  C. Perez,et al.  A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: Ramifications for the complex physiology of TNF , 1988, Cell.

[7]  H. Baum,et al.  Removal of endogenous leptin from the circulation by the kidney , 1997, International Journal of Obesity.

[8]  J S Yudkin,et al.  Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1997 by The Endocrine Society Subcutaneous Adipose Tissue Releases Interleukin-6, But Not Tumor Necrosis Factor-�, in Vivo* , 2022 .

[9]  M. Tadayyon,et al.  Leptin receptor long-form signalling in a human liver cell line. , 2001, Cytokine.

[10]  T. Saruta,et al.  Novel resistin promoter polymorphisms: association with serum resistin level in Japanese obese individuals. , 2004, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[11]  K. Fujioka,et al.  Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. , 1999, JAMA.

[12]  G. Knutsen,et al.  Human articular chondrocytes express functional leptin receptors. , 2001, Biochemical and biophysical research communications.

[13]  S. Maruoka,et al.  Inverse relationship between plasma adiponectin and leptin concentrations in normal-weight and obese women. , 2002, European journal of endocrinology.

[14]  U. Smith,et al.  Interleukin-6 (IL-6) Induces Insulin Resistance in 3T3-L1 Adipocytes and Is, Like IL-8 and Tumor Necrosis Factor-α, Overexpressed in Human Fat Cells from Insulin-resistant Subjects* , 2003, Journal of Biological Chemistry.

[15]  H. Lodish,et al.  Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: Acetyl–CoA carboxylase inhibition and AMP-activated protein kinase activation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[16]  R. Mooney,et al.  Interleukin-6 induces cellular insulin resistance in hepatocytes. , 2002, Diabetes.

[17]  M. Westerterp-Plantenga,et al.  Effects of weekly administration of pegylated recombinant human OB protein on appetite profile and energy metabolism in obese men. , 2001, The American journal of clinical nutrition.

[18]  R. Ahima,et al.  Adiponectin acts in the brain to decrease body weight , 2004, Nature Medicine.

[19]  D. Carling,et al.  AMP-activated Protein Kinase Plays a Role in the Control of Food Intake* , 2004, Journal of Biological Chemistry.

[20]  S. Chua,et al.  Obesity and diabetes in TNF-alpha receptor- deficient mice. , 1998, The Journal of clinical investigation.

[21]  Patricia R. Johnson,et al.  Relationship of plasma leptin to plasma insulin and adiposity in normal weight and overweight women: effects of dietary fat content and sustained weight loss. , 1996, The Journal of clinical endocrinology and metabolism.

[22]  J. Gerich,et al.  Role of the kidney in human leptin metabolism. , 1997, American journal of physiology. Endocrinology and metabolism.

[23]  David Carling,et al.  Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling. , 2006, Cell metabolism.

[24]  C. Russell,et al.  Regulation of leptin production in humans. , 2000, The Journal of nutrition.

[25]  B. Tomlinson,et al.  Impact of TNF inhibition on insulin resistance and lipids levels in patients with rheumatoid arthritis , 2007, Clinical Rheumatology.

[26]  G. Heigenhauser,et al.  The stimulatory effect of globular adiponectin on insulin-stimulated glucose uptake and fatty acid oxidation is impaired in skeletal muscle from obese subjects. , 2005, Diabetes.

[27]  B. Kemp,et al.  The suppressor of cytokine signaling 3 inhibits leptin activation of AMP-kinase in cultured skeletal muscle of obese humans. , 2006, The Journal of clinical endocrinology and metabolism.

[28]  K. Nakao,et al.  Central melanocortin signaling restores skeletal muscle AMP-activated protein kinase phosphorylation in mice fed a high-fat diet. , 2007, Cell metabolism.

[29]  J. Friedman,et al.  Abnormal splicing of the leptin receptor in diabetic mice , 1996, Nature.

[30]  S. Chapes,et al.  Adiponectin and leptin are secreted through distinct trafficking pathways in adipocytes. , 2008, Biochimica et biophysica acta.

[31]  U. Smith,et al.  Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. , 2006, The New England journal of medicine.

[32]  B. Kahn,et al.  Diet-induced Obesity Alters AMP Kinase Activity in Hypothalamus and Skeletal Muscle* , 2006, Journal of Biological Chemistry.

[33]  B. Monia,et al.  Role of resistin in diet-induced hepatic insulin resistance. , 2004, The Journal of clinical investigation.

[34]  P. Murdock,et al.  Resistin is expressed in human macrophages and directly regulated by PPAR gamma activators. , 2003, Biochemical and biophysical research communications.

[35]  K. Uysal,et al.  Protection from obesity-induced insulin resistance in mice lacking TNF-α function , 1997, Nature.

[36]  R. Lindsay,et al.  Adiponectin is present in cord blood but is unrelated to birth weight. , 2003, Diabetes care.

[37]  G. Heigenhauser,et al.  Leptin increases FA oxidation in lean but not obese human skeletal muscle: evidence of peripheral leptin resistance. , 2002, American journal of physiology. Endocrinology and metabolism.

[38]  S. O’Rahilly,et al.  ob gene mutations and human obesity , 1998, Proceedings of the Nutrition Society.

[39]  Kok Weng Chan,et al.  Post-translational Modifications of the Four Conserved Lysine Residues within the Collagenous Domain of Adiponectin Are Required for the Formation of Its High Molecular Weight Oligomeric Complex* , 2006, Journal of Biological Chemistry.

[40]  L. Rossetti,et al.  Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. , 2001, The Journal of clinical investigation.

[41]  J. Auwerx,et al.  Transient increase in obese gene expression after food intake or insulin administration , 1995, Nature.

[42]  P. Scherer,et al.  Secretion of the Adipocyte-Specific Secretory Protein Adiponectin Critically Depends on Thiol-Mediated Protein Retention , 2007, Molecular and Cellular Biology.

[43]  F. Lönnqvist,et al.  Signaling specificity of interleukin-6 action on glucose and lipid metabolism in skeletal muscle. , 2006, Molecular endocrinology.

[44]  G. Steinberg,et al.  Endurance training partially reverses dietary-induced leptin resistance in rodent skeletal muscle. , 2004, American journal of physiology. Endocrinology and metabolism.

[45]  Joanna D. Holbrook,et al.  Resistin is expressed in human macrophages and directly regulated by PPARγ activators , 2003 .

[46]  E. Chevet,et al.  Protein-tyrosine Phosphatase 1B Potentiates IRE1 Signaling during Endoplasmic Reticulum Stress* , 2004, Journal of Biological Chemistry.

[47]  B. Spiegelman,et al.  Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. , 1993, Science.

[48]  A. Yoshimura,et al.  Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity , 2004, Nature Medicine.

[49]  J. Flier,et al.  TLR4 links innate immunity and fatty acid-induced insulin resistance. , 2006, The Journal of clinical investigation.

[50]  D. Coleman.  Effects of parabiosis of obese with diabetes and normal mice , 1973, Diabetologia.

[51]  J. Olefsky,et al.  Adenovirus-mediated chronic "hyper-resistinemia" leads to in vivo insulin resistance in normal rats. , 2004, The Journal of clinical investigation.

[52]  M. Pelleymounter,et al.  Effects of the obese gene product on body weight regulation in ob/ob mice. , 1995, Science.

[53]  Steven L. Cohen,et al.  Weight-reducing effects of the plasma protein encoded by the obese gene. , 1995, Science.

[54]  John A Wagner,et al.  Complex Distribution, Not Absolute Amount of Adiponectin, Correlates with Thiazolidinedione-mediated Improvement in Insulin Sensitivity* , 2004, Journal of Biological Chemistry.

[55]  Rene Devos,et al.  Identification and expression cloning of a leptin receptor, OB-R , 1995, Cell.

[56]  Y. Terauchi,et al.  The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity , 2001, Nature Medicine.

[57]  J. Whitehead,et al.  Adiponectin multimerization is dependent on conserved lysines in the collagenous domain: evidence for regulation of multimerization by alterations in posttranslational modifications. , 2006, Molecular endocrinology.

[58]  Philippe Froguel,et al.  Cloning of adiponectin receptors that mediate antidiabetic metabolic effects , 2003, Nature.

[59]  M. Maffei,et al.  Positional cloning of the mouse obese gene and its human homologue , 1994, Nature.

[60]  P. Scherer,et al.  Plasma adiponectin complexes have distinct biochemical characteristics. , 2008, Endocrinology.

[61]  L. Tartaglia,et al.  The Leptin Receptor* , 1997, The Journal of Biological Chemistry.

[62]  B. Spiegelman,et al.  AdipoQ Is a Novel Adipose-specific Gene Dysregulated in Obesity (*) , 1996, The Journal of Biological Chemistry.

[63]  NoriyukiOuchi,et al.  Selective Suppression of Endothelial Cell Apoptosis by the High Molecular Weight Form of Adiponectin , 2004 .

[64]  R. Leibel,et al.  CCR2 modulates inflammatory and metabolic effects of high-fat feeding. , 2006, The Journal of clinical investigation.

[65]  A. Ognibene,et al.  Localization of leptin receptor splice variants in mouse peripheral tissues by immunohistochemistry , 1998, Proceedings of the Nutrition Society.

[66]  S. Uchida,et al.  Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase , 2002, Nature Medicine.

[67]  M. Lazar,et al.  How Obesity Causes Diabetes: Not a Tall Tale , 2005, Science.

[68]  M. Febbraio,et al.  Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro. , 2005, American journal of physiology. Endocrinology and metabolism.

[69]  M. Lazar,et al.  The hormone resistin links obesity to diabetes , 2001, Nature.

[70]  J. Flier,et al.  Identification of SOCS-3 as a potential mediator of central leptin resistance. , 1998, Molecular cell.

[71]  D. Hilton,et al.  Inhibitors of Cytokine Signal Transduction* , 2004, Journal of Biological Chemistry.

[72]  M. Birnbaum,et al.  AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus , 2004, Nature.

[73]  A. Xu,et al.  Hydroxylation and Glycosylation of the Four Conserved Lysine Residues in the Collagenous Domain of Adiponectin , 2002, The Journal of Biological Chemistry.

[74]  M. Desai,et al.  Obesity is associated with macrophage accumulation in adipose tissue. , 2003, The Journal of clinical investigation.

[75]  K. Clément,et al.  Relationship between Single Nucleotide Polymorphisms in Leptin, IL6 and Adiponectin Genes and their Circulating Product in Morbidly Obese Subjects before and after Gastric Banding Surgery , 2005, Obesity surgery.

[76]  F. Liu,et al.  Adiponectin Sensitizes Insulin Signaling by Reducing p70 S6 Kinase-mediated Serine Phosphorylation of IRS-1* , 2007, Journal of Biological Chemistry.

[77]  M. Febbraio,et al.  Ciliary neurotrophic factor suppresses hypothalamic AMP-kinase signaling in leptin-resistant obese mice. , 2006, Endocrinology.

[78]  J. Flier,et al.  Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3 , 2004, Nature Medicine.

[79]  M. Matsuda,et al.  PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. , 2001, Diabetes.

[80]  M. Arca,et al.  Human resistin gene, obesity, and type 2 diabetes: mutation analysis and population study. , 2002, Diabetes.

[81]  Feng Liu,et al.  APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function , 2006, Nature Cell Biology.

[82]  K. Nair,et al.  Regional leptin kinetics in humans. , 1999, The American journal of clinical nutrition.

[83]  Young-Bum Kim,et al.  Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase , 2002, Nature.

[84]  S. Elbein,et al.  Adiponectin receptor 1 gene (ADIPOR1) as a candidate for type 2 diabetes and insulin resistance. , 2004, Diabetes.

[85]  M. Stumvoll,et al.  Effects of Genetic Variation in the Human Retinol Binding Protein-4 Gene (RBP4) on Insulin Resistance and Fat Depot–Specific mRNA Expression , 2007, Diabetes.

[86]  H. Baum,et al.  Leptin is cleared from the circulation primarily by the kidney. , 1996, International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity.

[87]  Marnie L. Gruen,et al.  Diet-Induced Increases in Adiposity, but Not Plasma Lipids, Promote Macrophage Infiltration Into White Adipose Tissue , 2007, Diabetes.

[88]  J. Flier,et al.  Divergent Signaling Capacities of the Long and Short Isoforms of the Leptin Receptor* , 1997, The Journal of Biological Chemistry.

[89]  T. Zimmers,et al.  Suppressor of Cytokine Signaling-3 (SOCS-3), a Potential Mediator of Interleukin-6-dependent Insulin Resistance in Hepatocytes* , 2003, The Journal of Biological Chemistry.

[90]  G. Steinberg,et al.  Development of leptin resistance in rat soleus muscle in response to high-fat diets. , 2000, American journal of physiology. Endocrinology and metabolism.

[91]  Young-Bum Kim,et al.  PTP1B regulates leptin signal transduction in vivo. , 2002, Developmental cell.

[92]  A. Deshmukh,et al.  Interleukin-6 Directly Increases Glucose Metabolism in Resting Human Skeletal Muscle , 2007, Diabetes.

[93]  B. Neel,et al.  Neuronal PTP1B regulates body weight, adiposity and leptin action , 2006, Nature Medicine.

[94]  D. James,et al.  Interleukin-6 Increases Insulin-Stimulated Glucose Disposal in Humans and Glucose Uptake and Fatty Acid Oxidation In Vitro via AMP-Activated Protein Kinase , 2006, Diabetes.

[95]  G. Bray,et al.  HF diets increase hypothalamic PTP1B and induce leptin resistance through both leptin-dependent and -independent mechanisms. , 2009, American journal of physiology. Endocrinology and metabolism.

[96]  V. Sánchez-Margalet,et al.  Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway. , 2001, Cellular immunology.

[97]  J. Flier,et al.  SOCS3 Mediates Feedback Inhibition of the Leptin Receptor via Tyr985 * , 2000, The Journal of Biological Chemistry.

[98]  Nimesh Mody,et al.  Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes , 2005, Nature.

[99]  Alexander S. Banks,et al.  STAT3 signalling is required for leptin regulation of energy balance but not reproduction , 2003, Nature.

[100]  Kazuya Yamada,et al.  The G/G genotype of a resistin single-nucleotide polymorphism at -420 increases type 2 diabetes mellitus susceptibility by inducing promoter activity through specific binding of Sp1/3. , 2004, American journal of human genetics.

[101]  J. Park,et al.  Enhanced hypothalamic AMP-activated protein kinase activity contributes to hyperphagia in diabetic rats. , 2005, Diabetes.

[102]  G. Shulman,et al.  Mechanism by Which Fatty Acids Inhibit Insulin Activation of Insulin Receptor Substrate-1 (IRS-1)-associated Phosphatidylinositol 3-Kinase Activity in Muscle* , 2002, The Journal of Biological Chemistry.

[103]  S. O’Rahilly,et al.  Functional characterization of naturally occurring pathogenic mutations in the human leptin receptor. , 2008, Endocrinology.

[104]  R. Coleman,et al.  Leptin Directly Alters Lipid Partitioning in Skeletal Muscle , 1997, Diabetes.

[105]  T. Kadowaki,et al.  Selective purification and characterization of adiponectin multimer species from human plasma. , 2007, Biochemical and biophysical research communications.

[106]  R. Skoda,et al.  Defective STAT signaling by the leptin receptor in diabetic mice. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[107]  H. Münzberg,et al.  Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function. , 2007, The Journal of clinical investigation.

[108]  Kohjiro Ueki,et al.  Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. , 2007, Cell metabolism.

[109]  M. Maffei,et al.  Positional cloning of the mouse obese gene and its human homologue , 1995, Nature.

[110]  F. Lönnqvist,et al.  Leptin secretion from adipose tissue in women. Relationship to plasma levels and gene expression. , 1997, The Journal of clinical investigation.

[111]  L. Tartaglia,et al.  Evidence That the Diabetes Gene Encodes the Leptin Receptor: Identification of a Mutation in the Leptin Receptor Gene in db/db Mice , 1996, Cell.

[112]  K. Kandror,et al.  Lipoprotein Lipase and Leptin Are Accumulated in Different Secretory Compartments in Rat Adipocytes* , 2001, The Journal of Biological Chemistry.

[113]  S. O’Rahilly,et al.  Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans. , 2001, Diabetes.

[114]  M. Febbraio,et al.  CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK , 2006, Nature Medicine.

[115]  M. Lazar,et al.  Regulation of Fasted Blood Glucose by Resistin , 2004, Science.

[116]  N. Ruderman,et al.  Muscle glucose metabolism following exercise in the rat: increased sensitivity to insulin. , 1982, The Journal of clinical investigation.

[117]  N. Ruderman,et al.  Mice Lacking Adiponectin Show Decreased Hepatic Insulin Sensitivity and Reduced Responsiveness to Peroxisome Proliferator-activated Receptor γ Agonists* , 2006, Journal of Biological Chemistry.

[118]  S. Mudaliar,et al.  Selective regulation of cellular and secreted multimeric adiponectin by antidiabetic therapies in humans. , 2009, American journal of physiology. Endocrinology and metabolism.

[119]  A. Saltiel,et al.  Obesity induces a phenotypic switch in adipose tissue macrophage polarization. , 2007, The Journal of clinical investigation.

[120]  T. Golub,et al.  Profiling gene transcription in vivo reveals adipose tissue as an immediate target of tumor necrosis factor-alpha: implications for insulin resistance. , 2002, Diabetes.

[121]  Hong Wang,et al.  Adiponectin Secretion Is Regulated by SIRT1 and the Endoplasmic Reticulum Oxidoreductase Ero1-Lα , 2007, Molecular and Cellular Biology.

[122]  R. Nussbaum,et al.  Disulfide-Dependent Multimeric Assembly of Resistin Family Hormones , 2022 .

[123]  C. Russell,et al.  Regulation of the leptin content of obese human adipose tissue. , 2001, American journal of physiology. Endocrinology and metabolism.

[124]  M. Febbraio,et al.  Muscle‐derived interleukin‐6: mechanisms for activation and possible biological roles , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[125]  Y. Boirie,et al.  Expression of key genes of fatty acid oxidation, including adiponectin receptors, in skeletal muscle of Type 2 diabetic patients , 2004, Diabetologia.

[126]  T. Funahashi,et al.  Plasma adiponectin levels in women with anorexia nervosa. , 2003, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[127]  Alexander S. Banks,et al.  Activation of Downstream Signals by the Long Form of the Leptin Receptor* , 2000, The Journal of Biological Chemistry.

[128]  B. Viollet,et al.  Liver adenosine monophosphate-activated kinase-alpha2 catalytic subunit is a key target for the control of hepatic glucose production by adiponectin and leptin but not insulin. , 2006, Endocrinology.

[129]  J. Olefsky,et al.  Inflamed fat: what starts the fire? , 2005, The Journal of clinical investigation.

[130]  B. Kemp,et al.  Impaired activation of AMP-kinase and fatty acid oxidation by globular adiponectin in cultured human skeletal muscle of obese type 2 diabetics. , 2005, The Journal of clinical endocrinology and metabolism.

[131]  J Licinio,et al.  Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defe , 1999, The Journal of clinical endocrinology and metabolism.

[132]  B. Corkey,et al.  CYTOKINES INHIBIT FATTY ACID OXIDATION IN ISOLATED RAT HEPATOCYTES: SYNERGY AMONG TNF, IL‐6, AND IL‐1 , 1994, Shock.

[133]  A. Pfeiffer,et al.  Evidence That Kidney Function but Not Type 2 Diabetes Determines Retinol-Binding Protein 4 Serum Levels , 2008, Diabetes.

[134]  K. Gumireddy,et al.  Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-kappaB pathway in rat liver. , 2005, Diabetes.

[135]  J. Ohannesian,et al.  Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting. , 1996, The Journal of clinical investigation.

[136]  M. Birnbaum,et al.  Ciliary Neurotrophic Factor Stimulates Muscle Glucose Uptake by a PI3-Kinase–Dependent Pathway That Is Impaired With Obesity , 2009, Diabetes.

[137]  R. Devos,et al.  Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. , 1995, Science.

[138]  J. Flier,et al.  The Role of SOCS-3 in Leptin Signaling and Leptin Resistance* , 1999, The Journal of Biological Chemistry.

[139]  G. Heigenhauser,et al.  AMP-activated protein kinase is not down-regulated in human skeletal muscle of obese females. , 2004, The Journal of clinical endocrinology and metabolism.

[140]  Philipp E. Scherer,et al.  The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor , 1998, Current Biology.

[141]  J. Stephens,et al.  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* , 1997, The Journal of Biological Chemistry.

[142]  B. Pedersen,et al.  AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise. , 2004, Biochemical and biophysical research communications.

[143]  R. Considine,et al.  Leptin receptors in the adrenal medulla of the rat. , 1997, The American journal of physiology.

[144]  B. Kemp,et al.  Oligomeric resistin impairs insulin and AICAR-stimulated glucose uptake in mouse skeletal muscle by inhibiting GLUT4 translocation. , 2009, American journal of physiology. Endocrinology and metabolism.

[145]  G. C. Kennedy,et al.  The role of depot fat in the hypothalamic control of food intake in the rat , 1953, Proceedings of the Royal Society of London. Series B - Biological Sciences.

[146]  K. Clément,et al.  A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction , 1998, Nature.

[147]  P. Froguel,et al.  Impaired Multimerization of Human Adiponectin Mutants Associated with Diabetes , 2003, Journal of Biological Chemistry.

[148]  E. Ravussin,et al.  Adiponectin receptors gene expression and insulin sensitivity in non-diabetic Mexican Americans with or without a family history of Type 2 diabetes , 2004, Diabetologia.

[149]  S. Shoelson,et al.  Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB , 2005, Nature Medicine.

[150]  B. Kemp,et al.  Genetic model for the chronic activation of skeletal muscle AMP-activated protein kinase leads to glycogen accumulation. , 2007, American journal of physiology. Endocrinology and metabolism.

[151]  H. Motoshima,et al.  Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes. , 2003, Diabetes.

[152]  R. Kaufman,et al.  Signaling the Unfolded Protein Response from the Endoplasmic Reticulum* , 2004, Journal of Biological Chemistry.

[153]  E. Ravussin,et al.  Leptin levels in human and rodent: Measurement of plasma leptin and ob RNA in obese and weight-reduced subjects , 1995, Nature Medicine.

[154]  K. Uysal,et al.  Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. , 1997, Nature.

[155]  M. Stumvoll,et al.  Expression of adiponectin receptor mRNA in human skeletal muscle cells is related to in vivo parameters of glucose and lipid metabolism. , 2004, Diabetes.

[156]  P. Strålfors,et al.  Retinol‐binding protein‐4 attenuates insulin‐induced phosphorylation of IRS1 and ERK1/2 in primary human adipocytes , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[157]  M. Lazar,et al.  Loss of Resistin Improves Glucose Homeostasis in Leptin Deficiency , 2006, Diabetes.

[158]  NoriyukiOuchi,et al.  Adipocyte-Derived Plasma Protein, Adiponectin, Suppresses Lipid Accumulation and Class A Scavenger Receptor Expression in Human Monocyte-Derived Macrophages , 2001 .

[159]  S. Shoelson,et al.  Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. , 2005, Nature medicine.

[160]  P. Froguel,et al.  Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions , 2007, Nature Medicine.

[161]  Philipp E. Scherer,et al.  A Novel Serum Protein Similar to C1q, Produced Exclusively in Adipocytes (*) , 1995, The Journal of Biological Chemistry.

[162]  M. Birnbaum,et al.  Activation of SOCS-3 by Resistin , 2005, Molecular and Cellular Biology.

[163]  Jason Chung,et al.  Endoplasmic reticulum stress plays a central role in development of leptin resistance. , 2009, Cell metabolism.