Role of leptin and adiponectin in insulin resistance.

Adipose tissue is a major source of energy for the human body. It is also a source of major adipocytokines adiponectin and leptin. Insulin resistance is a condition in which insulin action is impaired in adipose tissue and is more strongly linked to intra-abdominal fat than to fat in other depots. The expression of adiponectin decreases with increase in the adiposity. Adiponectin mediates insulin-sensitizing effect through binding to its receptors AdipoR1 and AdipoR2, leading to activation of adenosine monophosphate dependent kinase (AMPK), PPAR-α, and presumably other yet-unknown signalling pathways. Weight loss significantly elevates plasma adiponectin levels. Reduction of adiponectin has been associated with insulin resistance, dyslipidemia, and atherosclerosis in humans. The other major adipokine is leptin. Leptin levels increase in obesity and subcutaneous fat has been a major determinant of circulating leptin levels. The leptin signal is transmitted by the Janus kinase, signal transducer and activator of transcription ((JAK-STAT) pathway. The net action of leptin is to inhibit appetite, stimulate thermogenesis, enhance fatty acid oxidation, decrease glucose, and reduce body weight and fat.

[1]  C. Drevon,et al.  Adiponectin and its receptors are expressed in bone-forming cells. , 2004, Bone.

[2]  R. Paschke,et al.  Growth hormone is a positive regulator of adiponectin receptor 2 in 3T3‐L1 adipocytes , 2004 .

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

[4]  H. Münzberg,et al.  Leptin Receptor Signaling and Action in the Central Nervous System , 2006, Obesity.

[5]  S. Kihara,et al.  Genomic structure and mutations in adipose-specific gene, adiponectin , 2000, International Journal of Obesity.

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

[7]  G. Hotamisligil.  The role of TNFα and TNF receptors in obesity and insulin resistance , 1999 .

[8]  C. Kahn,et al.  Critical nodes in signalling pathways: insights into insulin action , 2006, Nature Reviews Molecular Cell Biology.

[9]  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.

[10]  H. Lodish,et al.  Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[11]  T Nakamura,et al.  Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[12]  U. Broedl,et al.  Adipokines and Insulin Resistance , 2008, Molecular medicine.

[13]  M. Stumvoll,et al.  Induction of adiponectin gene expression in human myotubes by an adiponectin-containing HEK293 cell culture supernatant , 2003, Diabetologia.

[14]  T Nakamura,et al.  Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. , 1999, Biochemical and biophysical research communications.

[15]  H. Grill,et al.  The Neuroanatomical Axis for Control of Energy Balance , 2002, Frontiers in Neuroendocrinology.

[16]  J. Chan,et al.  Recombinant human leptin in women with hypothalamic amenorrhea. , 2004 .

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

[18]  A. Greenberg,et al.  Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1998 by The Endocrine Society Omental and Subcutaneous Adipose Tissues of Obese Subjects Release Interleukin-6: Depot Difference and Regulation by Glucocorticoid* , 1997 .

[19]  R. Considine,et al.  Serum immunoreactive-leptin concentrations in normal-weight and obese humans. , 1996, The New England journal of medicine.

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

[21]  T. Tobe,et al.  Regulation of gelatin-binding protein 28 (GBP28) gene expression by C/EBP. , 1999, Biological & pharmaceutical bulletin.

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

[23]  J. Weber,et al.  Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[24]  S. O’Rahilly,et al.  Induction of Adipocyte Complement-related Protein of 30 Kilodaltons by Ppar␥ Agonists: a Potential Mechanism of Insulin Sensitization , 2022 .

[25]  T. Funahashi,et al.  cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). , 1996, Biochemical and biophysical research communications.

[26]  M. Moscarello,et al.  The incorporation of [14C] D‐galactose and [3H] D‐mannose into Golgi fractions of rat liver and into serum , 1972, FEBS letters.

[27]  D. Hardie,et al.  AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. , 2005, Cell metabolism.

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

[29]  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.

[30]  M. Matsuda,et al.  Diet-induced insulin resistance in mice lacking adiponectin/ACRP30 , 2002, Nature Medicine.

[31]  K. Nakao,et al.  Structure-Function Studies of Human Leptin* , 1998, The Journal of Biological Chemistry.

[32]  K. Walsh,et al.  A novel role for adiponectin in the regulation of inflammation. , 2008, Arteriosclerosis, thrombosis, and vascular biology.

[33]  W. Rand,et al.  Arcuate Nucleus Ablation Prevents Fasting-Induced Suppression of ProTRH mRNA in the Hypothalamic Paraventricular Nucleus , 1998, Neuroendocrinology.

[34]  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.

[35]  R. Bergman,et al.  Central Role of the Adipocyte in Insulin Resistance , 1998, Journal of basic and clinical physiology and pharmacology.

[36]  M. Matsuda,et al.  Association of adiponectin mutation with type 2 diabetes: a candidate gene for the insulin resistance syndrome. , 2002, Diabetes.

[37]  Stephen R. Bloom,et al.  Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression , 1998, Nature.

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

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

[40]  R. Hoffmann,et al.  Leptin: A Significant Indicator of Total Body Fat but Not of Visceral Fat and Insulin Insensitivity in African-American Women , 1996, Diabetes.

[41]  S. Heymsfield,et al.  Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. , 2005, The Journal of clinical investigation.

[42]  Graham M Lord,et al.  Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. , 2002, The Journal of clinical investigation.

[43]  K. Houseknecht,et al.  The biology of leptin: a review. , 1998, Journal of animal science.

[44]  M. Schwartz,et al.  Insulin and its evolving partnership with leptin in the hypothalamic control of energy homeostasis , 2004, Trends in Endocrinology & Metabolism.

[45]  C. Mantzoros,et al.  Role of leptin in the neuroendocrine response to fasting , 1996, Nature.

[46]  H. Motoshima,et al.  Differential regulation of adiponectin secretion from cultured human omental and subcutaneous adipocytes: effects of insulin and rosiglitazone. , 2002, The Journal of clinical endocrinology and metabolism.

[47]  M. Matsuda,et al.  Visfatin: A Protein Secreted by Visceral Fat That Mimics the Effects of Insulin , 2005, Science.

[48]  S. Brichard,et al.  Induction of adiponectin in skeletal muscle by inflammatory cytokines: in vivo and in vitro studies. , 2004, Endocrinology.

[49]  P. Froguel,et al.  The genetics of adiponectin , 2003, Current diabetes reports.

[50]  L. Cornivelli,et al.  Multiple Regulatory Roles of a Novel Saccharomyces cerevisiae Protein, Encoded by YOL002c, in Lipid and Phosphate Metabolism* , 2002, The Journal of Biological Chemistry.

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

[52]  K. Takahashi,et al.  Change in expression of GBP28/adiponectin in carbon tetrachloride-administrated mouse liver. , 2001, Biochemical and biophysical research communications.

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

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

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

[56]  J. Flier.  Obesity Wars Molecular Progress Confronts an Expanding Epidemic , 2004, Cell.

[57]  H. Lodish,et al.  T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[58]  M. Matsuda,et al.  Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. , 2003, Diabetes.

[59]  G. Frühbeck,et al.  Leptin: physiology and pathophysiology. , 1998, Clinical physiology.

[60]  C. Dina,et al.  Genomewide search for type 2 diabetes-susceptibility genes in French whites: evidence for a novel susceptibility locus for early-onset diabetes on chromosome 3q27-qter and independent replication of a type 2-diabetes locus on chromosome 1q21-q24. , 2000, American journal of human genetics.

[61]  D. Eizirik,et al.  Expression of adiponectin receptors in pancreatic beta cells. , 2003, Biochemical and biophysical research communications.

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

[63]  H. Münzberg,et al.  Molecular and anatomical determinants of central leptin resistance , 2005, Nature Neuroscience.

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

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

[66]  S. Yamashita,et al.  Enhanced expression of PAI–1 in visceral fat: Possible contributor to vascular disease in obeisty , 1996, Nature Medicine.

[67]  J. Olefsky.  Treatment of insulin resistance with peroxisome proliferator–activated receptor γ agonists , 2000 .

[68]  G. Lopaschuk,et al.  gAd-globular Head Domain of Adiponectin Increases Fatty Acid Oxidation in Newborn Rabbit Hearts* , 2004, Journal of Biological Chemistry.

[69]  T. Funahashi,et al.  Elevated serum concentration of adipose-derived factor, adiponectin, in patients with type 1 diabetes. , 2002, Diabetes care.

[70]  C. Newgard,et al.  A novel leptin receptor isoform in rat , 1996, FEBS letters.

[71]  N. Shimizu,et al.  Organization of the gene for gelatin-binding protein (GBP28). , 1999, Gene.

[72]  J. Friedman.  Diabetes: Fat in all the wrong places , 2002, Nature.

[73]  P. Scherer,et al.  The adipocyte-secreted protein Acrp30 enhances hepatic insulin action , 2001, Nature Medicine.

[74]  C. Kahn,et al.  Insulin signalling and the regulation of glucose and lipid metabolism , 2001, Nature.

[75]  Y. Nakano,et al.  Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. , 1996, Journal of biochemistry.

[76]  Y. Lin,et al.  Chromosomal localization, expression pattern, and promoter analysis of the mouse gene encoding adipocyte-specific secretory protein Acrp30. , 2001, Biochemical and biophysical research communications.

[77]  T. Kadowaki,et al.  Adiponectin and adiponectin receptors. , 2005, Endocrine reviews.

[78]  J. Chan,et al.  The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. , 2003, The Journal of clinical investigation.

[79]  R. Piñeiro,et al.  Adiponectin is synthesized and secreted by human and murine cardiomyocytes , 2005, FEBS letters.

[80]  P. Froguel,et al.  Insulin/Foxo1 Pathway Regulates Expression Levels of Adiponectin Receptors and Adiponectin Sensitivity* , 2004, Journal of Biological Chemistry.