The adipocyte as an active participant in energy balance and metabolism.

Obesity is responsible for the mounting incidence of metabolic disease in adult and pediatric populations. Understanding of the pathogenesis and maintenance of the obese state has advanced rapidly over the past 10 years. Bodily energy reserves are managed actively by complex systems that regulate food intake, substrate partitioning, and energy expenditure. An underlying assumption that circulating factors released from storage organs were able to signal bodily energy reserves was confirmed with the discovery of the leptin system. This proof of concept has spurred on the discovery of a multitude of other adipocyte-generated factors. These circulating factors signal to the brain and other organs of metabolic importance, including adipose tissue, liver, muscle, and the immune system. Adipose-derived factors have numerous implications for the basic biology of obesity and provide prospective targets for the amelioration of obesity and its adverse metabolic consequences. In this review we detail the current understanding of leptin as a prototypical adipose tissue-derived hormone related to appetite and obesity. We also describe other important adipose-derived factors in relation to their metabolic effect.

[1]  A. Xu,et al.  Overexpression of angiopoietin-like protein 4 alters mitochondria activities and modulates methionine metabolic cycle in the liver tissues of db/db diabetic mice. , 2007, Molecular endocrinology.

[2]  M. Wolzt,et al.  Serum retinol-binding protein 4 is reduced after weight loss in morbidly obese subjects. , 2007, The Journal of clinical endocrinology and metabolism.

[3]  W. Chu,et al.  Retinol binding protein 4 as a candidate gene for type 2 diabetes and prediabetic intermediate traits. , 2007, Molecular genetics and metabolism.

[4]  K. Kos,et al.  Adiponectin and resistin in human cerebrospinal fluid and expression of adiponectin receptors in the human hypothalamus. , 2007, The Journal of clinical endocrinology and metabolism.

[5]  K. Park,et al.  Plasma Retinol-Binding Protein-4 Concentrations Are Elevated in Human Subjects With Impaired Glucose Tolerance and Type 2 Diabetes , 2007, Diabetes Care.

[6]  M. Blüher,et al.  Shortcomings in methodology complicate measurements of serum retinol binding protein (RBP4) in insulin-resistant human subjects , 2007, Diabetologia.

[7]  A. Kaser,et al.  Visfatin, an Adipocytokine with Proinflammatory and Immunomodulating Properties1 , 2007, The Journal of Immunology.

[8]  Spain,et al.  Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. , 2007, The New England journal of medicine.

[9]  Jeffrey I. Gordon,et al.  Mechanisms underlying the resistance to diet-induced obesity in germ-free mice , 2007, Proceedings of the National Academy of Sciences.

[10]  J. DeLany,et al.  Secretome of Primary Cultures of Human Adipose-derived Stem Cells , 2007, Molecular & Cellular Proteomics.

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

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

[13]  Arya M. Sharma,et al.  Retinol-Binding Protein 4 in Human Obesity , 2006, Diabetes.

[14]  Xiao-Bing Gao,et al.  Leptin Receptor Signaling in Midbrain Dopamine Neurons Regulates Feeding , 2006, Neuron.

[15]  S. Fulton,et al.  Leptin Regulation of the Mesoaccumbens Dopamine Pathway , 2006, Neuron.

[16]  R. Ahima,et al.  Area Postrema Neurons Are Modulated by the Adipocyte Hormone Adiponectin , 2006, The Journal of Neuroscience.

[17]  S. Fried,et al.  Multilevel regulation of leptin storage, turnover, and secretion by feeding and insulin in rat adipose tissue Published, JLR Papers in Press, May 31, 2006. , 2006, Journal of Lipid Research.

[18]  Kohjiro Ueki,et al.  Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. , 2006, The Journal of clinical investigation.

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

[20]  R. Kitazawa,et al.  MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. , 2006, The Journal of clinical investigation.

[21]  L. Bernstein,et al.  Effects of etanercept in patients with the metabolic syndrome. , 2006, Archives of internal medicine.

[22]  H. Cai,et al.  Induction of leptin resistance through direct interaction of C-reactive protein with leptin , 2006, Nature Medicine.

[23]  M. Febbraio,et al.  Discordant gene expression in skeletal muscle and adipose tissue of patients with type 2 diabetes: effect of interleukin-6 infusion , 2006, Diabetologia.

[24]  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.

[25]  Robert A. McGovern,et al.  Leptin Directly Activates SF1 Neurons in the VMH, and This Action by Leptin Is Required for Normal Body-Weight Homeostasis , 2006, Neuron.

[26]  W. Wahli,et al.  The Fasting-induced Adipose Factor/Angiopoietin-like Protein 4 Is Physically Associated with Lipoproteins and Governs Plasma Lipid Levels and Adiposity* , 2006, Journal of Biological Chemistry.

[27]  M. Fasshauer,et al.  Vaspin gene expression in human adipose tissue: association with obesity and type 2 diabetes. , 2006, Biochemical and biophysical research communications.

[28]  Eijiro Watanabe,et al.  Visceral adipose tissue-derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

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

[30]  T. Standiford,et al.  Pre-B-cell colony-enhancing factor as a potential novel biomarker in acute lung injury. , 2005, American journal of respiratory and critical care medicine.

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

[32]  L. V. Van Gaal,et al.  Visceral fat as a determinant of fibrinolysis and hemostasis. , 2005, Seminars in vascular medicine.

[33]  D. Porte,et al.  Diabetes, Obesity, and the Brain , 2005, Science.

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

[35]  Ting Wang,et al.  The gut microbiota as an environmental factor that regulates fat storage. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[36]  M. Reilly,et al.  An Inflammatory Cascade Leading to Hyperresistinemia in Humans , 2004, PLoS medicine.

[37]  S. O’Rahilly,et al.  Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy. , 2004, The Journal of clinical endocrinology and metabolism.

[38]  A. Rissanen,et al.  Overexpression of 11beta-hydroxysteroid dehydrogenase-1 in adipose tissue is associated with acquired obesity and features of insulin resistance: studies in young adult monozygotic twins. , 2004, The Journal of clinical endocrinology and metabolism.

[39]  W. Wahli,et al.  The Direct Peroxisome Proliferator-activated Receptor Target Fasting-induced Adipose Factor (FIAF/PGAR/ANGPTL4) Is Present in Blood Plasma as a Truncated Protein That Is Increased by Fenofibrate Treatment* , 2004, Journal of Biological Chemistry.

[40]  M. Suchard,et al.  Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

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

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

[43]  B. Lowell,et al.  Leptin Receptor Signaling in POMC Neurons Is Required for Normal Body Weight Homeostasis , 2004, Neuron.

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

[45]  L. Kuller,et al.  The Chronic Inflammatory Hypothesis for the Morbidity Associated with Morbid Obesity: Implications and Effects of Weight Loss , 2004, Obesity surgery.

[46]  A. Madan,et al.  Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. , 2004, Endocrinology.

[47]  A. Blanks,et al.  Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus , 2004, Nature Neuroscience.

[48]  J. Marshall,et al.  Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis. , 2004, The Journal of clinical investigation.

[49]  H. Sul,et al.  Dominant inhibitory adipocyte-specific secretory factor (ADSF)/resistin enhances adipogenesis and improves insulin sensitivity. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[50]  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.

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

[52]  J. Flier,et al.  Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 beta-hydroxysteroid dehydrogenase type 1-deficient mice. , 2004, Diabetes.

[53]  M. Lazar,et al.  The current biology of resistin , 2004, Journal of internal medicine.

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

[56]  O. McGuinness,et al.  Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. , 2004, Diabetes.

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

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

[59]  S. Zolotukhin,et al.  Sustained peripheral expression of transgene adiponectin offsets the development of diet-induced obesity in rats , 2003, Proceedings of the National Academy of Sciences of the United States of America.

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

[61]  J. Bunt,et al.  Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pima Indians and Caucasians. , 2003, The Journal of clinical endocrinology and metabolism.

[62]  L. Lönn,et al.  High expression of complement components in omental adipose tissue in obese men. , 2003, Obesity research.

[63]  D. Loskutoff,et al.  Monocyte chemoattractant protein 1 in obesity and insulin resistance , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[64]  M. Lazar,et al.  Resistin: molecular history and prognosis , 2003, Journal of Molecular Medicine.

[65]  K. Cianflone,et al.  Critical review of acylation-stimulating protein physiology in humans and rodents. , 2003, Biochimica et biophysica acta.

[66]  I. Bujalska,et al.  Expression of 11β-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue Is Not Increased in Human Obesity , 2002 .

[67]  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.

[68]  Kenichi Yoshida,et al.  Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase Published, JLR Papers in Press, September 16, 2002. DOI 10.1194/jlr.C200010-JLR200 , 2002, Journal of Lipid Research.

[69]  S Margetic,et al.  Leptin: a review of its peripheral actions and interactions , 2002, International Journal of Obesity.

[70]  O. Pedersen,et al.  Association studies between microsatellite markers within the gene encoding human 11beta-hydroxysteroid dehydrogenase type 1 and body mass index, waist to hip ratio, and glucocorticoid metabolism. , 2002, The Journal of clinical endocrinology and metabolism.

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

[72]  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.

[73]  P. Saha,et al.  Increased β-Oxidation but No Insulin Resistance or Glucose Intolerance in Mice Lacking Adiponectin* , 2002, The Journal of Biological Chemistry.

[74]  Philippe Froguel,et al.  Disruption of Adiponectin Causes Insulin Resistance and Neointimal Formation* , 2002, The Journal of Biological Chemistry.

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

[76]  P. Morange,et al.  Stromal Cells Are the Main Plasminogen Activator Inhibitor‐1‐Producing Cells in Human Fat: Evidence of Differences Between Visceral and Subcutaneous Deposits , 2002, Arteriosclerosis, thrombosis, and vascular biology.

[77]  J. Flier,et al.  A Transgenic Model of Visceral Obesity and the Metabolic Syndrome , 2001, Science.

[78]  J. Friedman,et al.  Selective deletion of leptin receptor in neurons leads to obesity. , 2001, The Journal of clinical investigation.

[79]  J. Whisstock,et al.  The Serpins Are an Expanding Superfamily of Structurally Similar but Functionally Diverse Proteins , 2001, The Journal of Biological Chemistry.

[80]  D. Loskutoff,et al.  Disruption of the plasminogen activator inhibitor‐1 gene reduces the adiposity and improves the metabolic profile of genetically obese and diabetic ob/ob mice , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[81]  M. Low,et al.  Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus , 2001, Nature.

[82]  M. Moreno-Aliaga,et al.  Transcriptional regulation of the leptin promoter by insulin-stimulated glucose metabolism in 3t3-l1 adipocytes. , 2001, Biochemical and biophysical research communications.

[83]  T. Funahashi,et al.  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. , 2001, Diabetes.

[84]  G. Shulman,et al.  Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver , 2001, Nature.

[85]  T. Kowalski,et al.  Transgenic complementation of leptin-receptor deficiency. I. Rescue of the obesity/diabetes phenotype of LEPR-null mice expressing a LEPR-B transgene. , 2001, Diabetes.

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

[87]  P. Strippoli,et al.  LACK OF MUTATIONS OF TYPE 1 11β-HYDROXYSTEROID DEHYDROGENASE GENE IN PATIENTS WITH ABDOMINAL OBESITY , 2001, Endocrine research.

[88]  P. Chambon,et al.  Characterization of the Fasting-induced Adipose Factor FIAF, a Novel Peroxisome Proliferator-activated Receptor Target Gene* , 2000, The Journal of Biological Chemistry.

[89]  Young-Bum Kim,et al.  Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice , 2000, Molecular and Cellular Biology.

[90]  B. Spiegelman,et al.  Peroxisome Proliferator-Activated Receptor γ Target Gene Encoding a Novel Angiopoietin-Related Protein Associated with Adipose Differentiation , 2000, Molecular and Cellular Biology.

[91]  Hong-Hee Kim,et al.  Hepatic expression, synthesis and secretion of a novel fibrinogen/angiopoietin-related protein that prevents endothelial-cell apoptosis , 2000 .

[92]  B. Walker,et al.  Understanding the Role of Glucocorticoids in Obesity: Tissue-Specific Alterations of Corticosterone Metabolism in Obese Zucker Rats1. , 2000, Endocrinology.

[93]  A. Prentice,et al.  Effects of recombinant leptin therapy in a child with congenital leptin deficiency. , 1999, The New England journal of medicine.

[94]  Clifford B Saper,et al.  Leptin Differentially Regulates NPY and POMC Neurons Projecting to the Lateral Hypothalamic Area , 1999, Neuron.

[95]  H. Fukuda,et al.  Transcriptional regulation of leptin gene promoter in rat , 1999, FEBS letters.

[96]  B. Kennedy,et al.  Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. , 1999, Science.

[97]  A. Boulton,et al.  Cortisol metabolism in human obesity: impaired cortisone-->cortisol conversion in subjects with central adiposity. , 1999, The Journal of clinical endocrinology and metabolism.

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

[99]  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.

[100]  A. Strosberg,et al.  A leptin missense mutation associated with hypogonadism and morbid obesity , 1998, Nature Genetics.

[101]  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 .

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

[103]  J. Seckl,et al.  11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[104]  S. O’Rahilly,et al.  Congenital leptin deficiency is associated with severe early-onset obesity in humans , 1997, Nature.

[105]  C. Mantzoros,et al.  Human leptin levels are pulsatile and inversely related to pituitary–ardenal function , 1997, Nature Medicine.

[106]  J. Flier,et al.  Leptin accelerates the onset of puberty in normal female mice. , 1997, The Journal of clinical investigation.

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

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

[109]  Roy Taylor,et al.  Effects of an Engineered Human Anti–TNF-α Antibody (CDP571) on Insulin Sensitivity and Glycemic Control in Patients With NIDDM , 1996, Diabetes.

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

[111]  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.

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

[113]  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.

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

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

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

[117]  I McNiece,et al.  Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor , 1994, Molecular and cellular biology.

[118]  M. Papa,et al.  Tumor necrosis factor-alpha suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates. , 1993, The Journal of biological chemistry.

[119]  B. Spiegelman,et al.  Human adipsin is identical to complement factor D and is expressed at high levels in adipose tissue. , 1992, The Journal of biological chemistry.

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

[121]  A. Zhao Is leptin an important physiological regulator of CRP? , 2007, Nature Medicine.

[122]  S. O’Rahilly,et al.  Is leptin an important physiological regulator of CRP? , 2007, Nature Medicine.

[123]  S. Reicher,et al.  Is leptin an important physiological regulator of CRP? , 2007, Nature Medicine.

[124]  M. Pepys,et al.  Is leptin an important physiological regulator of CRP? , 2007, Nature Medicine.

[125]  W. Banks,et al.  Adiponectin Does Not Cross the Blood-Brain Barrier but Modifies Cytokine Expression of Brain Endothelial Cells , 2006 .

[126]  T. Ludwig,et al.  The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity. , 2005, Cell metabolism.

[127]  Y. Deshaies,et al.  A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity. , 2004, Endocrinology.

[128]  B. Kahn,et al.  Leptin signaling in the central nervous system and the periphery. , 2004, Recent progress in hormone research.

[129]  B. Walker,et al.  Glucocorticoids and 11beta-hydroxysteroid dehydrogenase in adipose tissue. , 2004, Recent progress in hormone research.

[130]  Arya M. Sharma,et al.  Regulation of 11β‐HSD Genes in Human Adipose Tissue: Influence of Central Obesity and Weight Loss , 2004 .

[131]  J. Flier,et al.  Clinical review 94: What's in a name? In search of leptin's physiologic role. , 1998, The Journal of clinical endocrinology and metabolism.

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

[133]  M. Reitman,et al.  Regulation of leptin promoter function by Sp1, C/EBP, and a novel factor. , 1998, Endocrinology.