[Novel physiological and therapeutic implications of leptin].

The adipose tissue is an endocrine organ that produces a variety of protein hormones. One of them is leptin, which regulates several critical functions at the central nervous system such as caloric intake, basal energy expenditure, reproduction, glucose and lipid metabolism and osteogenesis. Acting at a local level, leptin modulates the immune system and promotes liver fibrogenesis. The most promising therapeutic implications of leptin will possibly be in type 1 diabetes mellitus (DM1). Its supplementation in animal models of DM1 prevents hyperglycemia and ketoacidosis. These actions depend on the activation of leptin receptors in the central nervous system and the suppression of glucagon signaling in the liver.

[1]  M. J. Charron,et al.  Metabolic manifestations of insulin deficiency do not occur without glucagon action , 2012, Proceedings of the National Academy of Sciences.

[2]  A. Hasty,et al.  Haematopoietic leptin receptor deficiency does not affect macrophage accumulation in adipose tissue or systemic insulin sensitivity. , 2012, The Journal of endocrinology.

[3]  P. Gorden,et al.  Insulin resistance is a sufficient basis for hyperandrogenism in lipodystrophic women with polycystic ovarian syndrome. , 2012, The Journal of clinical endocrinology and metabolism.

[4]  A. Cherrington,et al.  Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. , 2012, The Journal of clinical investigation.

[5]  F. Haj,et al.  Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats , 2011, Proceedings of the National Academy of Sciences.

[6]  M. J. Charron,et al.  Glucagon Receptor Knockout Prevents Insulin-Deficient Type 1 Diabetes in Mice , 2011, Diabetes.

[7]  Rudolph L. Leibel,et al.  Obesity and leptin resistance: distinguishing cause from effect , 2010, Trends in Endocrinology & Metabolism.

[8]  R. Coppari,et al.  Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice , 2010, Proceedings of the National Academy of Sciences.

[9]  O. Ilkayeva,et al.  Leptin therapy in insulin-deficient type I diabetes , 2010, Proceedings of the National Academy of Sciences.

[10]  Qi Sun Leptin and Soluble Leptin Receptor Levels in Plasma and Risk of Type 2 Diabetes in US Women: A Prospective Study , 2009 .

[11]  J. Capeau,et al.  Serum adipokine levels predictive of liver injury in non‐alcoholic fatty liver disease , 2009, Liver international : official journal of the International Association for the Study of the Liver.

[12]  Kenji F. Tanaka,et al.  A Serotonin-Dependent Mechanism Explains the Leptin Regulation of Bone Mass, Appetite, and Energy Expenditure , 2009, Cell.

[13]  E. Ravussin,et al.  Enhanced Weight Loss With Pramlintide/Metreleptin: An Integrated Neurohormonal Approach to Obesity Pharmacotherapy , 2009, Obesity.

[14]  M. Santos,et al.  Leptin-melanocortin system, body weight regulation and obesity. , 2009 .

[15]  I. Leclercq,et al.  Kupffer cells mediate leptin-induced liver fibrosis. , 2009, Gastroenterology.

[16]  Byung-Hyun Park,et al.  Making insulin-deficient type 1 diabetic rodents thrive without insulin , 2008, Proceedings of the National Academy of Sciences.

[17]  C. Kahn,et al.  Central insulin action regulates peripheral glucose and fat metabolism in mice. , 2008, The Journal of clinical investigation.

[18]  M. Fujisawa,et al.  Expression of leptin and leptin receptor in the testis of fertile and infertile patients. , 2007, Andrologia.

[19]  J. Richards,et al.  Effect of selective serotonin reuptake inhibitors on the risk of fracture. , 2007, Archives of internal medicine.

[20]  R. Klein,et al.  Role of brain insulin receptor in control of body weight and reproduction. , 2006, Science.

[21]  B. Ford,et al.  Influence of a leptin deficiency on testicular morphology, germ cell apoptosis, and expression levels of apoptosis-related genes in the mouse. , 2006, Journal of andrology.

[22]  G. Matarese,et al.  The weight of leptin in immunity , 2004, Nature Reviews Immunology.

[23]  G. Mazziotti,et al.  High leptin levels in women developing postpartum thyroiditis , 2004, Clinical endocrinology.

[24]  L. Tartaglia,et al.  Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. , 2003, The Journal of clinical investigation.

[25]  P. Tonali,et al.  Leptin as a marker of multiple sclerosis activity in patients treated with interferon-beta , 2003, Journal of Neuroimmunology.

[26]  M. Vasson,et al.  Leptin Regulates Functional Capacities of Polymorphonuclear Neutrophils , 2003, Free radical research.

[27]  Patricia Ducy,et al.  Leptin Regulates Bone Formation via the Sympathetic Nervous System , 2002, Cell.

[28]  R. Sun,et al.  Impaired natural killer (NK) cell activity in leptin receptor deficient mice: leptin as a critical regulator in NK cell development and activation. , 2002, Biochemical and biophysical research communications.

[29]  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.

[30]  G. Bifulco,et al.  Menstrual status and serum leptin levels in anorectic and in menstruating women with low body mass indexes. , 2002, Fertility and sterility.

[31]  I. Leclercq,et al.  Leptin is essential for the hepatic fibrogenic response to chronic liver injury. , 2002, Journal of hepatology.

[32]  B. Otlu,et al.  Serum leptin concentration is increased in patients with Behçet's syndrome and is correlated with disease activity , 2002, The British journal of dermatology.

[33]  A. Garcia-Gonzalez,et al.  Serum leptin levels in women with systemic lupus erythematosus , 2002, Rheumatology International.

[34]  Y. Takei,et al.  Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. , 2002, Gastroenterology.

[35]  S. Friedman,et al.  Leptin in hepatic fibrosis: Evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice , 2002, Hepatology.

[36]  O. Ziegler,et al.  Obesity is associated with decreasing levels of the circulating soluble leptin receptor in humans , 2002, International Journal of Obesity.

[37]  W. Banks,et al.  Characterizaton of short isoforms of the leptin receptor in rat cerebral microvessels and of brain uptake of leptin in mouse models of obesity. , 2002, Endocrinology.

[38]  M. Reitman,et al.  Leptin-replacement therapy for lipodystrophy. , 2002, The New England journal of medicine.

[39]  R. Faggioni,et al.  Leptin regulation of the immune response and the immunodeficiency of malnutrition 1 , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[40]  M. Bidlingmaier,et al.  High-Dose Leptin Activates Human Leukocytes Via Receptor Expression on Monocytes1 , 2001, The Journal of Immunology.

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

[42]  Y. Takei,et al.  Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals , 2001, Hepatology.

[43]  M. Westerterp-Plantenga,et al.  Weekly subcutaneous pegylated recombinant native human leptin (PEG-OB) administration in obese men. , 2000, The Journal of clinical endocrinology and metabolism.

[44]  S. Friedman Molecular Regulation of Hepatic Fibrosis, an Integrated Cellular Response to Tissue Injury* , 2000, The Journal of Biological Chemistry.

[45]  Arndt F Schilling,et al.  Leptin Inhibits Bone Formation through a Hypothalamic Relay A Central Control of Bone Mass , 2000, Cell.

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

[47]  Graham M Lord,et al.  Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. , 1999, The Journal of clinical investigation.

[48]  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.

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

[50]  N. Chinookoswong,et al.  Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat. , 1999, Diabetes.

[51]  A. Klibanski,et al.  Severity of osteopenia in estrogen-deficient women with anorexia nervosa and hypothalamic amenorrhea. , 1999, The Journal of clinical endocrinology and metabolism.

[52]  J. Halaas,et al.  Leptin and the regulation of body weight in mammals , 1998, Nature.

[53]  J. Flier Lowered leptin slims immune response , 1998, Nature Medicine.

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

[55]  A. Bado,et al.  The stomach is a source of leptin , 1998, Nature.

[56]  C. Saper,et al.  Distributions of leptin receptor mRNA isoforms in the rat brain , 1998, The Journal of comparative neurology.

[57]  K. Nakao,et al.  Nonadipose tissue production of leptin: Leptin as a novel placenta-derived hormone in humans , 1997, Nature Medicine.

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

[59]  F. Casanueva,et al.  Serum immunoreactive leptin concentrations in patients with anorexia nervosa before and after partial weight recovery. , 1997, Biochemical and molecular medicine.

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

[61]  K. Mounzih,et al.  Leptin treatment rescues the sterility of genetically obese ob/ob males. , 1997, Endocrinology.

[62]  A. Mikhail,et al.  Novel B219/OB receptor isoforms: Possible role of leptin in hematopoiesis and reproduction , 1996, Nature Medicine.

[63]  F. Chehab,et al.  Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin , 1996, Nature Genetics.

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

[65]  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.

[66]  J. Bue-Valleskey,et al.  The role of neuropeptide Y in the antiobesity action of the obese gene product , 1995, Nature.

[67]  Thomas Madej,et al.  Threading analysis suggests that the obese gene product may be a helical cytokine , 1995, FEBS letters.

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

[69]  M. Mandel,et al.  Impairment of cell-mediated immunity in mutation diabetic mice (db/db). , 1978, Journal of immunology.

[70]  G. Bray,et al.  Reproductive hormonal function in the genetically obese (ob/ob) mouse. , 1976, Endocrinology.

[71]  J. Santos M [Leptin-melanocortin system, body weight regulation and obesity]. , 2009, Revista medica de Chile.

[72]  G. Frühbeck,et al.  Intracellular signalling pathways activated by leptin. , 2006, The Biochemical journal.

[73]  J. I. Botella Carretero,et al.  [Leptin: physiological and clinical role]. , 2001, Anales de medicina interna.

[74]  W. Alvord,et al.  Interleukin 1 alpha increases serum leptin concentrations in humans. , 1997, The Journal of clinical endocrinology and metabolism.

[75]  R. Chandra Cell-mediated immunity in genetically obese C57BL/6J ob/ob) mice. , 1980, The American journal of clinical nutrition.