The central regulation of bone mass, the first link between bone remodeling and energy metabolism.

Evolutionary consideration and clinical observations led us to hypothesize 10 yr ago that there may be a coordinated regulation, endocrine in nature, of bone remodeling and energy metabolism. The existence of this coordinated regulation is motivated by the energetic needs of the skeleton; therefore, this regulation relies on hormones that appear during evolution with the skeleton, not with energy metabolism. Leptin is such a hormone, and it is a critical regulator of bone mass as well as of appetite and energy expenditure. This review goes over the anatomical route and molecular pathways used by leptin to inhibit both bone mass accrual and appetite through its signaling in the brain.

[1]  A. Schilling,et al.  Leptin Inhibits Bone Formation Not Only in Rodents, but Also in Sheep , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[2]  M. Casteels,et al.  Osteoporosis after combined use of a neuroleptic and antidepressants , 2008, Pharmacy World & Science.

[3]  R. Jilka,et al.  Sex steroids and bone. , 2002, Recent progress in hormone research.

[4]  G Shimamoto,et al.  Osteoprotegerin: A Novel Secreted Protein Involved in the Regulation of Bone Density , 1997, Cell.

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

[6]  W. Kaye,et al.  Serotonin neuronal function and selective serotonin reuptake inhibitor treatment in anorexia and bulimia nervosa , 1998, Biological Psychiatry.

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

[8]  S. Morony,et al.  OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis , 1999, Nature.

[9]  A. Hofman,et al.  Selective Serotonin Reuptake Inhibiting Antidepressants Are Associated With an Increased Risk of Nonvertebral Fractures , 2008, Journal of clinical psychopharmacology.

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

[11]  Steven A. Thomas,et al.  Thermoregulatory and metabolic phenotypes of mice lacking noradrenaline and adrenaline , 1997, nature.

[12]  R. Hen,et al.  Serotonin Receptors: Genetic insights into serotonin function , 1995, Current Biology.

[13]  E. Wagner,et al.  The Molecular Clock Mediates Leptin-Regulated Bone Formation , 2005, Cell.

[14]  G. Karsenty,et al.  A paradigm of integrative physiology, the crosstalk between bone and energy metabolisms , 2009, Molecular and Cellular Endocrinology.

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

[16]  Michael Bader,et al.  Synthesis of Serotonin by a Second Tryptophan Hydroxylase Isoform , 2003, Science.

[17]  P. J. Larsen,et al.  Hypothalamic CART is a new anorectic peptide regulated by leptin , 1998, Nature.

[18]  Clifford B. Saper,et al.  Leptin Regulation of Neuroendocrine Systems , 2000, Frontiers in Neuroendocrinology.

[19]  X. Guo,et al.  Dissociation of the neuronal regulation of bone mass and energy metabolism by leptin in vivo , 2008, Proceedings of the National Academy of Sciences.

[20]  G. Karsenty,et al.  Convergence between bone and energy homeostases: leptin regulation of bone mass. , 2006, Cell metabolism.

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

[22]  T. Martin,et al.  Therapeutic approaches to bone diseases. , 2000, Science.

[23]  S. Takeda,et al.  Serum leptin level is a regulator of bone mass. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[24]  H. Horvitz,et al.  Serotonin and octopamine in the nematode Caenorhabditis elegans. , 1982, Science.

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

[26]  Yun-Fei Chen,et al.  Absence of Cocaine- and Amphetamine-Regulated Transcript Results in Obesity in Mice Fed a High Caloric Diet. , 2001, Endocrinology.

[27]  S. Manolagas.  Corticosteroids and Fractures: A Close Encounter of the Third Cell Kind , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[28]  S. Mundlos,et al.  Cbfa1, a Candidate Gene for Cleidocranial Dysplasia Syndrome, Is Essential for Osteoblast Differentiation and Bone Development , 1997, Cell.

[29]  J Glowacki,et al.  Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. , 1994, Genes & development.

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

[31]  R. Ahima.  Adipose Tissue as an Endocrine Organ , 2006, Obesity.

[32]  J. John Mann,et al.  Lrp5 Controls Bone Formation by Inhibiting Serotonin Synthesis in the Duodenum , 2008, Cell.

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

[34]  J. Cauley,et al.  Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men. , 2007, Archives of internal medicine.

[35]  Bruce M. Spiegelman,et al.  Obesity and the Regulation of Energy Balance , 2001, Cell.

[36]  Kaveh Ashrafi,et al.  Serotonin regulates C. elegans fat and feeding through independent molecular mechanisms. , 2008, Cell metabolism.

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

[38]  G. Bray,et al.  The MONA LISA hypothesis in the time of leptin. , 1998, Recent progress in hormone research.

[39]  W. O'Fallon,et al.  Long‐Term Effects of Calcium Supplementation on Serum Parathyroid Hormone Level, Bone Turnover, and Bone Loss in Elderly Women , 1998, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[40]  R. Ahima.  Body fat, leptin, and hypothalamic amenorrhea. , 2004, The New England journal of medicine.

[41]  M. McKee,et al.  Endocrine Regulation of Energy Metabolism by the Skeleton , 2007, Cell.

[42]  Gideon A. Rodan,et al.  Control of osteoblast function and regulation of bone mass , 2003, Nature.

[43]  E. Wagner,et al.  Bone and haematopoietic defects in mice lacking c-fos , 1992, Nature.

[44]  C. Saper,et al.  Chemical characterization of leptin‐activated neurons in the rat brain , 2000, The Journal of comparative neurology.

[45]  K. Desai,et al.  Targeted Disruption of the β2 Adrenergic Receptor Gene* , 1999, The Journal of Biological Chemistry.

[46]  L. Melton,et al.  Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. , 2001, The Journal of clinical endocrinology and metabolism.

[47]  K. Kaestner,et al.  The sympathetic tone mediates leptin's inhibition of insulin secretion by modulating osteocalcin bioactivity , 2008, The Journal of cell biology.

[48]  Masaki Noda,et al.  Leptin regulation of bone resorption by the sympathetic nervous system and CART , 2005, Nature.

[49]  G. Karsenty,et al.  Osteocalcin differentially regulates β cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice , 2008, Proceedings of the National Academy of Sciences.

[50]  S. Teitelbaum.  Osteoclasts, integrins, and osteoporosis , 2000, Journal of Bone and Mineral Metabolism.