Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass.
Gonadal failure induces bone loss while obesity prevents it. This raises the possibility that bone mass, body weight, and gonadal function are regulated by common pathways. To test this hypothesis, we studied leptin-deficient and leptin receptor-deficient mice that are obese and hypogonadic. Both mutant mice have an increased bone formation leading to high bone mass despite hypogonadism and hypercortisolism. This phenotype is dominant, independent of the presence of fat, and specific for the absence of leptin signaling. There is no leptin signaling in osteoblasts but intracerebroventricular infusion of leptin causes bone loss in leptin-deficient and wild-type mice. This study identifies leptin as a potent inhibitor of bone formation acting through the central nervous system and therefore describes the central nature of bone mass control and its disorders.
Ducy
P
P
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Amling
M
M
Takeda
S
S
Priemel
M
M
Schilling
A F
AF
Beil
F T
FT
Shen
J
J
Vinson
C
C
Rueger
J M
JM
Karsenty
G
G
D000818:Animals; D015519:Bone Density / Q000235:genetics; D016723:Bone Remodeling / Q000187:drug effects / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D007031:Hypothalamus / Q000502:physiology*; D007276:Injections, Intraventricular; D020738:Leptin / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D009478:Neuropeptide Y / Q000502:physiology; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D015398:Signal Transduction / Q000502:physiology
D002352:Carrier Proteins; D020738:Leptin; D009478:Neuropeptide Y; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C515447:leptin receptor, mouse