An Osteoblast-dependent mechanism contributes to the leptin regulation of insulin secretion.
Our work focuses on genetic and molecular mechanisms for the reciprocal regulation of bone and energy metabolism orchestrated by leptin and osteocalcin. In the context of this reciprocal regulation, the finding that leptin inhibits insulin secretion by beta cells while osteocalcin favors it is surprising. In exploring the molecular bases of this paradox we found that leptin, as is the case for most of its functions, uses a neuronal relay to inhibit insulin secretion. Cell-specific gene-deletion experiments revealed that a component of this neuronal regulation is the sympathetic innervation to osteoblasts. Under the control of leptin the sympathetic tone favors expression in osteoblasts of Esp, which inhibits the metabolic activity of osteocalcin. We further identify ATF4 as a transcription factor that regulates Esp expression and thereby insulin secretion and sensitivity. Taken together these data illustrate the tight connections between bone remodeling and energy metabolism and add further credence to the notion that the osteoblast is a bona fide endocrine cell type.
Hinoi
Eiichi
E
Department of Genetics and Development, Columbia University, New York, New York, USA.
Gao
Nan
N
Jung
Dae Young
DY
Yadav
Vijay
V
Yoshizawa
Tatsuya
T
Kajimura
Daisuke
D
Myers
Martin G
MG
Chua
Streamson C
SC
Wang
Qin
Q
Kim
Jason K
JK
Kaestner
Klaus H
KH
Karsenty
Gerard
G
D017667:Adipocytes / Q000502:physiology; D000818:Animals; D016723:Bone Remodeling / Q000187:drug effects / Q000502:physiology; D001842:Bone and Bones / Q000294:innervation / Q000502:physiology*; D003000:Clonidine / Q000494:pharmacology; D004734:Energy Metabolism / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology; D020738:Leptin / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008820:Mice, Obese; D009474:Neurons / Q000502:physiology; D010006:Osteoblasts / Q000187:drug effects / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology
D007328:Insulin; D020738:Leptin; D010656:Phenylephrine; D007545:Isoproterenol; D003000:Clonidine