title: An Osteoblast-dependent mechanism contributes to the leptin regulation of insulin secretion.
abstract: 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.
authors.affiliation: Department of Genetics and Development, Columbia University, New York, New York, USA.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hinoi
authors.forename: Nan
authors.initials: N
authors.lastname: Gao
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Jung
authors.forename: Vijay
authors.initials: V
authors.lastname: Yadav
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yoshizawa
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kajimura
authors.forename: Martin G
authors.initials: MG
authors.lastname: Myers
authors.forename: Streamson C
authors.initials: SC
authors.lastname: Chua
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
mesh_terms: 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
chemical_list: D007328:Insulin; D020738:Leptin; D010656:Phenylephrine; D007545:Isoproterenol; D003000:Clonidine