Insulin Receptor Signaling in Osteoblasts Regulates Postnatal Bone Acquisition and Body Composition

Keertik Fulzele, Ryan C. Riddle, Douglas J. DiGirolamo, Xuemei Cao, Chao Wan, Dongquan Chen, Marie Claude Faugere, Susan Aja, Mehboob A. Hussain, Jens C. Brüning, Thomas L. Clemens

Research output: Contribution to journalArticlepeer-review

Abstract

Global energy balance in mammals is controlled by the actions of circulating hormones that coordinate fuel production and utilization in metabolically active tissues. Bone-derived osteocalcin, in its undercarboxylated, hormonal form, regulates fat deposition and is a potent insulin secretagogue. Here, we show that insulin receptor (IR) signaling in osteoblasts controls osteoblast development and osteocalcin expression by suppressing the Runx2 inhibitor Twist2. Mice lacking IR in osteoblasts have low circulating undercarboxylated osteocalcin and reduced bone acquisition due to decreased bone formation and deficient numbers of osteoblasts. With age, these mice develop marked peripheral adiposity and hyperglycemia accompanied by severe glucose intolerance and insulin resistance. The metabolic abnormalities in these mice are improved by infusion of undercarboxylated osteocalcin. These results indicate the existence of a bone-pancreas endocrine loop through which insulin signaling in the osteoblast ensures osteoblast differentiation and stimulates osteocalcin production, which in turn regulates insulin sensitivity and pancreatic insulin secretion.

Original languageEnglish (US)
Pages (from-to)309-319
Number of pages11
JournalCell
Volume142
Issue number2
DOIs
StatePublished - Jul 2010

Keywords

  • Humdisease
  • Signaling

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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