Signaling pathway for adiponectin expression in adipocytes by osteocalcin

In addition to providing skeletal support, the bone is an endocrine organ that produces osteocalcin, whose uncarboxylated form (GluOC) increases insulin secretion either directly or indirectly by promoting incretin secretion. We have now investigated the signaling pathway by which GluOC increases expression of adiponectin in adipocytes. Activation of its putative receptor GPRC6A by GluOC induced the intracellular accumulation of cAMP and consequent activation of protein kinase A (PKA) in differentiated 3T3-L1 adipocytes. It also induced phosphorylation of CREB (cAMP response element binding protein), but this effect appeared to be mediated indirectly by extracellular signal-regulated kinase (ERK) rather than directly by PKA, given that it was attenuated by the ERK signaling inhibitor U0126. Activated PKA also induced activation of the tyrosine kinase Src, the small GTPase Rap1, an upstream of ERK and CREB phosphorylation. Activated CREB up-regulated the expression of peroxisome proliferator-activated receptor γ (PPARγ), which in turn led to induction of adiponectin expression. Finally, intermittent oral administration of GluOC in mice reduced the size of gonadal white adipocytes as well as increased the expression of PPARγ and adiponectin in these cells. Our results have thus revealed the signaling pathway by which GluOC induces adiponectin expression in adipocytes.