The endocrine role of the skeleton in regulating energy metabolism is supported by a feed forward loop between circulating osteoblasts (OBs)-derived undercaboxylated osteocalcin (Glu-OCN) and pancreatic β-cell-insulin; in turn insulin favors osteocalcin bioactivity. These data suggest the existence of a negative regulation of this cross-talk between osteocalcin and insulin. Recently, we have identified DLK1 (Delta like-1), as an endocrine regulator of bone turnover. Since, DLK1 is co-localized with insulin in pancreatic β-cells, we examined the role of DLK1 in insulin signalling in OB and energy metabolism. Here, we show that Glu-OCN specifically stimulated Dlk1 expression by the pancreas. Conversely, Dlk1 deficient (Dlk1-/-) mice exhibited increased in circulating Glu-OCN levels and increased insulin sensitivity, whereas mice overexpressing Dlk1 in OB displayed reduced insulin secretion and sensitivity due to impaired insulin signaling in OB and lowered Glu-OCN serum levels. Furthermore, Dlk1-/- mice treated with Glu-OC experience significantly lowered blood glucose levels compared to Glu-OCN-treated wild type mice. Our data suggest that Glu-OCN-controlled production of DLK1 by pancreatic β cells acts as a negative feedback mechanism to counteract the stimulatory effects of insulin on osteoblast production of Glu-OCN, a potential mechanism preventing OCN-induced hypoglycemia.
Abdallah, B., Ditzel, N., Laborda, J., Karsenty, G., & Kassem, M. (2015). DLK1 regulates whole body glucose metabolism: A negative feedback regulation of the osteocalcin-insulin loop. Diabetes, 64(9), 3069-3080. https://doi.org/10.2337/db14-1642