Abdallah Basem M, Ditzel Nicholas, Laborda Jorge, Karsenty Gerard, Kassem Moustapha
Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital and University of Southern Denmark, Odense, Denmark
Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital and University of Southern Denmark, Odense, Denmark.
Diabetes. 2015 Sep;64(9):3069-80. doi: 10.2337/db14-1642. Epub 2015 Apr 27.
The endocrine role of the skeleton in regulating energy metabolism is supported by a feed-forward loop between circulating osteoblast (OB)-derived undercarboxylated osteocalcin (Glu-OCN) and pancreatic β-cell insulin; in turn, insulin favors osteocalcin (OCN) bioactivity. These data suggest the existence of a negative regulation of this cross talk between OCN and insulin. Recently, we identified delta like-1 (DLK1) as an endocrine regulator of bone turnover. Because DLK1 is colocalized with insulin in pancreatic β-cells, we examined the role of DLK1 in insulin signaling in OBs and energy metabolism. We show that Glu-OCN specifically stimulates Dlk1 expression by the pancreas. Conversely, Dlk1-deficient (Dlk1(-/-) ) mice exhibited increased 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 experienced significantly lower blood glucose levels than Glu-OCN-treated wild-type mice. The 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 OB production of Glu-OCN, a potential mechanism preventing OCN-induced hypoglycemia.
循环中的成骨细胞（OB）衍生的未羧化骨钙素（Glu-OCN）与胰腺β细胞胰岛素之间的前馈回路支持了骨骼在调节能量代谢中的内分泌作用；反过来，胰岛素有利于骨钙素（OCN）的生物活性。这些数据表明在OCN与胰岛素之间的这种相互作用存在负调控。最近，我们确定了δ样1（DLK1）是骨转换的内分泌调节因子。由于DLK1与胰岛素在胰腺β细胞中共定位，我们研究了DLK1在成骨细胞胰岛素信号传导和能量代谢中的作用。我们发现Glu-OCN特异性刺激胰腺中Dlk1的表达。相反，Dlk1基因敲除（Dlk1(-/-)）小鼠的循环Glu-OCN水平升高且胰岛素敏感性增加，而在成骨细胞中过表达Dlk1的小鼠由于成骨细胞中胰岛素信号受损和血清Glu-OCN水平降低，胰岛素分泌和敏感性降低。此外，用Glu-OC处理的Dlk1(-/-)小鼠的血糖水平明显低于用Glu-OCN处理的野生型小鼠。数据表明胰腺β细胞中由Glu-OCN控制的DLK1产生作为一种负反馈机制，以抵消胰岛素对成骨细胞产生Glu-OCN的刺激作用，这是一种预防OCN诱导的低血糖的潜在机制。
