Cain Corey J, Valencia Joel T, Ho Samantha, Jordan Kate, Mattingly Aaron, Morales Blanca M, Hsiao Edward C
Department of Medicine, Division of Endocrinology and Metabolism; Institute for Human Genetics; and Program in Craniofacial Biology (C.J.C., S.H., K.J., A.M., B.M.M., and E.C.H.); and the Biomedical Sciences Graduate Program (J.T.V. and E.C.H.); University of California, San Francisco, San Francisco, California 94143-0794.
Endocrinology. 2016 Apr;157(4):1481-94. doi: 10.1210/en.2015-1867. Epub 2016 Feb 22.
Bone is increasingly recognized as an endocrine organ that can regulate systemic hormones and metabolism through secreted factors. Although bone loss and increased adiposity appear to be linked clinically, whether conditions of increased bone formation can also change systemic metabolism remains unclear. In this study, we examined how increased osteogenesis affects metabolism by using an engineered G protein-coupled receptor, Rs1, to activate Gs signaling in osteoblastic cells in ColI(2.3)(+)/Rs1(+) transgenic mice. We previously showed that these mice have dramatically increased bone formation resembling fibrous dysplasia of the bone. We found that total body fat was significantly reduced starting at 3 weeks of age. Furthermore, ColI(2.3)(+)/Rs1(+) mice showed reduced O2 consumption and respiratory quotient measures without effects on food intake and energy expenditure. The mice had significantly decreased serum triacylglycerides, leptin, and adiponectin. Resting glucose and insulin levels were unchanged; however, glucose and insulin tolerance tests revealed increased sensitivity to insulin. The mice showed resistance to fat accumulation from a high-fat diet. Furthermore, ColI(2.3)(+)/Rs1(+) mouse bones had dramatically reduced mature adipocyte differentiation, increased Wingless/Int-1 (Wnt) signaling, and higher osteoblastic glucose utilization than controls. These findings suggest that osteoblasts can influence both local and peripheral adiposity in conditions of increased bone formation and suggest a role for osteoblasts in the regulation of whole-body adiposity and metabolic homeostasis.
骨骼越来越被认为是一个内分泌器官，它可以通过分泌因子调节全身激素和代谢。虽然临床上骨质流失和肥胖增加似乎有关联，但骨形成增加的情况是否也能改变全身代谢仍不清楚。在本研究中，我们通过使用一种工程化的G蛋白偶联受体Rs1，激活ColI(2.3)(+)/Rs1(+)转基因小鼠成骨细胞中的Gs信号，来研究成骨增加如何影响代谢。我们之前表明，这些小鼠的骨形成显著增加，类似于骨纤维发育不良。我们发现，从3周龄开始，全身脂肪显著减少。此外，ColI(2.3)(+)/Rs1(+)小鼠的耗氧量和呼吸商测量值降低，而对食物摄入量和能量消耗没有影响。这些小鼠的血清甘油三酯、瘦素和脂联素显著降低。静息血糖和胰岛素水平未改变；然而，葡萄糖和胰岛素耐量试验显示对胰岛素的敏感性增加。这些小鼠对高脂饮食引起的脂肪堆积具有抗性。此外，与对照组相比，ColI(2.3)(+)/Rs1(+)小鼠的骨骼中成熟脂肪细胞分化显著减少，Wingless/Int-1（Wnt）信号增加，成骨细胞葡萄糖利用率更高。这些发现表明，在骨形成增加的情况下，成骨细胞可以影响局部和外周脂肪，并提示成骨细胞在全身脂肪和代谢稳态调节中的作用。
