Bone-specific insulin resistance disrupts whole-body glucose homeostasis via decreased osteocalcin activation

• Published in: The Journal of clinical investigation Vol. 124; no. 4; pp. 1781 - 1793
• Main Authors: Wei, Jianwen, Ferron, Mathieu, Clarke, Christopher J., Hannun, Yusuf A., Jiang, Hongfeng, Blaner, William S., Karsenty, Gerard
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.04.2014
• Subjects: Animals; Antigens, CD - genetics; Antigens, CD - metabolism; Biomedical research; Bone and Bones - metabolism; Bone Resorption - metabolism; Bone Resorption - pathology; Development and progression; Diet, High-Fat; Fatty Acids, Nonesterified - metabolism; Glucose; Glucose - metabolism; Glucose Intolerance - metabolism; Homeostasis; Humans; Insulin; Insulin resistance; Insulin Resistance - physiology; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; Muscle, Skeletal - metabolism; Osteoblasts; Osteoblasts - metabolism; Osteocalcin - metabolism; Receptor, Insulin - genetics; Receptor, Insulin - metabolism; Receptors; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Signal Transduction; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Up-Regulation
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI72323

Insulin signaling in osteoblasts has been shown recently to contribute to whole-body glucose homeostasis in animals fed a normal diet; however, it is unknown whether bone contributes to the insulin resistance that develops in animals challenged by a high-fat diet (HFD). Here, we evaluated the consequences of osteoblast-specific overexpression of or loss of insulin receptor in HFD-fed mice. We determined that the severity of glucose intolerance and insulin resistance that mice develop when fed a HFD is in part a consequence of osteoblast-dependent insulin resistance. Insulin resistance in osteoblasts led to a decrease in circulating levels of the active form of osteocalcin, thereby decreasing insulin sensitivity in skeletal muscle. Insulin resistance developed in osteoblasts as the result of increased levels of free saturated fatty acids, which promote insulin receptor ubiquitination and subsequent degradation. Together, these results underscore the involvement of bone, among other tissues, in the disruption of whole-body glucose homeostasis resulting from a HFD and the involvement of insulin and osteocalcin cross-talk in glucose intolerance. Furthermore, our data indicate that insulin resistance develops in bone as the result of lipotoxicity-associated loss of insulin receptors.