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.
Jianwen Wei, Mathieu Ferron, Christopher J. Clarke, Yusuf A. Hannun, Hongfeng Jiang, William S. Blaner, Gerard Karsenty
This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.