Role of osteoblastic Hdac3 in the regulation of systemic energy metabolism

Type 2 diabetes is a health epidemic in the United States, and new therapies to treat and prevent this condition are desperately needed. Innovative approaches for developing better treatments are being uncovered by understanding how body systems interact under normal and diabetic conditions. One of the earliest changes seen at the onset of type 2 diabetes is evidence that the liver stops responding properly to insulin. Importantly, recent studies have shown that that factors released from the skeleton, and in particular from the cells that form new bone (osteoblasts), can possibly prevent the liver from becoming insensitive to insulin. The proposed study aims to investigate how this happens, using a unique mouse model. These mice have been genetically modified so that they are missing a specific protein, called Hdac3, only in osteoblasts. Surprisingly, these mice do not develop insulin resistance when they are fed a high-fat diet that causes type 2 diabetes in normal mice. This suggests that losing Hdac3 expression in bone alters production of a factor that can communicate with the liver and help it to keep responding to insulin. The proposed project will clarify how these mice lacking Hdac3 in their skeletons are able to prevent type 2 diabetes. These studies will help explain how the skeleton can act as an endocrine organ when it interacts with other body systems, like the liver, and may ultimately identify new targets for developing better therapies for preventing type 2 diabetes in the millions of Americans suffering from metabolic disorders