Effects of osteoblastic Hdac3 expression on hepatic inflammation and insulin sensitivity via OPG

Type 2 diabetes is a health epidemic in the United States, and new therapies to treat and prevent this condition are desperately needed. One of the earliest changes seen at the onset of type 2 diabetes is evidence that the liver no longer properly responds 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. Research from our laboratory suggests that one molecule osteoblasts release to target the liver is a protein called osteoprotegerin, which helps prevent inflammation in the liver and in doing so helps maintain its sensitivity to insulin. Our data suggest that expression of osteoprotegerin is regulated in bone by another molecule called histone deacetylase 3 (Hdac3). During this minority internship program, the student will help uncover the molecular mechanisms by which Hdac3 regulates Opg in bone cells to prevent liver inflammation. Cell culture studies will uncover how Hdac3 controls Opg gene and protein expression, and studies of liver tissue from mice deficient in Hdac3 and/or Opg will reveal the effects of each protein on inflammation in the liver under diabetic conditions. 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 treating and preventing type 2 diabetes in the millions of Americans suffering from metabolic disorders