2013 Grant Award - Meghan E. McGee-Lawrence, Ph.D.

Regulation of Hepatic Insulin Action by Skeletal Hdac3 and Osteoprotegerin

Meghan E. McGee-Lawrence, Ph.D.
Department of Orthopedic Surgery, Mayo Clinic

Type II diabetes is a major health epidemic affecting over 23 million Americans, 80 to 90% of whom are also obese. Another 19 million Americans, including 248,000 Minnesotans have prediabetes and are at risk for progression to overt diabetes. Unfortunately, lifestyle modification and weight loss are the only effective means at present to prevent this progression. Beyond that, the long-term efficacy of interventions to treat glucose intolerance is low, and as such, new therapeutic agents and strategies for treating type II diabetes are urgently needed. Exciting foundations for new therapies are emerging from the integrative study of interactions between different body systems, which recently identified bone and osteoblast-derived factors as novel endocrine regulators of energy metabolism. Importantly, a new report suggests that bone-derived factors that reduce inflammatory RANKL/NF-κb signaling in the liver improve hepatic insulin resistance and prevent type II diabetes in mice and possibly in humans [1]. Preliminary studies from our laboratory, using a novel mouse model, are consistent with these data, and support the hypothesis that bone-derived factors may suppress inflammatory pathways that lead to insulin resistance in type II diabetes. Our data show that conditional knockout (CKO) of an epigenetic regulator, histone deacetylase 3 (Hdac3), in bone progenitor cells prevents high fat diet-induced glucose intolerance, insulin resistance and hepatic steatosis. Serum and skeletal gene expression levels of the bone-derived factor osteoprotegerin (Opg), which is a natural inhibitor of RANKL signaling, are elevated in these mice. In the proposed research, we will test the hypothesis that increased Opg secretion from osteoblasts is the reason why Hdac3-CKO remain lean after extended times on high fat diets. This work is significant because it explores novel molecular mechanisms by which bone-derived factors can prevent type II diabetes.