2008 Grant Award - Laura J. Mauro, Ph.D.
Role of Skeletal Hormones in Adipocyte Differentiation and Function
A paradigm shift in our understanding of metabolic regulation has occurred with the discovery that the skeleton can serve as an endocrine organ capable of modulating glucose metabolism and energy balance. Osteoblasts, the bone-forming cells of the skeleton, are the primary source of a novel skeletal hormone recently identified as osteocalcin. When osteoblasts are engineered to express the bioactive form of osteocalcin called uncarboxylated osteocalcin (uOcn), transgenic mice expressing these cells exhibit lean body mass, hyperinsulinemia, and enhanced insulin sensitivity. At present, the actions of uOcn on adipose tissue have not been characterized. The goal of this proposal is to determine the direct effects of this skeletal hormone on adipocytes by pursuing two specific aims. In our first specific aim, we will test the hypothesis that uOcn can modulate adipocyte differentiation, utilizing the 3T3-L1 preadipocytes. We will treat these cells with uOcn during differentiation and monitor the expression of critical adipocyte-specific genes. These studies will define the actions of this hormone in inhibiting the progression from preadipocyte to mature adipocyte. In our second specific aim, we will test the hypothesis that uOcn can also regulate the metabolism of mature adipocytes. The ability of differentiated 3T3-L1 adipocytes to undergo cAMP-stimulated lipolysis and insulin-stimulated glucose transport will be examined following exposure to uOcn. In addition, the activation of insulin signaling pathways in these pretreated cells will be determined, these studies will show that uOcn can inhibit lipolysis and enhance responsiveness to insulin stimulation. This proposed research project will clarify the role of this novel skeletal hormone in modulating adipogenesis and adipocyte function. In addition, it will provide the foundation for future studies to establish the signaling mechanisms activated by uOcn in adipose and other tissues that will ultimately control energy balance. Our result will aid in the development of new therapeutics for treatment of serious metabolic disorders such as diabetes mellitus and obesity.