The long-term goals of this Merit project are focused on characterizing the mechanisms, which distinguish the actions of insulin and IGF-1 in skeletal cells. During the last funding period we identified a novel endocrine loop through which insulin stimulates the production of osteocalcin by osteoblasts, which in turn, functions as a hormone to increase pancreatic insulin production and enhance insulin sensitivity in peripheral tissues. Additional studies defined the insulin targe mTOR as a key checkpoint that integrates osteoblast developmental programs with fuel consumption and energy metabolism. Our findings, together with complementary work from other labs, suggest a regulatory link between osteoblasts and global energy homeostasis. Implicit in this model is the notion that bone formation, remodeling, and repair are energy- expensive processes, which require osteoblasts to adjust their fuel metabolism and bioenergetics to accomplish stage-specific functions during their life cycle. New preliminary data described in this proposal demonstrate that the ability of osteoblasts to oxidize glucose and fatty acids varies with their differentiation status and is controlled by distinct developmental signals. Thus, insulin receptor signaling in osteoblasts is required for GLUT4 dependent glucose uptake and oxidation, whereas Wnt/LRP5 signaling regulates the activity of key enzymes in ?-oxidation of fatty acids. In this project, we will use new genetic mouse models to determine the impact of energy substrate oxidation and metabolism by osteoblasts on global fuel flux in adult bone and in response to anabolic therapies. We will test the hypothesis that fuel consumption by osteoblasts and osteocytes significantly impact global fuel requirements and that these cells adjust their bioenergetic programs to meet different demands during their life span and in settings where in osteoblast energy demands are heightened. In Specific Aim 1, we will determine the relative requirement for glucose and fatty acid as substrates for oxidative metabolism in mature mouse bone by examining the bone and metabolic phenotypes of mice engineered to be deficient for obligate enzymes in glucose (hexokinase 2, Hk2) and fatty acid (carnitine palmitoyltransferase-2, Cpt2) metabolism in mature osteoblasts and osteocytes. In Specific Aim 2, we will determine the importance of osteoblast fuel consumption during acute episodes of anabolic activity. Specifically, we will determine the impact of acute loss of either glucose (Hk2 KO) or fatty acid oxidation (Cpt2 KO) on load induced bone formation and in response to an anabolic regimen of anti- sclerostin antibody. While these studies have been conducted in mice, their significance to human health is supported by an increasing body of evidence linking osteocalcin levels and other markers for osteoblast acidity with body mass index, fat mass, insulin secretion, and insulin resistance. We firmly believe that the information gained from our studies will improve understanding of how the metabolic activity of the skeleton impacts global metabolic activity. Such information is expected to significantly improve the diagnosis and management and treatment and prevention of the related metabolic disturbances prevalent in aging Veterans.