Bone-Adipose Interactions During Skeletal Anabolism

Abstract Bone formation by osteoblasts requires significant energy input to fuel the synthesis, deposition, and mineralization of bone matrix. Fatty acids liberated by the lipolysis of triglycerides stored in adipose tissue are a rich source of energy that is used to fuel the energy-intensive functions of a number of tissues. In this application we will explore the interaction of bone and adipose tissue in response to two signals that stimulate new bone formation: intermittent parathyroid hormone administration and exercise. Both of these stimuli are also associated with increases in adipose tissue lipolysis. Our studies will determine the requirement for fatty acids to be transferred from adipose to osteoblasts by examining bone formation in transgenic mouse models in which lipolysis is impaired in adipocytes, via ablation of Atgl expression or fatty acid oxidation is impaired in osteoblasts, via the ablation of Cpt2 expression. Our hypothesis predicts that manipulation of lipid metabolism in either tissue will impair the bone formation response to each stimulus. Our approach will inform on the integrative physiologic networks that regulate skeletal homeostasis and the energy substrates required for bone formation during states of heighted anabolism. Additionally, these studies will enable us to define mechanisms by which obesity and metabolic dysfunction, conditions which are now epidemic in our society, inhibit bone formation