The skeleton, populated by large numbers of osteoblasts and osteocytes, requires a constant supply of energy-rich molecules to fuel the synthesis, deposition, and mineralization of bone matrix during bone modeling and remodeling. As a result, studies performed over the last decade have expanded our understanding of the physiologic functions of bone beyond locomotion, mineral ion storage, and protection of vital organs to now include the secretion of hormones that contribute to the regulation of whole-body metabolism. Our previous studies suggest that sclerostin, an osteocyte-secreted factor that inhibits Wnt signaling in bone, influences body composition and glucose homeostasis by augmenting adipocyte differentiation. Preliminary studies suggest that sclerostin may exert its effect on adipose tissue in vivo by modulating the sensitivity of adipocytes to -adrenergic signals that stimulate adipose tissue browning. In this renewal application, we will utilize a combination of genetic and pharmacological approaches to explore the interaction between endocrine sclerostin and -adrenergic signaling. Our hypothesis predicts that sclerostin deficiency leads to adipose tissue browning due to an increase in -adrenergic sensitivity; and the loss of negative feedback inhibition since sclerostin gene expression appears to be responsive to thermogenic signaling. Our approach will expand our understanding of the physiologic functions of sclerostin; and help to determine if sclerostin neutralization, now approved for the treatment of osteopenia/osteoporosis, can be leveraged to treat metabolic disorders like obesity and diabetes. 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, management, treatment, and prevention of the related metabolic disturbances of diabetes and bone disease in aging Veterans.