Characterization of a receptor mediating adiponectin functions on bone

? DESCRIPTION (provided by applicant): We have been interested in recent years in the biology of the most abundant adipokine, adiponectin. In addressing what could be the functions(s) of adiponectin in animals fed a normal diet we considered the fact that adiponectin appears during evolution with bone and is regulated by the bone-derived hormone osteocalcin. We then asked whether adiponectin was regulating bone mass. Our results obtained in vivo showed that 1) adiponectin inhibits bone formation by acting directly on osteoblasts while it favors bone formation by inhibiting the sympathetic nerves through its signaling in the brain; 2) none of the known receptors for adiponectin seem to mediate any of these two functions and adiponectin does not recruit AMPK and does not regulate ceramide activity in osteoblasts; 3) the signaling pathway triggered by adiponectin in osteoblasts suggested that the receptor for this hormone in osteoblasts is a receptor tyrosine kinase. Further analysis presented in this application strongly suggest, based on molecular and biochemical grounds, that the receptor for adiponectin in osteoblasts and possibly in neurons of the locus coeruleus may be the discoidin receptor 2 (DDR2), a RTK with a slow kinetic of phosphorylation. Based on preliminary findings presented in this application we now propose to test this hypothesis in vivo. The specific aims of this application are: To demonstrate that DDR2 mediates adiponectin signaling in osteoblasts. To demonstrate that in vivo FoxO1 lies downstream of DDR2-dependent signaling in osteoblasts. To determine in vivo the biological significance of the interactions occurring between DDR2, AdipoR1 and T-cadherin. To demonstrate in vivo that DDR2 and/or DDR1 mediates adiponectin signaling in neurons of the locus coeruleus.