Obesity has reached epidemic proportions and poses serious public health challenges, in particular type 2diabetes, cardiovascular disease, sleep apnea, osteoarthritis and cancer. Adipocyte hormones may providekey insights into the pathogenesis of obesity-related diseases. Leptin and adiponectin stimulate fatty acidoxidation, decrease lipid levels and increase insulin sensitivity. In contrast, resistin decreases insulinsensitivity, and increases glucose and lipids. Leptin acts in the CMS to suppress appetite and increaseenergy expenditure, but also has direct effects on peripheral tissues. Adiponectin and resistin have directactions on liver and muscle, but recent observations suggest that these adipokines also have central effects.We hypothesize that the divergent effects of these adipocytes on metabolism are mediated, at least in part,through distinct neuronal targets and signaling pathways in the hypothalamus.
Specific Aim 1 will comparethe effects of CMS administration of leptin, adiponectin and resistin on energy and glucose metabolism. Wewill examine the regulation of peripheral glucose fluxes using insulin clamp and radioactive tracer kinetics.Based on our preliminary studies showing an attenuation of the CMS effects of leptin and adiponectin inagouti mice, we will determine whether the opposite effects of leptin/adiponectin versus resistin on glucoselevels is mediated through melanocortin (MC)4 receptor signaling.
Specific Aim 2 will determine the sites ofaction of these adipocyte hormones in the hypothalamus, using Fos immunohistochemistry and in situhybridization. Finally, Specific Aim 3 will determine whether the opposing metabolic effects of leptin,adiponectin and resistin occur through AMP-kinase and SOCS-3 in the hypothalamus. We will test thehypothesis that central administration of resistin antagonizes the central effects of leptin and adiponectin onmetabolism, through reciprocal regulation of AMPK, SOC-3, or both signaling pathways. Understanding thehypothalamic and signaling pathways that mediate the effects of leptin, adiponctin and resistin will providenovel insights into the pathophysiology of obesity and diabetes that will facilitate novel diagnostic andtreatment strategies.
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