Molecular Basis of Centrally-controled Energy Homeostasis -Focusing on Leptin Resistance-

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In the past three years, we have mainly focused our attention on the molecular basis of the leptin receptor signaling in the pathophysiology of obesity and related metabolic disorders. Of note, we have successfully identified a novel homozygous mutation on the gene of melanocortin type 4 receptor (MC4R) in the early-onset, morbid obese woman. This is exactly the first report of MC4R mutant with severe adiposity in Japan. Furthermore, using transgenic skinny mice overexpressing leptin (Lep Tg) and A-ZIP transgenics, a representative mouse model for human lipodystrophy, we have revealed that both β-adrenergic activation and suppression of the hypothalamic-pituitary-adrenal axis strongly contribute to beneficial effect on glucose metabolism by leptin. Moreover, by use of Lep Tg, we have explored the therapeutic usefulness of leptin for the treatment of insulin-deficient or type 1-like diabetes. Data strongly suggested that leptin can ameliorate glucose dyshomeostasis via both insulin-sensitizing effect and anorectic effect, thus implicating coordinated role of leptin and insulin.In centrally-mediated glucose metabolism. Our studies further highlight the importance of leptin signaling in the pathophysiology of obesity-associated metabolic dysregulation and provide evidence that therapeutic modalities which overcome the proposed leptin resistance should be powerful tools to treat such prevalent diseases.