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

在过去的三年里，我们主要关注瘦素受体信号在肥胖及相关代谢紊乱病理生理中的分子基础。值得注意的是，我们已经成功地在早发性病态肥胖女性的黑素皮素4型受体（MC4R）基因上发现了一种新的纯合突变。这正是日本首次报道的MC4R突变体伴严重肥胖。此外，我们利用过表达瘦素（Lep Tg）和a - zip转基因瘦小鼠（人类脂肪营养不良的代表性小鼠模型），揭示了β-肾上腺素能的激活和下丘脑-垂体-肾上腺轴的抑制对瘦素对葡萄糖代谢的有益作用。此外，通过使用瘦Tg，我们已经探索了瘦素治疗胰岛素缺乏症或1型糖尿病的治疗作用。数据强烈提示瘦素可以通过胰岛素增敏和厌食作用改善葡萄糖代谢异常，从而提示瘦素和胰岛素的协同作用。在中央介导的葡萄糖代谢中。我们的研究进一步强调了瘦素信号在肥胖相关代谢失调的病理生理学中的重要性，并提供了证据，证明克服瘦素抵抗的治疗方式应该是治疗此类流行疾病的有力工具。

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.