Elucidation of molecular mechanism of leptin resistance, using transgenic mice over-expressing leptin

美国正在进行重组瘦素治疗肥胖症的临床试验。然而，有报道称，外周给药治疗瘦素的疗效相当有限，可能是因为最肥胖的人可能处于瘦素抵抗状态。最近，我们开发了高表达瘦素的转基因小鼠，尽管血清瘦素浓度与肥胖者相当，但它们对瘦素具有很高的敏感性。在本课题中，我们利用转基因小鼠和ob/ob小鼠研究了高脂餐对瘦素抵抗的致病机制，因为我们发现转基因小鼠也会因高脂餐负荷而肥胖。然而，我们发现，在不同血清瘦素浓度的小鼠中，高脂餐负荷诱导肥胖的作用是相似的。因此，瘦素在高脂膳食诱导肥胖中最有可能是中性的。

Clinical trial of recombinant leptin for the treatment of obesity is on going in the United States. However, it has been reported that the efficacy of leptin treatment by the peripheral administration is quite limited, probably because the most obese people may be in a leptin-resistant state. Recently, we developed transgenic mice over-expressing leptin, which have high sensitivity to leptin, despite an increased concentration of serum leptin comparable to that in obese people. In this project, we explored the pathogenic mechanism of leptin resistance by high fat meal using the transgenic mice and ob/ob mice, because we found that the transgenic mice also became obese by the load of high fat meal. However, we found that the induction of obesity by the high fat meal load was comparable in mice with different concentrations of serum leptin. Therefore, it is the most likely that leptin is neutral in the induction of obesity by high fat meal.