Regulation of Leptin Signaling

描述（由申请人提供）：肥胖已经成为一个普遍的健康问题，在我们的社会中达到了流行病的水平，受影响的个人有很高的风险患糖尿病、心脏病、高血压和癌症。脂肪细胞衍生的激素瘦素通过控制食物摄入和新陈代谢来调节能量平衡。瘦素受体长形（LepRb或ObRb）介导重要的瘦素反应，在下丘脑核中高度表达，已知其调节体重和食欲。很明显，大多数肥胖者会随着血浆瘦素水平的显著升高而产生瘦素抵抗。缺乏对瘦素信号传导机制的理解阻碍了我们设计有效的瘦素抵抗治疗干预。根据体外数据显示，酪氨酸磷酸酶Shp2对Jak2/Stat3通路有负面影响，因此有人提出，酪氨酸磷酸酶Shp2失活可能克服肥胖并增强瘦素敏感性。然而，我们最近证明，前脑神经元中缺乏Shp2表达的小鼠会出现早发性肥胖和瘦素抵抗，但不会出现贪食。因此，我们相信本实验室创建的新型肥胖小鼠模型为描述能量稳态的神经元控制机制提供了前所未有的机会。我们假设Shp2促进下丘脑瘦素信号流，而增强Shp2磷酸酶活性可能改善瘦素敏感性。在本项目中，我们将阐明Shp2在LepRb下游信号事件中的生理作用。我们还将确定Shp2和StatS这两个LepRb下游的重要参与者在下丘脑瘦素信号传递中的协同作用。最后，我们将确定下丘脑中显性活性Shp2突变体的选择性表达是否会增强瘦素信号并减轻小鼠饮食诱导的肥胖。这些研究可能会产生一个新的范式，它将阐明瘦素在控制能量稳态中的分子信号机制。

DESCRIPTION (provided by applicant): Obesity has become a widespread health problem reaching an epidemic level in our society, with the affected individuals having a high risk for diabetes, heart disease, hypertension and cancer. The adipocyte- derived hormone leptin regulates energy balance by controlling food intake and metabolism. The leptin receptor long form (LepRb, or ObRb), which mediates important leptin responses, is highly expressed in hypothalamic nuclei known to regulate body weight and appetite. It has become clear that most obese individuals develop leptin resistance with dramatically increased plasma leptin levels. The lack of mechanistic understanding of leptin signaling has prevented us from designing effective therapeutic intervention of leptin resistance. It was proposed that inactivation of the tyrosine phosphatase Shp2 might overcome obesity and enhance leptin sensitivity, based on in vitro data showing a negative effect of Shp2 on the Jak2/Stat3 pathway. We have demonstrated recently, however, that mice deficient for Shp2 expression in forebrain neurons developed early-onset obesity and leptin resistance, but were not hyperphagic. Thus, we believe the novel obese mouse model created in this laboratory offers an unprecedented opportunity to delineate the neuronal control mechanism of energy homeostasis. We hypothesize that Shp2 acts to promote hypothalamic leptin signal flow and that enhancing the Shp2 phosphatase activity may improve leptin sensitivity. For this project, we will elucidate the physiological role of Shp2 in signaling events downstream of LepRb. We will also determine the concerted functions of Shp2 and StatS, two important players downstream of LepRb, in relay of hypothalamic leptin signals. Finally, we will determine whether selective expression of a dominant active Shp2 mutant in the hypothalamus potentiates leptin signals and alleviates diet-induced obesity in mice. A new paradigm will likely emerge from the proposed studies, which will illuminate the molecular signaling mechanism for leptin action in control of energy homeostasis.