LEPTIN RECEPTOR PATHWAYS IN MAMMALIAN PHYSIOLOGY

在美国和其他工业化国家，肥胖症的发病率不断增加，这是一个主要的健康问题：肥胖是2型糖尿病、心血管疾病和某些形式的癌症等疾病的主要危险因素。 最近，阐明了一些神经内分泌介质的食欲和代谢控制和确定的病变，在啮齿类动物的单基因肥胖综合征，使肥胖症的研究在详细的分子水平。 激素瘦素在脂肪组织中产生，并通过控制进食和能量消耗来调节能量平衡。 瘦素在调节内分泌反应以平衡身体能量方面也起着关键作用。 瘦素受体（LR）的LRb亚型在下丘脑核团中高度表达，已知其调节身体能量平衡和内分泌功能，并介导重要的瘦素反应。 在瘦素刺激过程中，鼠LRb上至少有两个酪氨酸残基被磷酸化并介导不同的细胞内信号。 我们已经产生了突变型LRb亚型（LRbmut）缺陷的取代单一的酪氨酸残基，无法介导的特定的细胞内信号。 为了了解LRb启动的单个信号如何控制生理学，我们在小鼠中从同源靶向的LR基因表达这些LRbmut。 因此，LRbmut应该在与野生型LRb相同的组织中以相同的水平表达，从而促进生理学研究。 这项题为“瘦素受体信号通路在哺乳动物生理学中的作用”的提案旨在了解由LRb调节的特定信号通路在生理学控制中的作用。 我们将首先描述完整动物中（LRbmut）的表达和信号传导，然后研究这些小鼠中能量平衡，葡萄糖稳态以及内分泌和神经内分泌功能的调节。 这些研究产生的信息将弥合我们知识中的关键差距，即瘦素信号的基本生物化学和瘦素对关键生理过程的控制之间的差距。此外，对特定细胞信号和生理学之间联系的理解将有助于识别潜在的治疗靶点。

The increasing incidence of obesity in the US and other industrialized countries represents a major health problem: Obesity is a major risk factor for type 2 diabetes, cardiovascular disease, and certain forms of cancer, among other diseases. Recently, the elucidation of a number of neuroendocrine mediators of appetite and metabolic control and the identification of the lesions in rodent single gene obesity syndromes have enabled the study of obesity at a detailed molecular level. The hormone leptin is produced in adipose tissue and regulates energy balance by controlling feeding and energy expenditure. Leptin also plays a critical role in regulating the endocrine response to body energy balance. The LRb isoform of the leptin receptor (LR) is highly expressed in hypothalamic nuclei known to regulate body energy balance and endocrine function and mediates important leptin responses. At least two tyrosine residues on murine LRb become phosphorylated and mediate distinct intracellular signals during leptin stimulation. We have generated mutant LRb isoforms (LRbmut) defective by the substitution of single tyrosine residues that fail to mediate the specific intracellular signals. In order to understand how the individual signals initiated by the LRb act to control physiology, we are expressing these LRbmut in mice from the homologously targeted LR gene. Thus, the LRbmut should be expressed at the same levels in the same tissues as wild type LRb, facilitating physiologic studies. This proposal, entitled "Role of leptin receptor signaling pathways in mammalian physiology," seeks to understand the role of the specific signaling pathways regulated by the LRb in the control of physiology. We will first characterize the expression and signaling of (LRbmut) in intact animals and then investigate the regulation of energy balance, glucose homeostasis, and endocrine and neuroendocrine function in these mice. The information these studies yield will bridge the critical gap in our knowledge that lies between the basic biochemistry of leptin signaling and the control of critical physiologic processes by leptin. Furthermore, the understanding gained about the connection between specific cellular signals and physiology will aid in the identification of potential therapeutic targets.