LEPTIN RECEPTOR PATHWAYS IN MAMMALIAN PHYSIOLOGY

在美国和其他工业化国家，肥胖发病率的增加代表了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以及其他疾病的主要风险因素。近年来，一些控制食欲和代谢的神经内分泌介质的阐明，以及啮齿动物单基因肥胖综合征中病变的鉴定，使肥胖在分子水平上的详细研究成为可能。瘦素这种激素在脂肪组织中产生，通过控制摄食和能量消耗来调节能量平衡。瘦素在调节人体能量平衡的内分泌反应中也起着关键作用。瘦素受体（LR）的LRb亚型在调节身体能量平衡和内分泌功能的下丘脑核中高度表达，并介导重要的瘦素反应。在瘦素刺激下，小鼠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的LRb亚型（lrmut），通过替换单个酪氨酸残基而无法介导特定的细胞内信号。为了了解LRb启动的单个信号如何控制生理，我们在小鼠中从同源靶向LR基因中表达这些lrmut。因此，lrmut应该在与野生型LRb相同的组织中以相同的水平表达，以便于生理学研究。这个题为“瘦素受体信号通路在哺乳动物生理学中的作用”的提案，试图理解由LRb调节的特定信号通路在生理学控制中的作用。我们将首先表征（LRbmut）在完整动物中的表达和信号传导，然后研究这些小鼠的能量平衡、葡萄糖稳态、内分泌和神经内分泌功能的调节。这些研究所得的信息将弥合我们在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知识鸿沟。此外，对特定细胞信号和生理之间的联系的理解将有助于确定潜在的治疗靶点。

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.