Role of PTP1B in Body Mass Regulation

描述（由申请方提供）：控制体重对哺乳动物的生存至关重要。身体质量调节障碍（例如，肥胖）是常见的，并且具有严重的医学后果，包括胰岛素抵抗/2型糖尿病和血脂异常/心血管疾病。生物体通过控制食物摄入和能量消耗来调节体重。这些过程的调节是复杂的，涉及多种介质在脑和外周组织中的几个部位起作用。脂肪细胞激素瘦素起着特别重要的作用。瘦素作用于CMS瘦素受体（LR）以抑制食物摄入并促进能量消耗。LRs存在于下丘脑的弓状核（ARC）中，其被认为是瘦素作用的主要部位，并且存在于大脑的几个其他区域中。最近的细胞特异性基因敲除研究证实了ARC神经元的重要性，但也表明大脑其他部位也是瘦素作用所必需的。大多数肥胖的人对瘦素有抵抗力。定义正常的LR信号传导机制，以及如何以及在哪些神经元中，这些通路在瘦素抵抗中受到干扰，可能会提出新的抗肥胖疗法。LR激活酪氨酸激酶Jak 2，促进下游信号。我们发现，蛋白酪氨酸磷酸酶，PTP 1B，是一个关键的负调节瘦素信号和体重控制。PTP 1B通过使Jak 2去磷酸化而起作用，从而终止LR信号传导。通过产生和研究全身和神经元特异性的PTP 1 B-/-小鼠，我们还发现神经元中的PTP 1 B对于瘦素抵抗的发展是必需的。本研究的总体目标是阐明PTP 1B调节肥胖的机制。具体目标是：1）确定神经元PTP 1 B-/-小鼠中体重减少的细胞和分子基础; 2）使用仅在特定神经元亚型中表达Cre重组酶的小鼠系，确定PTP 1 B在下丘脑神经元的特定亚群中调节肥胖的作用; 3）利用遗传和生物化学方法，确定PTP 1 B如何与瘦素作用的另一个负调节因子Socs 3以及PTP 1 B的近亲相互作用，T细胞-蛋白酪氨酸磷酸酶，调节瘦素信号。这些研究将促进我们对瘦素抵抗机制的理解。这些结果将对理解正常体重控制和肥胖的失调具有重要意义。

DESCRIPTION (provided by applicant): Control of body mass is essential for mammalian survival. Disorders of body mass regulation (e.g, obesity) are common, and have serious medical consequences, including insulin resistance/Type 2 diabetes and dyslipidemia/cardiovascular disease. Organisms regulate body mass by controlling food intake and energy expenditure. Regulation of these processes is complex, involving multiple mediators acting at several sites in the brain and peripheral tissues. The adipocyte hormone leptin plays an especially important role. Leptin acts on CMS leptin receptors (LR) to inhibit food intake and promote energy expenditure. LRs are found in the arcuate nucleus (ARC) of the hypothalamus, which has been viewed as the major site of leptin action, and in several other regions of the brain. Recent cell-specific knockout studies confirm the importance of ARC neurons, but indicate that sites elsewhere in the brain also are essential for leptin action. Most obese humans are resistant to leptin. Defining normal LR signaling mechanisms and how, and in which neurons, these pathways are perturbed in leptin resistance may suggest new anti-obesity therapies. The LR activates tyrosine kinase, Jak2, promoting downstream signals. We identified that protein-tyrosine phosphatase, PTP1B, is a key negative regulator of leptin signaling and body mass control. PTP1B acts by dephosphorylating Jak2, thereby terminating LR signaling. By generating and studying whole body and neuronal-specific PTP1 B-/-mice, we also found that PTP1B in neurons is essential for the development of leptin resistance. The overall goal of studies in this proposal is to elucidate the mechanisms bv which PTP1B regulates adiposity. Specific Aims are: 1) To determine the cellular and molecular basis for reduced body mass in neuronal PTP1 B-/- mice; 2) To determine the role of PTP1B in specific subpopulations of hypothalamic neurons in regulating adiposity, using mouse lines that express Cre recombinase only in specific subtypes of neurons; 3) Using genetic and biochemical approaches, to determine how PTP1B interacts with Socs3, another negative regulator of leptin action, as well as PTP1 B's close relative, T cell- Protein Tyrosine Phosphatase, to regulate leptin signaling. These studies will advance our understanding of the mechanisms for resistance to leptin action. The results will have important implications for understanding normal body mass control and its dysregulation in obesity.