Role of PTP1B in Body Mass Regulation

描述（由申请人提供）：控制体重对哺乳动物的生存至关重要。体重调节紊乱（如肥胖）是常见的，并有严重的医疗后果，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。这些过程的调控是复杂的，涉及多种介质作用于大脑和外周组织的几个部位。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），抑制食物摄入，促进能量消耗。LRs存在于下丘脑的弓状核（ARC），这被认为是瘦素作用的主要部位，以及大脑的其他几个区域。最近的细胞特异性敲除研究证实了ARC神经元的重要性，但表明大脑其他部位也对瘦素的作用至关重要。大多数肥胖的人对瘦素有抵抗力。定义正常的LR信号机制，以及这些通路在瘦素抵抗中是如何受到干扰的，以及在哪些神经元中受到干扰，可能会提出新的抗肥胖疗法。LR激活酪氨酸激酶Jak2，促进下游信号。我们发现蛋白酪氨酸磷酸酶PTP1B是瘦素信号和体重控制的关键负调节因子。PTP1B通过使Jak2去磷酸化，从而终止LR信号。通过生成和研究全身和神经元特异性PTP1B -/-小鼠，我们还发现神经元中的PTP1B对于瘦素抵抗的发展至关重要。本研究的总体目标是阐明PTP1B调控肥胖的机制。具体目的是：1)确定神经元PTP1 B-/-小鼠体重减少的细胞和分子基础；2)利用仅在特定神经元亚型中表达Cre重组酶的小鼠品系，确定PTP1B在下丘脑神经元特定亚群中调节肥胖的作用；3)利用遗传和生化方法，确定PTP1B如何与瘦素作用的另一个负调节因子Socs3以及PTP1B的近亲T细胞蛋白酪氨酸磷酸酶相互作用，以调节瘦素信号传导。这些研究将促进我们对瘦素作用抵抗机制的理解。该结果将对理解正常体重控制及其在肥胖中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.