Role of PTP1B in Body Mass Regulation

描述(申请人提供)：控制体重对哺乳动物的生存至关重要。体重调节障碍(如肥胖)很常见，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量和能量消耗来调节体重。对这些过程的调控是复杂的，涉及到大脑和外周组织中几个部位的多个介质。脂肪细胞荷尔蒙瘦素起着特别重要的作用。瘦素作用于CMS的瘦素受体(LR)，抑制食物摄入，促进能量消耗。LRs在下丘脑的弓状核(ARC)以及大脑的其他几个区域被发现，该核被视为瘦素的主要作用部位。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对瘦素的作用至关重要。大多数肥胖的人对瘦素有抵抗力。确定正常的LR信号机制、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治疗方法。该受体激活酪氨酸激酶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性调节因子。PTP1B的作用是使JAK2去磷酸化，从而终止LR信号。通过建立和研究全身和神经元特异的PTP1B-/-小鼠，我们还发现神经元中的PTP1B在瘦素抵抗的发展中是必不可少的。这项研究的总体目标是阐明PTP1B调节肥胖的机制。具体目的是：1)确定神经元PTP1B-/-小鼠体重减少的细胞和分子基础；2)利用仅在特定类型神经元中表达Cre重组酶的小鼠系，确定PTP1B在调节肥胖中的特定亚群下丘脑神经元中的作用；3)利用遗传学和生化方法，确定PTP1B如何与SOCS3(瘦素作用的另一个负调控因子)以及PTP1B的近亲T细胞蛋白酪氨酸磷酸酶相互作用来调节瘦素信号。这些研究将促进我们对瘦素抵抗作用机制的理解。这一结果将对理解正常的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.