Role of adipose protein-tyrosine phosphatase 1B in glucose homeostasis and body m

描述（由申请人提供）：体重调节障碍，如肥胖，是发病和死亡的常见原因。尽管取得了重大进展，但能量稳态的许多细胞和分子细节仍然未知。对分子信号传导机制的进一步了解将有助于开发更有效的肥胖及其相关疾病（如2型糖尿病）的治疗方法。蛋白质酪氨酸磷酸化和去磷酸化是细胞中的基本信号传导机制，并且受到蛋白质酪氨酸激酶和蛋白质酪氨酸磷酸酶（PTPs）的相反作用的严格控制。蛋白酪氨酸磷酸酶1B（Protein-tyrosine phophatase 1B，PTP 1B）是一种重要的代谢生理调节因子。PTP 1B全身敲除（KO）小鼠对胰岛素和瘦素超敏，并且对高脂肪饮食诱导的肥胖有抵抗力。使用组织特异性缺失的其他研究揭示了PTP 1B在各种外周胰岛素反应组织（肝脏和肌肉）和大脑中的多样和复杂功能。然而，脂肪PTP 1B的代谢作用仍然在很大程度上未被探索。为了充分评估脂肪PTP 1B的生理作用，我们将采用三种互补的方法。我们将产生脂肪特异性PTP 1B KO小鼠，这将能够评估体内脂肪组织中PTP 1B损失的后果。同样重要的是解剖介导PTP 1B功能的分子机制，并以高空间和时间分辨率表征动态PTP 1B-底物相互作用。在初步研究中，我们表明：（i）脂肪-PTP 1B缺失的小鼠对高脂饮食诱导的肥胖有抵抗力，（ii）这至少部分是这些小鼠能量消耗增加的结果。(iii)此外，脂肪PTP 1B缺失改善全身胰岛素敏感性和葡萄糖稳态。(iv)鉴定丙酮酸激酶M2为PTP 1B的新底物。因此，我们的初步研究表明，脂肪PTP 1B是体重和葡萄糖稳态的主要调节因子。该提案的广泛目标是研究脂肪PTP 1B的代谢作用。PTP 1B是治疗肥胖和糖尿病的一个有吸引力的靶点，许多制药公司开发了PTP 1B抑制剂。因此，了解脂肪PTP 1B如何发挥作用对于评估其作为治疗干预靶点的用途至关重要。 公共卫生相关性：肥胖和2型糖尿病是非常普遍的代谢疾病，影响美国和全世界数百万人。本提案的目标是利用基因工程小鼠模型和先进的生物化学和成像方法来确定脂肪蛋白酪氨酸磷酸酶1B在葡萄糖稳态和体重调节中的生理作用。从该提案中产生的数据将有助于确定预防和治疗肥胖和2型糖尿病的治疗靶点。

DESCRIPTION (provided by applicant): Disorders of body mass regulation such as obesity are increasingly common causes of morbidity and mortality. Despite significant progress, many cellular and molecular details of energy homeostasis remain unknown. Increased understanding of the molecular signaling mechanisms will aid in the development of more effective therapies for obesity and its associated disorders, such as type 2 diabetes. Protein tyrosine phosphorylation and dephosphorylation is a fundamental signaling mechanism in cells, and is tightly controlled by the opposing actions of protein-tyrosine kinases and protein-tyrosine phosphatases (PTPs). Protein-tyrosine phophatase 1B (PTP1B) is an important physiological regulator of metabolism. PTP1B whole-body knockout (KO) mice are hypersensitive to insulin and leptin, and are resistant to high fat diet-induced obesity. Additional studies using tissue-specific deletion, revealed a diverse and complex function of PTP1B in various peripheral insulin-responsive tissues (liver and muscle) and brain. However, the metabolic role of adipose PTP1B remains largely unexplored. To fully assess the physiological role of adipose PTP1B, we will employ three complementary approaches. We will generate adipose-specific PTP1B KO mice which will enable assessment of consequences of PTP1B loss in adipose tissue in vivo. Equally important are the dissection of molecular mechanisms mediating PTP1B function, and characterization of the dynamic PTP1B-substrate(s) interaction with high spatial and temporal resolution. In preliminary studies, we show that: (i) mice with adipose-PTP1B deletion are resistant to high fat diet-induced obesity, (ii) this is a result, at least in part, of increased energy expenditure in these mice. (iii) In addition, adipose PTP1B deletion improves systemic insulin sensitivity and glucose homeostasis. (iv) Indentify pyruvate kinase M2 as a novel substrate of PTP1B. Thus, our preliminary studies indicate that adipose PTP1B is a major regulator of body mass and glucose homeostasis. The broad goals of this proposal are to investigate the metabolic role of adipose PTP1B. PTP1B is an attractive target for therapy of obesity and diabetes with many pharmaceutical companies developing PTP1B inhibitors. Therefore, understanding how adipose PTP1B acts is vital for its evaluation of use as a target for therapeutic intervention. PUBLIC HEALTH RELEVANCE: Obesity and type 2 diabetes are very prevalent metabolic diseases affecting millions of people in the United States and worldwide. The goal of this proposal is to utilize genetically engineered mouse models and advanced biochemical and imaging approaches to determine the physiological role of adipose protein-tyrosine phosphatase 1B in glucose homeostasis and body mass regulation. Data generated from this proposal will aid in the identification of therapeutic targets for prevention and treatment of obesity and type 2 diabetes.