The role of PTP1B in leptin receptor-dependent and -independent regulation of ene

PTP1B 在瘦素受体依赖性和非依赖性 ene 调节中的作用

• 批准号: 8261094
• 负责人: Ryan Tsou
• 金额: $ 4.22万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261094
• 关键词: Adipocytes; Adipose tissue; Adult; Affect; Basic Science; Biological Assay; Body Weight; Brain; Cells; Chronic; Cultured Cells; Cytokine Signaling; Diet; Disease; Dose; Eating; Endocrine; Energy Metabolism; Enzymes; Epidemic; Evaluation; Fatty acid glycerol esters; Feedback; Fellowship; Food Energy; Genes; Genetic; Goals; Health; Homeostasis; Hormones; Hypothalamic structure; In Vitro; Individual; Injection of therapeutic agent; Interleukin-6; Janus kinase 2; Knock-out; Knockout Mice; Leptin; Leptin resistance; Light; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolism; Molecular Biology Techniques; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathway interactions; Peripheral; Phenotype; Phosphoric Monoester Hydrolases; Physiology; Play; Population; Protein Tyrosine Kinase; Public Health; Rattus; Recombinant Interleukins; Regulation; Research; Research Design; Resistance; Risk; Role; Signal Pathway; Signal Transduction; Synapsins; Testing; Tissues; Training; United States; Viral; Work; base; cytokine; diabetic; energy balance; glucose tolerance; human PTPRT protein; in vitro Model; in vivo; insulin tolerance; knock-down; leptin receptor; mRNA Expression; mouse model; mutant; novel; protein tyrosine phosphatase 1B; public health relevance; small hairpin RNA

DESCRIPTION (provided by applicant): Obesity is a major health concern in the United States and abroad. Recent estimates within the US classify more than 30% of the adult population as obese (BMI > 30). Since obesity increases the health risks for other associated metabolic and non-metabolic disorders, the increasing obesity epidemic is a major concern for public health. The brain functions as an organized and integrative center in the control of body weight, regulating both food intake and energy expenditure. Leptin is a hormone secreted from the peripheral adipose tissue that acts primarily in the brain to suppress food intake and increase energy expenditure. Mice with a mutation in the gene encoding leptin (ob/ob) are obese and diabetic. Protein tyrosine phosphatase 1B (PTP1B) has been shown to negatively regulate leptin signaling, and whole body and brain-specific PTP1B -/- mice are resistant to diet-induced obesity and are leptin hyper-sensitive. Interestingly, leptin and PTP1B double knockouts (PTP1B-/- ob/ob) mice are leaner than ob/ob single knockouts, suggesting that PTP1B may regulate additional non-leptin signaling pathways which regulate body weight and metabolism. Thus, whether PTP1B requires intact leptin signaling for its metabolic effects remains unclear. Other non-leptin circulating factors have been implicated in the control of energy homeostasis. Interleukin-6 (IL-6) is a circulating cytokine that, like leptin, is found at levels which correlate with adipose mass. Central injection of low dose IL-6 was shown to increase energy expenditure in rats, and chronic daily injections of IL-6 suppressed body weight. IL- 6 has been shown to signal through an intracellular pathway similar to that of leptin. This pathway involves downstream activity by Janus kinase 2 (JAK2), a known substrate of PTP1B. The goal of this proposal is to train the fellowship applicant in a variety of molecular biology techniques, mouse genetics, and in vivo physiology in order to test the hypothesis that PTP1B's metabolic effects are mediated by both leptin- dependent and leptin-independent signaling. Additionally, this proposal aims to test the hypothesis that PTP1B regulates IL-6 signaling. The first aim is to determine whether PTP1B regulates energy balance through a leptin receptor-dependent or -independent manner in the CNS. This will be done with mouse genetics by generating CNS-specific leptin receptor and PTP1B double mutants and comparing their metabolic phenotypes with those of single mutants and wild type controls. The second aim is to determine whether PTP1B regulates IL-6 signaling involved in the central control of metabolism. PTP1B expression will be knocked down in cultured cells via viral-mediated shRNA, and activation of downstream effectors of IL-6 (pJAK, pSTAT) will be measured. Additionally, IL-6 sensitivity in vivo will be assessed based upon the in vitro results. PUBLIC HEALTH RELEVANCE: The proposed work is basic research designed to elucidate the role of protein tyrosine phosphatase 1B (PTP1B) in the central control of energy homeostasis. Understanding the function and pathways of PTP1B in the brain may shed light on new targets and novel pathways for treating metabolic disorders such as obesity and type 2 diabetes.

描述（由申请人提供）：肥胖是美国和国外的主要健康问题。美国的最新估计将超过30％的成年人口归类为肥胖（BMI> 30）。由于肥胖会增加其他相关代谢和非代谢疾病的健康风险，因此肥胖流行的增加是公共卫生的主要关注点。大脑在控制体重的控制方面充当有组织的综合中心，调节食物摄入和能量消耗。瘦素是一种从周围脂肪组织分泌的激素，主要作用于大脑，以抑制食物摄入并增加能量消耗。编码瘦素（OB/OB）基因中具有突变的小鼠肥胖和糖尿病。蛋白质酪氨酸磷酸酶1B（PTP1B）已显示出负调节瘦素信号，并且整个身体和脑特异性PTP1B - / - 小鼠对饮食诱导的肥胖症具有抗性，并且是瘦素过敏的。有趣的是，瘦素和PTP1B双基因敲除（PTP1B - / - OB/OB）小鼠比OB/OB单个敲除更精细，这表明PTP1B可能调节调节体重和代谢的其他非leptin信号通路。因此，是否需要PTP1B是否需要完整的瘦素信号传导其代谢作用，尚不清楚。其他非左右循环因素也与控制能量稳态有关。白介素6（IL-6）是一种循环的细胞因子，与瘦素一样，在与脂肪质量相关的水平上发现。表明低剂量IL-6的中央注射可增加大鼠的能量消耗，并每天慢性注射IL-6抑制体重。已显示IL-6通过类似于瘦素的细胞内途径发出信号。该途径涉及Janus激酶2（JAK2）的下游活动，这是PTP1B的已知底物。该提案的目的是在各种分子生物学技术，小鼠遗传学和体内生理学中训练奖学金申请人，以检验以下假说：PTP1B的代谢作用均由瘦素依赖性和瘦素独立的信号传导介导。此外，该建议旨在检验PTP1B调节IL-6信号传导的假设。第一个目的是确定PTP1B是否通过中枢神经系统中的瘦素受体依赖性或非依赖性方式调节能量平衡。这将通过小鼠遗传学来实现CNS特异性瘦素受体和PTP1B双突变体，并将其代谢表型与单个突变体和野生型对照的表型进行比较。第二个目的是确定PTP1B是否调节与代谢中心控制有关的IL-6信号传导。将通过病毒介导的shRNA在培养的细胞中击倒PTP1b的表达，并将测量IL-6（PJAK，PSTAT）下游效应子的激活。另外，将根据体外结果评估体内IL-6敏感性。 公共卫生相关性：拟议的工作是旨在阐明蛋白酪氨酸磷酸酶1B（PTP1B）在能量稳态中心控制中的作用的基础研究。了解PTP1B在大脑中的功能和途径可能会阐明新的靶标和新的途径，以治疗肥胖症和2型糖尿病等代谢疾病。