Role of permethrin in development of obesity and type 2 diabetes

氯菊酯在肥胖和 2 型糖尿病发展中的作用

• 批准号: 8621995
• 负责人: Yeonhwa Park
• 金额: $ 18.86万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8621995
• 关键词: 5' -AMP-activated protein kinase; Adipocytes; Animals; Behavior; Biochemical; Biological Models; Body Weight; Calcium; Chemicals; Chronic Disease; Data; Development; Diabetes Mellitus; Diet; Dietary Fats; Disease; Disease Outbreaks; Dose; Environmental Exposure; Environmental Pollution; Epidemic; Epidemiologic Studies; Epidemiology; Exposure to; Fatty acid glycerol esters; Female; Future; Goals; Guidelines; Health; In Vitro; Incidence; Individual; Insecticides; Insulin; Insulin Resistance; Investigation; Knowledge; Laboratories; Life; Link; Mediating; Mission; Modeling; Mus; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Outcome; Pathology; Permethrin; Prevention; Public Health; Research; Role; Societies; Testing; Weight Gain; Work; base; blood glucose regulation; burden of illness; chlorohydrocarbon insecticide; disability; glucose metabolism; human disease; in vivo; innovation; insulin receptor substrate 1 protein; interest; lipid biosynthesis; lipid metabolism; male; mouse model; prevent; public health relevance; pyrethroid; research study; response; sex; treatment strategy

DESCRIPTION (provided by applicant): A growing body of epidemiological and laboratory evidence suggests a connection between environmental exposures to chemicals, including insecticides, with development of obesity and type 2 diabetes. However there is a paucity of investigation into the mechanism(s) by which these insecticides influence lipid and glucose metabolisms contributing to weight gain, development of type 2 diabetes, and related chronic disease conditions. The long-term goal is to elucidate the underlying causes of obesity and type 2 diabetes. The specific objective of this project is to determine the potential contribution of permethrin (a pyrethroid insecticide) to development of obesity and type 2 diabetes. The central hypothesis is exposure to permethrin will alter lipid metabolism and glucose homeostasis along with dietary fat, resulting in potentiated weight gain and impaired insulin responses. The rationale of this proposed research is: that by understanding biochemical mechanisms by which exposure to environmental contaminants (permethrin in this case) may result in development of obesity and type 2 diabetes, more efficient prevention and/or treatment strategies for these and related pathologies will be available now and in the future. Thus, the proposed research is relevant to that part of NIH's mission that pertains to developing knowledge that will potentially help to reduce human diseases. Based on preliminary data, the hypothesis will be tested by pursuing the following specific aim: Determine mechanisms of permethrin on development of obesity and type 2 diabetes. In Objective 1, effects of permethrin on altered lipid metabolisms will be tested using 3T3-L1 adipocytes under the hypothesis that permethrin promotes adipogenesis by modulating AMP-activated protein kinase (AMPK) via a calcium-dependent mechanism. In Objective 2, the role of permethrin on impaired glucose homeostasis will be tested using C2C12 myotubes under the hypothesis that permethrin modulates insulin-receptor substrate-1 (IRS-1) via a calcium-mediated mechanism. In Objective 3, effects of permethrin on development of obesity and type 2 diabetes will be determined in C57BL/6J mice model under the hypotheses that [i] exposure to permethrin potentiates weight gain and the development of insulin resistance in a dose- and sex-dependent manner and [ii] interactions between permethrin and dietary fat will influence weight gain and development of insulin-resistance. The innovative aspect of this proposed research is targeting permethrin, a pyrethroid insecticide, as a potential contributing factor for obesity and type 2 diabetes. Of particular interest, this proposed research includes experiments to determine the potential interaction between permethrin exposure and dietary fat. The results from the proposed research will be significant as the outcome will provide a clearer understanding of how exposure to environmental contaminants may contribute to the development of obesity and type 2 diabetes.

描述（由申请人提供）：越来越多的流行病学和实验室证据表明，环境中接触化学物质（包括杀虫剂）与肥胖和 2 型糖尿病的发生之间存在联系。然而，对于这些杀虫剂影响脂质和葡萄糖代谢从而导致体重增加、2 型糖尿病的发展和相关慢性疾病的机制的研究很少。长期目标是阐明肥胖和 2 型糖尿病的根本原因。该项目的具体目标是确定氯菊酯（一种拟除虫菊酯杀虫剂）对肥胖和 2 型糖尿病的潜在影响。中心假设是接触氯菊酯会改变脂质代谢和葡萄糖稳态以及膳食脂肪，导致体重增加和胰岛素反应受损。这项拟议研究的基本原理是：通过了解暴露于环境污染物（本例中为氯菊酯）可能导致肥胖和 2 型糖尿病发生的生化机制，现在和将来将可以针对这些疾病和相关病症制定更有效的预防和/或治疗策略。因此，拟议的研究与 NIH 使命的一部分相关，即开发可能有助于减少人类疾病的知识。根据初步数据，该假设将通过追求以下具体目标进行检验：确定氯菊酯对肥胖和 2 型糖尿病发展的机制。在目标 1 中，将使用 3T3-L1 脂肪细胞测试氯菊酯对脂质代谢改变的影响，假设氯菊酯通过钙依赖性机制调节 AMP 激活蛋白激酶 (AMPK) 来促进脂肪生成。在目标 2 中，假设氯菊酯通过钙介导机制调节胰岛素受体底物 1 (IRS-1)，将使用 C2C12 肌管测试氯菊酯对葡萄糖稳态受损的作用。在目标 3 中，将在 C57BL/6J 小鼠模型中确定氯菊酯对肥胖和 2 型糖尿病发展的影响，假设 [i] 接触氯菊酯会以剂量和性别依赖性方式增强体重增加和胰岛素抵抗的发展，[ii] 氯菊酯与膳食脂肪之间的相互作用将影响体重增加和胰岛素抵抗的发展。这项拟议研究的创新之处在于将氯菊酯（一种拟除虫菊酯杀虫剂）作为肥胖和 2 型糖尿病的潜在影响因素。特别有趣的是，这项拟议的研究包括确定氯菊酯暴露与膳食脂肪之间潜在相互作用的实验。拟议研究的结果将具有重要意义，因为该结果将使人们更清楚地了解接触环境污染物如何导致肥胖和 2 型糖尿病的发生。