Role of permethrin in 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，环境暴露于化学品（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，缺乏对这些杀虫剂影响脂质和葡萄糖代谢的机制的研究，这些代谢有助于体重增加、2型糖尿病的发展和相关的慢性疾病状况。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（一种拟除虫菊酯类杀虫剂）对肥胖症和2型糖尿病发展的潜在影响。中心假设是暴露于氯菊酯将改变脂质代谢和葡萄糖稳态沿着膳食脂肪，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（在这种情况下，氯菊酯）可能导致肥胖症和2型糖尿病发展的生化机制，现在和将来将可获得这些和相关病理学的更有效的预防和/或治疗策略。因此，拟议中的研究与NIH的使命的一部分有关，该使命涉及开发可能有助于减少人类疾病的知识。基于初步数据，将通过追求以下具体目标来验证该假设：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3 T3-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活化蛋白激酶（AMPK）促进脂肪形成。在目标2中，将使用C2 C12肌管在假设氯菊酯通过钙介导的机制调节胰岛素受体底物-1（IRS-1）的情况下测试氯菊酯对葡萄糖稳态受损的作用。在目标3中，将在C57 BL/6 J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]氯菊酯暴露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]氯菊酯和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方面是针对氯菊酯，一种拟除虫菊酯类杀虫剂，作为肥胖和2型糖尿病的潜在促成因素。特别有趣的是，这项拟议的研究包括实验，以确定氯菊酯暴露和膳食脂肪之间的潜在相互作用。拟议研究的结果将具有重要意义，因为其结果将更清楚地了解暴露于环境污染物如何导致肥胖和2型糖尿病的发展。

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.