Hypothalamic Inflammation and PM2.5 Exposure-Induced Insulin Resistance

描述（由申请人提供）：2型糖尿病（T2DM）是世界上导致死亡的主要原因之一。流行病学研究发现，除了缺乏运动和营养过剩外，物理环境中的污染物等因素也可能与2型糖尿病有关。我们和其他人提供的证据表明，空气中< 2.5¿m （PM2.5）的颗粒物暴露可调节T2DM发病的关键过程，包括胰岛素抵抗、内脏脂肪积累、促炎免疫激活和肝内质网应激。目前还缺乏暴露调节这些不同影响的综合途径。在本研究中，我们假设PM2.5暴露诱导下丘脑抑制剂？激酶2 (IKK2)/核因子-？B (NF - ?B)激活与随之发生的外周胰岛素敏感性/炎症的变化，因此建议使用最先进的体内暴露来模拟真实的空气暴露，以追求3个离散但相互关联的目标

DESCRIPTION (provided by applicant): Type 2 diabetes mellitus (T2DM) is one of the leading causes of death around the world. Epidemiological studies have uncovered that in addition to lack of exercise and over-nutrition, factors in the physical environment such as pollutants may also be associated with T2DM. We and others have provided evidence that airborne particulate matter < 2.5 ¿m (PM2.5) exposure modulates key processes in the pathogenesis of T2DM including insulin resistance, visceral fat accumulation, pro-inflammatory immune activation, and hepatic endoplasmic reticulum stress. Integrated pathways by which exposure may modulate these diverse effects are currently lacking. In this proposal, we postulate that PM2.5 exposure induces hypothalamic Inhibitor ?B Kinase 2 (IKK2)/Nuclear Factor-?B (NF-?B) activation with consequent changes in peripheral insulin sensitivity/inflammation, and thus propose to pursue 3 discrete yet linked aims using state of art in vivo exposures that mimic real-world exposure to air pollution. Aim 1: To determine if PM2.5 exposure induces hypothalamic IKK2/NF-?B activation and inflammatory response. Aim 2: To determine if central IKK2/NF-?B signaling is essential for PM2.5 exposure-induced abnormalities in insulin sensitivity/inflammation. Aim 3. To determine if TNF¿ is essential for PM2.5 exposure-induced hypothalamic inflammation and insulin resistance. Our results will provide a renewed understanding of the protean effects of air pollution exposure and have obvious global public health implications.