Hypothalamic Inflammation and PM2.5 Exposure-Induced Insulin Resistance

描述（由申请人提供）：2型糖尿病（T2 DM）是全球主要死亡原因之一。流行病学研究发现，除了缺乏运动和营养过剩外，物理环境因素如污染物也可能与T2 DM有关。我们和其他人提供的证据表明，空气中< 2.5 μ m的颗粒物（PM2.5）暴露可调节T2 DM发病机制中的关键过程，包括胰岛素抵抗、内脏脂肪堆积、促炎性免疫激活和肝内质网应激。目前缺乏暴露可调节这些不同影响的综合途径。在这个建议中，我们假设，PM2.5暴露诱导下丘脑抑制剂？B激酶2（IKK 2）/核因子-？B（NF-？B）激活，随之而来的是外周胰岛素敏感性/炎症的变化，因此提出使用模拟真实世界暴露于空气的现有技术水平的体内暴露来追求3个离散但相关的目标 污染目的1：确定PM2.5暴露是否诱导下丘脑IKK 2/NF-？B活化和炎症反应。目的2：为了确定是否中央IKK 2/NF-？B信号传导对于PM2.5吸入诱导的胰岛素敏感性/炎症异常是必不可少的。目标3.确定TNF α是否是PM2.5吸入诱导的下丘脑炎症和胰岛素抵抗所必需的。我们的研究结果将提供一个新的认识的千变万化的空气污染暴露的影响，并有明显的全球公共卫生的影响。

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.