Hypothalamic Inflammation and PM2.5 Exposure-Induced Insulin Resistance

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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.