The dual epidemic of obesity and type 2 diabetes mellitus in the US and worldwide represents one of the most costly and pressing healthcare burdens confronting modern society today. The multifactorial nature of obesity and the incomplete understanding of its pathogenesis have limited the development of effective treatments. Since overnutrition triggers immune cell activation in peripheral tissues and the brain, strategies that target the inflammatory response have important therapeutic potential. Recent work from the applicant's laboratory indicates that the consumption of a high-fat diet is associated with hypothalamic inflammation and sustained activation of surrounding astrocytes and microglia. An overarching goal of this proposal is to delineate the physiological relevance of inflammatory signaling in astrocytes and microglia to the maintenance of energy homeostasis. Based on previous studies and our preliminary data, we hypothesize that glial inflammation promotes diet-induced obesity and insulin resistance. We therefore propose to determine if the development of diet-induced obesity is altered in mice with inactivated immune signaling pathways in glial cells. Using viral and genetic approaches to generate mice deficient in NFkB/IKKb signaling specifically in microglia (Aim 1) or astrocytes (Aim 2), we will assess the effects of high-fat diet feeding on body weight, food intake, metabolic endpoints, and glucose homeostasis parameters. Together, these studies will clarify the physiological and pathophysiological roles of glial inflammation in energy homeostasis and provide a rationale for the development of novel drug targets to treat obesity and diabetes.