Increased understanding of the mechanisms underlying obesity and diseases to which obesity predisposes - T2D, fatty liver, CHD, dementia and cancer - is of great significance for developing new and effective treatments to improve human health. Nnat is a gene highly expressed in the brain, endocrine glands and adipose tissue. It encodes an ER membrane proteolipid concerned with intracellular signaling. While our preliminary work and published work of others implicate Nnat in appetite control, metabolic-inflammation, insulin resistance, adipogenesis, obesity and obesity genetics, little is known about the physiology of Nnat, the regulation of Nnat expression or its downstream effector pathways. The goals of this proposal are to examine the proposition that Nnat integrates optimum nutrient/hormone signaling with energy homeostasis, acting through central and peripheral mechanisms. Results will be achieved by physiological, electrophysiological, biochemical, molecular biological studi es in adipose tissue and brain specific Nnat-deleted mice, and derived cells. Molecular biology and bioinformatic analysis will be used to evaluate regulation of Nnat expression, and downstream signal transduction from Nnat. We anticipate that characterization of Nnat regulatory pathways in hypothalamus and white adipose tissue (WAT) will provide important insights into regulation of food intake and the pathogenesis of obesity, insulin resistance and T2D.