Bariatric surgery is increasingly used for the treatment of obesity and associated type-2 diabetes, but the mechanisms for the beneficial effects are not well understood. Recent clinical studies show that the large early suppression of food intake may be more important for remission of the diabetic state than previously assumed, as pair-feeding non-surgical control subjects to the low level of food intake of gastric bypass patients improved glycemic control just as much. However, dieting typically fails because of increased hunger and reduced metabolism - counter-regulatory responses that are suspiciously absent after bypass surgery. Here, in a new mouse model for Roux-en-Y gastric bypass surgery (RYGB), we focus on the potential mechanisms responsible for keeping the strong hunger drive in check. Preliminary observations in RYGB mice and rats show that: (a) eating a meal excessively activates calcitonin-gene- related peptide-expressing neurons in the external lateral parabrachial nucleus, (b) reduced food intake is the result of smaller meal size and early satiety, and (c) food choice gradually shifts from high-fat to low-fat foods. We hypothesize that the brainstem anorexia pathway centered around the lateral parabrachial nucleus is critically involved in the reduced food intake after RYGB and that the anorexic power of this neural pathway can be leveraged to prevent and reverse obesity without surgery. To this end, we will identify the critical components of the anorexia pathway in Aim 1. We will test the hypothesis that inhibition of the anorexia pathway moderates the reduction in food intake and weight loss after RYGB in Aim 2. Finally, we will test the ability of chronically stimulating the anorexia pathway to prevent or reverse high-fat diet- induced obesity and to prevent weight regain after calorie restriction-induced weight loss in non- surgical animals in Aim 3. Neuron- and site-specific inhibition and stimulation of the anorexia pathway will be achieved by novel pharmacogenetic manipulations. The results of these studies have the potential to identify some critical neural and behavioral mechanisms that make bariatric surgeries so efficient and to translate these mechanistic insights into new pharmacological and behavioral anti-obesity therapies.