The long-term goal of this research project is to understand the mechanism underlying the regulation of energy balance. Over 30% of adults and 16% of children are obese in the United States. Obese children and adults are developing type 2 diabetes at high rates, and are at significant risk for life-threatening cardiovascular disease and cancer. Despite the enormous economic cost of obesity, no effective drugs are currently available for obesity treatment. The mechanistic understanding of the regulation of energy intake and energy expenditure provides an opportunity to develop novel therapeutic interventions. Brain-derived neurotrophic factor (BDNF) plays crucial roles in energy balance. Mutations in the genes for BDNF and its receptor TrkB lead to severe obesity in both mice and humans. Furthermore, BDNF is one of 18 genes that have been associated with human obesity in genome-wide association studies. However, the mechanism by which BDNF regulates energy balance remains unknown. On the basis of our exciting and strong preliminary data, we hypothesize that BDNF-expressing neurons in the paraventricular hypothalamus (PVH) regulate energy balance by stimulating thermogenesis in brown adipose tissue (BAT) and suppressing food intake. We propose to test this hypothesis in four specific aims. Aim 1 is to confirm a criticl role of PVH BDNF neurons in the control of thermogenesis and food intake using Cre-expressing adeno-associated virus (AAV) and the DREADD (designer receptors exclusively activated by designer drugs) technology; Aim 2 is to determine under what conditions PVH BDNF neurons regulate thermogenesis; Aim 3 is to map the neural circuits that are connected to PVH BDNF neurons; Aim 4 is to profile gene expression of PVH BDNF neurons. Findings from the proposed studies will provide insights into the mechanism governing the regulation of energy balance.