Abstract: Obesity which has become common in the United States is a major cause of hypertension, a principal reversible risk factor for cardiovascular disease. However, the mechanisms underlying the relationship between obesity and hypertension remain largely unknown. The goal of this proposal is to identify the neuronal and molecular processes that control energy homeostasis and blood pressure and how dysregulation in these processes contribute to obesity and obesity-associated hypertension. This proposal is based on our recent work demonstrating the importance of neuronal Bardet Biedl syndrome (BBS) proteins in the regulation of energy homeostasis and blood pressure. We discovered that the BBSome, a complex of eight BBS proteins, is required for the trafficking of receptors that underlie neural control of energy homeostasis. We further hypothesize that defects in the hypothalamic BBSome contribute to common dietary obesity and associated increase in sympathetic nerve activity and blood pressure. This is supported by our recent intriguing preliminary data implicating dysfunction of the BBSome in the hypertensive high fat diet-induced obese mice. To test our hypothesis, we will investigate whether restoring the BBSome in the hypothamus of diet-induced obese mice alleviate the increased adiposity, energy imbalance, activation of the brain renin-angiotensin system and the increase in blood pressure and sympathetic nerve activity. We will also determine the cellular processes underlying the BBSome-mediated trafficking of the receptors regulating energy homeostasis and use chemogenetics to assess the specificity and extend of the defects caused by disruption of the BBsome in hypothalamic neurons. These innovative studies which will employ unique and sophisticated genetic strategies, neuro-techniques and physiologic approaches should unravel novel mechanisms that underlie obesity and obesity-associated cardiovascular risks, making our work of high clinical relevance. Insights into the cellular and molecular processes that control energy balance and cardiovascular function may make it possible to selectively interfere with the damage obesity inflicts on cardiovascular function.