Project 444340

Obesity affects nearly 14 million Canadians and is a major risk factor for diabetes (type 2). The hypothalamus is a brain region that plays a critical role in controlling body weight by regulating food intake and amount of calories burned. The activity of hypothalamic neurons is strongly regulated by metabolic hormones and nutrients circulating in the blood. In turn, these neurons activate appropriate physiological responses to maintain proper body weight. Our preliminary findings suggest that the activity of hypothalamic neurons is regulated by an enzyme called Adipose Triglyceride Lipase (ATGL) that degrades lipid stores inside these neurons. Indeed, gene invalidation of neuronal ATGL leads to fat deposition in worms and flies, and affect calorie intake and expenditure in mice. Together, these results support a conserved mechanism throughout evolution by which neuronal ATGL acts as a regulator of body fat and energy balance. The overall goal of our research is to determine the role and the mechanisms by which neuronal ATGL modulates the activity of hypothalamic neurons to regulate energy balance. In addition, we will examine if neuronal ATGL is involved in the etiology of obesity and diabetes. We propose to explore our goals using a combination of pharmacological and genetic strategies to precisely modulate hypothalamic ATGL and its signaling in flies and rodents. With growing health concerns regarding obesity and diabetes, it is critical to understand the mechanisms underlying these diseases. We believe the novel contribution of neuronal lipid stores and ATGL in the hypothalamus are key to controlling energy balance and the underlying cause to these pathologies. Identifying a causative and druggable target for obesity and diabetes that could be challenged with prospective therapies remains an unmet clinical need.