Grant: Project Grant

Obesity affects nearly 14 million Canadians and is a major risk factor for diabetes (type 2). The brain plays a critical role in controlling blood glucose and body weight by regulating food intake and amount of calories burned. The activity of specific neurons is strongly regulated by signals from surrounding glial cells including microglia, the resident immune cells of the brain. However, the mechanisms by which microglia regulate the activity of neurons important for glycemia and energy balance are still elusive. Our published and preliminary findings suggest that microglia release signals that are derived from intracellular fat stores (named lipid droplets) via an enzyme called Adipose Triglyceride Lipase (ATGL). These microglial signals then regulate the activity of neurons that are essential for maintenance of blood glucose. Indeed, gene invalidation of microglial ATGL leads to glucose intolerance and poor insulin secretion in male and female mice. Together, these results support a mechanism by which microglia ATGL acts as a regulator of whole body glucose balance. The overall goal of our research is to determine the role and the mechanisms by which microglia ATGL modulates the activity of neurons to regulate glucose and energy homeostasis. We propose to explore our goals using a combination of pharmacological and genetic strategies to precisely modulate microglia ATGL and its signaling in cultured cells and mouse models. With growing health concerns regarding obesity and diabetes, it is critical to understand the mechanisms underlying these diseases. We believe the novel contribution of microglial lipid stores and ATGL in the brain are key to controlling glucose and 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.