Grant: Project Grant

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. We, as well as others, suggest that hypothalamic astrocytes, a cell type surrounding neurons, can regulate neuronal activity via cell-to-cell communication and energy balance. Currently, the peptide signals sent from astrocytes to neurons and their role in energy balance control are unknown. We have generated preliminary results suggesting a protein called Diazepam Binding Inhibitor (DBI), derived from astrocytes, inhibits feeding by activating anorectic neurons whereas the loss of DBI in astrocytes favors obesity in mice. The overall goal of our research is to determine the role and the mechanisms by which DBI in astrocytes modulates the activity of hypothalamic neurons to regulate energy balance. In addition, we will examine if DBI and its receptor are potential targets for the treatment of obesity and diabetes. We propose to explore our goals using a combination of pharmacological and genetic strategies to precisely modulate hypothalamic DBI production and signaling in 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 astrocyte-derived signals in the hypothalamus is 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.