B cell-intrinsic insulin resistance as a mechanism of obesity-linked immune dysfunction

Obesity predisposes to insulin resistance (IR), a state where the body responds poorly to the metabolic hormone, insulin. Obesity/IR pose a significant global health threat, as the accompanying inflammatory changes in obese individuals sprout serious health complications such as cardiovascular disease and type 2 diabetes. In addition, obesity and IR undermine immune function and are associated with significantly elevated risks of severe infections and mortality, as exemplified by the H1N1 influenza pandemic (2009) and the current COVID19 pandemic. Complex physiological changes and immune-endocrine interactions are thought to contribute to the observed immune defects, although the precise mechanisms are not well understood. Following the clues that insulin resistance can occur in a manner that is intrinsic to immune cells, and that insulin receptor on immune cells modulate their metabolism and function, we hypothesize that insulin resistance in immune cells, such as B cells, is a major link between obesity and an impaired anti-viral response, leading to increased disease severity and associated mortality. In this study, we will explore the role of the insulin receptor by deleting it from B cells, a type of white blood cells that mediate protective immune responses by secreting antibodies. We will also utilize a high fat diet-fed obese mouse model to study the adverse effects of obesity and IR on B cell function during severe respiratory infections with H1N1 influenza. Importantly, we will determine whether the severity of these infections can be improved with drugs used to treat diabetes. Findings from this study will provide new and important insights into how obesity impacts B cell function, and lay a foundation for the development of therapeutic/vaccination strategies to better cater to the obese, insulin resistant population during current and future viral pandemics.