Abstract

Microglia are brain-resident immune cells and have been identified as sensors of dietary excess and mediators of diet-induced hypothalamic dysfunction. Work in our lab and others has implicated microglia, particularly in the hypothalamus, in the pathogenesis obesity and diabetes. However, (1) how microglia are activated by an unhealthy high fat diet and (2) how hypothalamic microglia mediate weight gain and glucose intolerance remain important unanswered questions. To investigate these questions, I have used single-cell RNA sequencing and identified a population of microglia which respond to diet and are specifically located in the mediobasal hypothalamus, a key region in the regulation of food intake and energy homeostasis. These diet-responsive microglia have transcriptional similarities to microglial states associated with neurodegenerative disease, notably high expression of apolipoprotein E (apoE). Further, in mice lacking apoE, microglia in the mediobasal hypothalamus have reduced responsiveness to nutritional fat. APOE polymorphism, the strongest genetic risk factor for Alzheimer’s disease, is also associated with obesity risk in human studies and knock-in mouse models. My objective is to identify the mechanisms by which diet-responsive microglia in the mediobasal hypothalamus contribute to risk of obesity and diabetes, with particular focus on the roles of apoE and human APOE polymorphisms. To achieve these goals, I will use state-of-the-art tools including single-cell RNA sequencing and mouse models of human APOE polymorphisms to characterize microglial responsiveness to diet at the single-cell level, and to specifically investigate the effects of human APOE polymorphisms on microglial function and response to dietary excess.