Abstract

Obesity and type 2 diabetes are not caused only by problems in organs such as the pancreas. They also arise when the brain loses its ability to properly sense and respond to nutrients in the blood. A small but critical brain region called the hypothalamic median eminence sits at the interface between the brain and circulation, allowing it to directly sense nutrients and immune signals while making it especially vulnerable to unhealthy diets. Within this region, brain resident immune cells called microglia maintain healthy hypothalamic function by recycling cholesterol-rich debris from damaged myelin and dying cells, a process essential for preserving the neural circuits that regulate food intake, energy balance, and glucose homeostasis. However, the immune signals that disrupt this process during obesity remain poorly understood.

Our preliminary studies identify chronic interferon (IFN) signaling as a previously unrecognized driver of microglial dysfunction. Rather than resolving after a normal immune response, interferon signaling remains persistently active during Western-style diet feeding, blocking cholesterol efflux, promoting lipid accumulation and inflammation, and impairing the brain’s ability to regulate blood sugar levels. This process is further amplified by infiltrating T cells that sustain inflammatory signaling.

My objective is to understand how chronic IFN signaling disrupts microglial cholesterol metabolism and whether restoring cholesterol balance can reverse these changes. To achieve this, I will combine microglia-specific genetic models, neuron–microglia–oligodendrocyte tri-culture systems, and targeted synthetic HDL nanoparticles that restore cholesterol efflux. These studies will reveal how chronic immune activation disrupts the brain’s control of metabolism and may point new therapeutic strategies for obesity and type 2 diabetes.