Abstract

Obesity affects more than one-third of U.S. adults and is a major driver of type 2 diabetes, yet central nervous system targets capable of coordinating both energy intake and expenditure remain limited. Sustained weight loss requires circuits that jointly regulate both processes, and the specific neurons involved remain poorly defined. Our laboratory previously identified a population of cholecystokinin-expressing neurons in the dorsomedial hypothalamus (DMH-CCK) as key regulators of energy balance. Chemogenetic activation of these neurons increases energy expenditure and suppresses feeding, producing weight loss even on a high-fat diet, while inhibition promotes weight gain. Notably, this activation occurs without engaging the hypothalamic-pituitary-adrenal stress axis, indicating that DMH-CCK neurons can drive metabolic change independent of the classic stress response and may be a safer therapeutic target.

This project will define the circuit mechanisms underlying DMH-CCK-mediated control of energy balance and establish their relevance to human obesity. Using in vivo chemogenetics and calcium imaging, we will test the causal role of sustained DMH-CCK activity and peptidergic signaling and record neural dynamics during conditions that increase energy expenditure in lean and obese mice. By leveraging intersectional anatomical tracing techniques such as rabies tracing, ChR2-assisted circuit mapping, and activity-dependent transsynaptic viral labeling, we will map their presynaptic inputs and postsynaptic targets. Finally, we will characterize CCK expression across body mass index, age, and sex in both mouse and human DMH using Xenium spatial transcriptomics. Together, these studies will define circuit mechanisms of energy balance and establish translational relevance to human obesity and diabetes.