Abstract
Obesity is associated with hypothalamic inflammation, leptin resistance and increased cardiometabolic risk, but the neuroimmune signals linking nutrient excess to these outcomes remain incompletely defined. Here we show that diet-induced obesity is accompanied by local complement activation in the mouse hypothalamus, leading to C3a generation that signals through C3a receptor (C3aR) on leptin receptor (ObRb)-expressing neurons and blunts leptin signaling. Deletion of C3aR in ObRb-expressing neurons preserves leptin responsiveness, reduces food intake and weight gain, and improves glucose homeostasis during dietary challenge. Systemic pharmacological C3aR targeting induces weight loss and improves leptin responsiveness in established obesity. Genetic or pharmacological C3aR targeting also attenuates obesity-associated diastolic dysfunction and myocardial fibrosis; pair-feeding experiments reveal an additional component of cardiac protection beyond reduced weight gain, associated with lower cardiac sympathetic innervation. In humans, circulating complement activation markers are elevated in obesity and decline after bariatric surgery. Together, our findings identify C3aR signaling in ObRb-expressing neurons as a neuroimmune pathway contributing to hypothalamic leptin resistance and obesity-associated cardiac remodeling, highlighting complement signaling as a potential therapeutic target in cardiometabolic disease.