Key result
Targeting neuronal C3aR curbs weight gain and attenuates obesity-associated diastolic dysfunction.
Why the study?
The neuroimmune signals linking nutrient excess to hypothalamic inflammation, leptin resistance, and obesity-associated cardiometabolic risk remain incompletely defined.
Does genetic deletion or pharmacological inhibition of C3aR improve leptin resistance and prevent obesity-associated cardiac remodeling in mice on a high-fat/high-fructose diet?
Does genetic deletion or pharmacological inhibition of C3aR improve leptin resistance and prevent obesity-associated cardiac remodeling in mice on a high-fat/high-fructose diet?
Neuronal C3aR signaling drives obesity-associated leptin resistance, and its pharmacological or genetic inhibition protects against cardiometabolic dysfunction and subsequent cardiac remodeling.
C3aR targeting in ObRb neurons may mitigate obesity-linked diastolic dysfunction; leaves open translation from rodent models to human therapy.
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.
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Rawish et al. (2026) studied Diet-induced obesity, leptin resistance, and obesity-associated cardiac remodelling. C3aR genetic deletion in ObRb-expressing neurons or pharmacological C3aR targeting (JR14a) vs. Wild-type/control mice fed high-fat/high-fructose diet was evaluated on Development of diet-induced obesity, leptin resistance, and cardiac diastolic dysfunction. Genetic deletion or pharmacological targeting of C3aR in leptin receptor-expressing neurons preserves leptin responsiveness, reduces weight gain, and attenuates obesity-associated diastolic dysfunction.
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