Background:
Obesity is a major global health challenge and a critical risk factor for diabetes, hypertension, dyslipidemia, and subsequent cardiovascular morbidity and mortality. The hypothalamus plays a central role in maintaining energy homeostasis by integrating hormonal and nutrient signals to regulate appetite and metabolism. A hallmark of diet-induced obesity is impaired hypothalamic sensitivity to the adipocyte-derived hormone leptin, leading to dysregulation of food intake and energy expenditure. Several inflammatory pathways have been implicated in the dysregulation of hypothalamic leptin signaling in obesity; however, a mechanistic link between central leptin resistance and the complement system remains elusive.
Methods:
We employed a multi-modal approach combining transgenic reporter mice, conditional knockout models, and pharmacological interventions. Neuronal C3aR expression was localized using tdTomato-C3aR reporter mice. Astrocyte-derived complement C3 was identified as the source for hypothalamic C3a. Functional relevance was assessed using a conditional C3aR knockout line (C3aR flox × ObRb Cre) targeting appetite-regulating hypothalamic nuclei. Additionally, selective C3aR antagonists were administered to HFD-fed mice in both preventive and therapeutic settings. Leptin signaling integrity was evaluated via STAT3 phosphorylation and SOCS3 expression both in hypothalamic tissue and in vitro.
Results:
For the first time, we show that complement C3a receptor (C3aR) controls hypothalamic sensitivity to leptin, hypothalamic neuroinflammation and ultimately, the development of obesity. First, we identified astrocyte-derived complement C3 as the source for C3a generation. Using a tdTomato-C3aR reporter mice, we demonstrated neuronal C3aR expression in the hypothalamus. Activation of this C3a/C3aR axis impaired leptin signaling leading to metabolic dysfunction. Using a conditional C3aR knockout mouse model that provides Cre recombinase activity specifically in appetite-regulating hypothalamic neurons, we observed protection against diet-induced obesity and preserved leptin sensitivity. Further, specific pharmacological inhibition of C3aR corroborated these findings. Such C3aR targeting prevented the development of obesity and improved metabolic parameters not only in a preventive but also in a therapeutic setting. Mechanistically, we show that C3aR activation impairs leptin signaling by inducing SOCS3 expression in appetite-regulating neurons, thereby disrupting central regulation of energy balance.
Conclusions:
These results uncover a previously unrecognized role of the complement system in central energy regulation, highlighting the astrocytic C3–neuronal C3aR axis as a critical mediator of hypothalamic dysfunction in obesity. Our findings not only expand the understanding of neuroimmune interactions in metabolic disorders but also identify C3aR as a promising therapeutic target to combat obesity and its associated cardiovascular sequels.
