ORF27-03 - Complement Factor D Is a Female-Enriched Adipokine That Regulates Brown Adipogenesis through C3aR1

Regulation of metabolic homeostasis differs between men and women and therefore sex differences in the prevalence of obesity and metabolic diseases exist. Interestingly, premenopausal women show lower prevalence of diabetes and cardiovascular disease, suggesting a role for sex hormones in cardiometabolic health. Brown adipose tissue (BAT) is a key contributor to systemic energy expenditure and exhibits sexual dimorphism, being more prevalent and active in females than in males. BAT thermogenesis consumes energy to generate heat, and its activity is associated with a healthier metabolic profile in rodents and in humans. Unravelling the molecular mechanisms controlling sex-dependent BAT metabolism may reveal novel therapeutic targets.
Here, we identified complement factor D (CFD), also known as adipsin, as a brown adipokine that is 5-fold more abundant in BAT and plasma of female compared to male mice. In addition, its levels were downregulated upon ovariectomy to levels observed in males. In vitro, CFD expression and secretion increased during brown adipocyte differentiation. Silencing either CFD or the downstream C3a receptor (C3aR1) in cell lines impaired brown adipogenesis, reducing lipid accumulation and expression of adipogenic and thermogenic markers. Conversely, pharmacological activation of C3aR1 accelerated brown adipocyte differentiation. Transcriptomic analysis showed that BAT-related metabolic pathways were significantly downregulated upon CFD silencing and upregulated after C3aR1 activation. Consistent with the role of CFD in the complement pathway promoting C3 cleavage, we further demonstrate that CFD expression determines C3a levels in cultured brown adipose cells, and that CFD and C3a abundance exhibit a parallel regulation in mice. Stimulation of C3aR1 in CFD-deficient cells partially rescued their adipogenic potential, functionally linking CFD with C3a/C3aR1 signaling in brown adipocyte differentiation. Importantly, this mechanism was found to be preserved in male and female cells.
Together, these findings identify CFD as a female-enriched regulator of brown fat, uncovering a molecular basis for sex differences in BAT and energy metabolism. Targeting CFD or its downstream signaling pathway may be used as a therapeutic strategy in males and postmenopausal women to protect against weight gain and metabolic decline.