Alba Sabaté Pérez1, Yini Yuan1, Jacobie Steenbergen1, Afonso de Oliveira Santos Goulart1, Jenny Visser1, Alba Sabaté Pérez1, Yini Yuan1, Jacobie Steenbergen1, Afonso de Oliveira Santos Goulart1, Jenny Visser1
(1) Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands. (2) Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands. (3) Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands. (4) Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands. (5) Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands. (6) Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands. (7) Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands. (8) Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands. (9) Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands. (10) Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.
Background and aim:
Regulation of metabolic homeostasis differs between men and women and subsequently sex differences in the prevalence of obesity and metabolic diseases exist. It is well known that white adipose tissue shows a sex-dimorphic distribution. However, also brown adipose tissue (BAT) exhibits sexual dimorphism in rodents, being more active in females than in males, and some studies suggest that this is also the case in humans. A higher thermogenic activity of brown adipose tissue is associated with a healthier metabolic profile both in rodents and in humans. Thus, unravelling the sex-dependent molecular mechanisms that control BAT metabolism may reveal novel therapeutic targets. We previously identified complement factor D (Cfd), also known as adipsin, as a sex-differentially expressed gene in mouse BAT. Here, we studied the origin of this sex difference and evaluated the role of Cfd in BAT metabolism.
Material and methods:
BAT from female and male mice that underwent gonadectomy or a sham surgery was collected for gene expression analysis. The brown adipocyte cell line T37i was transfected with siRNA against Cfd or C3aR, or treated with 5µM C3aR agonist to evaluate the impact on differentiation. RNAseq was performed to determine the effects on gene expression after both interventions.
Results:
Gonadectomy reduced Cfd expression in female BAT, but had limited effect in male BAT, thereby abolishing Cfd sex-differential expression. Silencing of Cfd or the downstream signalling receptor C3aR in T37i cells blocked differentiation, leading to a complete downregulation of adipogenic and thermogenic markers, such as Ucp1 and Pparg. Treatment with the C3aR agonist accelerated differentiation, evidenced by an earlier lipid accumulation and induction of Ucp1. In line, RNAseq analysis revealed that BAT-related metabolic pathways were significantly reduced after Cfd silencing and upregulated upon C3aR agonist treatment.
Conclusion:
Our results indicate that Cfd contributes to BAT sexual dimorphism by favouring BAT adipogenesis through the C3aR receptor signalling.