Identification of an Intracellular Role for Complement Factor D: Lipid Droplet Biogenesis in Differentiating Adipocytes

Complement factor D (CFD, also known as adipsin) is a secreted serine protease classically known for activating the alternative complement pathway and regulating systemic metabolism. Although CFD is highly expressed in adipocytes, its roles in adipogenesis remain to be elucidated. Here, we show that intracellularly localized CFD promoted lipid droplet (LD) formation in its catalytic activity‐independent manner. Using mammary adipose tissue‐derived stem cells (mADSCs) isolated from wild‐type (WT) and Cfd ‐knockout ( Cfd ‐KO) mice, we demonstrated that the lack of CFD significantly reduced LD number in mature adipocytes. Lentiviral expression of the secretion signal sequence‐deficient (SD) or catalytically inactive CFD mutant, as well as the cytosolic CFD3 splice variant, rescued LD formation to WT levels in Cfd ‐KO adipocytes. In contrast, exogenously supplemented CFD proteins were unable to restore LD formation in our culture system. These findings uncover a previously unrecognized intracellular function for CFD, revealing its regulatory role in LD biogenesis during adipocyte differentiation.