Serpina3c regulates adipose differentiation via the Wnt/β-catenin-PPARγ pathway

Objective: The Serpin protein family plays an important role in regulating the functioning of the adipose tissue. This study aimed to study the underlying mechanisms of Serpina3c in regulating adipogenesis. Methods: We developed a Serpina3c knockout (Serpina3c(-/-)) mouse model and Serpina3c knockdown and overexpression 3T3-L1 preadipocyte models to evaluate the role of Serpina3c in adipose differentiation. Mice were fed on ND for 12-month or HFD for one month. The body weight, glucose tolerance, and insulin tolerance of the mice were subsequently measured. Lipid depositions and adipose tissue morphology were then detected using Oil red O staining and HE staining. qRT-PCR and Western blot were used to detect the expression of adipose differentiation transcription factors. Results: Serpina3c(-/-)mice exhibited lower body weight and white adipose tissue (WAT) weight than WT mice after 12 months of being fed on ND. Additionally, there was an increase in serum and hepatic triglyceride (TG) levels in Serpina3c(-/-) mice, without changes in glucose metabolism. Wnt/beta-catenin was upregulated while PPAR gamma expression was decreased in knockout mice WAT. Impaired adipocyte differentiation caused by Serpina3c knockdown was reversed by IWR-1 and kallistatin through an increase in PPAR gamma expression. Serpina3c(-/-) mice fed on HFD for one month had a lower body weight and WAT than WT, accompanied by increased lipid depositions in the liver and muscles and severe insulin resistance. Conclusion: Serpina3c promotes adipogenesis and maintains normal fat function by inhibiting the Wnt/beta-catenin pathway.