The Serpina3c Regulates Adipose Differentiation Through The Wnt/β-catenin-PPARγ Pathway

Background:The synthesis,decomposition and energy metabolism of adipose tissue are essential to maintain the balance of glucose and lipid metabolism.Meanwhile,adipose tissue is also an important target organ for insulin.Adipose tissue dysfunction caused by obesity or lipodystrophy can lead to ectopic fat deposition and insulin resistance.Previous studies have shown that Serpina3c is closely related to the differentiation of 3T3-L1 preadipocytes,but the role of Serpina3c in mice adipose tissue is unclear,and the specific mechanism needs to be explored.Objective:To explore the relationship between Serpina3c and adipogenesis,and its related mechanisms.Methods:Serpina3c^-/-mouse models,Serpina3c^-/-and Serpina3c^+/+3T3-L1preadipocyte models were constructed.Different mice groups were fed by high-fat diet for 1 month or normal diet for 12 months.The weight,food intake,fasting blood glucose,glucose tolerance and insulin tolerance of knockout mice and wild-type mice were measured.Fat deposits was detected by Oil red O staining.The cell size in adipose tissue was observed by HE staining.Fluorescence quantitative PCR and western blot were used to detect the expression of adipose differentiation transcription factors,autophagy,apoptosis and Wnt/β-catenin pathway in the adipose tissue.Results:（1）Compared with wild-type mice,the weight of 12-month-old Serpina3c^-/-mice was decreased,as well as the weight of the white adipose tissue.The size of fat cells was decreased,and the ectopic fat deposition in the liver was increased.（2）Oil red O staining showed that Serpina3c^-/-preadipocytes had poorer differentiation ability after induction,and the number of lipid droplets was decreased.（3）The m RNA expression of PPARγ,C/EBPβ,vaspin and leptin in the adipose tissue was decreased.The protein expression of PPARγwas decreased andβ-catenin expression was increased.（4）Cell experiments showed that the Wnt pathway inhibitor IWR-1 can rescue the differentiation ability of knockout cells and promote the expression of PPARγ.（5）12-month-old Serpina3c^-/-mice and Serpina3c^-/-cells showed decreased autophagy and increased apoptosis.（6）Male Serpina3c^-/-mice on a high-fat diet for 1month lost weight in white adipose tissue,developed insulin resistance and increased triglyceride deposition in the liver and muscle.Conclusion:Serpina3c promotes the expression of PPARγand normal fat production by inhibiting the Wnt pathway.Serpina3c inhibits ectopic fat deposition and improves insulin resistance in mice.