Combination therapy of metformin and p-coumaric acid mitigates metabolic dysfunction associated with obesity and nonalcoholic fatty liver disease in high-fat diet obese C57BL/6 mice

Metformin (MET) has been demonstrated to have favorable impact on nonalcoholic fatty liver disease (NAFLD); however, the combined effect of this drug with p-coumaric acid (PCA) on liver steatosis is unclear. The aim of the current study was to evaluate the combined effects of MET and PCA on NAFLD in a high-fat diet (HFD)-induced NAFLD mouse model. The obese mice received MET (230 mg/kg), PCA (200 mg/kg) monotherapies, and MET combination with PCA in the diet for 10 weeks. Our results showed that the combination of MET and PCA markedly ameliorated weight gain and fat deposition in HFD fed mice. Furthermore, the combination of MET and PCA lowered liver triglyceride (TG) content which was accompanied by decreased expression of lipogenic and increased expression of β-oxidation related genes and proteins. In addition, combination therapy of MET and PCA mitigated liver inflammation through inhibiting hepatic macrophage infiltration (F4/80), switching macrophage from M1 into M2 phenotype, and ameliorating nuclear factor-κB (NF-κB) activity in comparison with the monotherapy of MET or PCA. Furthermore, we found that MET and PCA combination therapy upregulated thermogenesis-related genes in BAT and sWAT. Combination therapy results in stimulating brown-like adipocyte (beige) formation in the sWAT of HFD mice. Taken together, these findings indicate that MET combined with PCA can improve NAFLD through decreasing lipid accumulation, inhibiting inflammation and inducing thermogenesis, and adipose tissue browning.