Aims The aims were to examine whether oral sodium propionate supplementation regulate lipid metabolism through modulating gut microbiota. Methods and Results ICR male mice (26 center dot 98 +/- 0 center dot 30 g) were randomly assigned to three groups (n = 10) and fed control diet (Con), high-fat diet (HFD) and HFD plus propionate (Pro) respectively. In this study, we found that HFD increased the weight of final body, inguinal white adipose tissues (iWAT), epididymal white adipose tissue (eWAT) and perirenal white adipose tissue (pWAT), as well as the adipocyte mean area of iWAT and eWAT in mice (P < 0 center dot 05), whereas sodium propionate treatment reduced the weight of iWAT and pWAT as well as adipocyte mean area of iWAT in mice fed a HFD (P < 0 center dot 05). Moreover, in the iWAT, the mRNA expression of lipogenesis genes, including peroxisome proliferator activated receptor gamma, acetyl-CoA carboxylase and carnitine palmitoyl transferase-1 beta, was upregulated by HFD challenge (P < 0 center dot 05), and the elevation of these genes was nearly reversed to the level of control diet-fed mice by sodium propionate treatment. Meanwhile, sodium propionate treatment increased the hormone-sensitive lipase mRNA expression in the iWAT of HFD-fed mice (P < 0 center dot 05). High-throughput pyrosequencing of the 16S rRNA demonstrated that sodium propionate treatment significantly recovered the gut microbiota dysbiosis in HFD-fed mice, including the richness and diversity of microbiota and the ratio of Firmicutes to Bacteroidetes. Furthermore, the HFD-induced reductions in colonic levels of butyrate and valerate were reversed by sodium propionate treatment, which also normalized the serum LPS level seen in HFD-fed mice to the levels of the control diet-fed mice. Conclusions Collectively, these results indicated that sodium propionate treatment could improve lipid metabolism in HFD-fed mice, and the potential mechanisms might be via regulating gut microbiota. Significance and Impact of the Study We demonstrated for the first time that oral sodium propionate significantly improved HFD-induced dysbiosis of gut microbiota, indicating that the mitigative effect of propionate for HFD-induced lipid dysmetabolism might be mediated by gut microbiota in mice.