摘要
The circulating bile acids(BAs)play critical roles in regulating the glycolipid metabolism,inflammation,and other physiological functions.Male C57BL/6J mice were given high-fat diet(HFD)with 500 mg/kg and 2500 mg/kg caffeic acid phenethyl ester(CAPE)for 16 weeks(CAPE500 and CAPE2500).The results showed that both the two dose of CAPE treatment improved the glycolipid metabolism and inflammation in HFD-induced obese mice.The BA profile analysis revealed that CAPE2500 increased hepatic and serum circulating BA levels compared to HFD(P-value of 0.347 and 0.467,respectively),while CAPE500 showed decreased serum circulating BA levels compare to CAPE2500(P-value of 0.0881),suggesting dose-specific ameliorative mechanisms of CAPE on obesity based on BA signaling.Further study found significantly lower bile salt hydrolase(BSH)activity in the ileal contents of the CAPE500 group compared to the HFD group,which resulted in suppressed intestinal FXR signaling and improved glycolipid metabolism through inhibiting ileal FXR-enhanced ceremide synthesis.However,CAPE2500 increased serum circulating BA levels by significantly decreasing BA excretion compared with the HFD and CAPE500 groups(P<0.0001 and P<0.01,respectively),enhancing brown adipose tissue thermogenesis by activating the TGR5/UCP-1 signaling axis.Furthermore,CAPE also ameliorated the gut microbiota disorders and obesity induced by HFD.This study reveals a dose-specific effect of CAPE treatment on circulating BA content,ileal BSH-FXR signaling and gut microbiota,which improves glucose and lipid dyshomeostasis through different mechanisms.
基金
supported by National Natural Science Foundation of China(32172214,32001693,31972079).
