Curcumin alleviates visceral adiposity via inhibiting GIP release from hypoxic intestinal damage in MASH rats

Visceral adiposity is an important characteristic of metabolic dysfunction-associated steatohepatitis (MASH) that affects its development. Curcumin (Cur) attenuates MASH through microbial biotransformation. However, antibiotics (Abx) do not weaken but rather enhance the resistance to weight gain of Cur on MASH rats. The resistance to weight gain mechanism of Cur is different from its anti-MASH effect, which may relate to alleviate visceral adiposity. Here we investigated the mechanism of Cur against visceral adiposity in high-fat diet-induced MASH rats. The results demonstrated that Cur and Abx reduced body, liver and visceral fat weights of MASH rats. Unlike Abx, which induces resistance to weight gain by reducing appetite, Cur mainly reduced the weight of visceral fat, especially that of perirenal fat. Intriguingly, the reduction in perirenal fat caused by Cur was attributed to its specific inhibition of gastric inhibitory polypeptide (GIP) release. The Cur-induced decrease in intestinal GIP release inhibited the activation of GIP receptors to alleviate adipogenesis and inflammation in perirenal adipose tissue. Moreover, Cur alleviated intestinal epithelium and vascular barrier disruption-mediated hypoxia to inhibit GIP release. In summary, the pharmacological effects of Cur on visceral adiposity were mainly contributed by inhibiting gut barrier disruption-mediated hypoxia to attenuate GIP release.