Safflower yellow and its main component hydroxysafflor yellow A alleviate hyperleptinemia in diet‐induced obesity mice through a dual inhibition of the GIP‐GIPR signaling axis

Abstract

Glucose‐dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone secreted by K cells in the small intestine and is considered an obesity‐promoting factor. In this study, we systematically investigated the anti‐obesity effects of intragastric safflower yellow (SY)/hydroxysafflor yellow A (HSYA) and the underlying mechanism for the first time. Our results showed that intragastric SY/HSYA, rather than an intraperitoneal injection, notably decreased serum GIP levels and GIP staining in the small intestine in diet‐induced obese (DIO) mice. Moreover, intragastric SY/HSYA was also first found to significantly suppress GIP receptor (GIPR) signaling in both the hypothalamus and subcutaneous White adipose tissue. Our study is the first to show that intragastric SY/HSYA obviously reduced food intake and body weight gain in leptin sensitivity experiments and decreased serum leptin levels in DIO mice. Further experiments demonstrated that SY treatment also significantly reduced leptin levels, whereas the inhibitory effect of SY on leptin levels was reversed by activating GIPR in 3 T3‐L1 adipocytes. In addition, intragastric SY/HSYA had already significantly reduced serum GIP levels and GIPR expression before the serum leptin levels were notably changed in high‐fat‐diet‐fed mice. These findings suggested that intragastric SY/HSYA may alleviate diet‐induced obesity in mice by ameliorating hyperleptinemia via dual inhibition of the GIP‐GIPR axis.

Intragastric Safflower Yellow Alleviates HFD Induced Metabolic Dysfunction-Associated Fatty Liver Disease in Mice through Regulating Gut Microbiota and Liver Endoplasmic Reticulum Stress

“…It was well established that hypocaloric diet was the cornerstone of treatment for MAFLD [ 57 , 59 ]. Our study found that intragastric SY obviously reduced the food intake of DIO mice during the intervention, which has also been found in our previous results [ 38 ]. Our further correlation analysis of the metabolic phenotypes and gut microbiota showed that Bacteroides, Bacteroides_acidifaciens and Bacteroides_intestinalls were negatively correlated with food intake of DIO mice, while their abundance was significantly increased in SY-treated mice.…”

“…Our previous study indicated intragastric SY/HSYA, rather than an intraperitoneal injection, notably decreased serum Gip levels and Gip staining in the small intestine in diet-induced obese (DIO) mice [ 38 ], suggesting intragastric intervention played an important role in gut. Given the important role of gut microbiota plays in the occurrence and development of MAFLD and the potential link between the effects of SY and gastrointestinal tract, the potential contributions of gut microbiota to the benefits of SY treatment on MAFLD were investigated in our present study.…”