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.