Inhibition of Gastric Inhibitory Polypeptide Receptor Signaling in Adipose Tissue Reduces Insulin Resistance and Hepatic Steatosis in High-Fat Diet–Fed Mice

Abstract

Gastric inhibitory polypeptide receptor (GIPR) directly induces energy accumulation in adipose tissue in vitro. However, the importance of the direct effect of GIPR signaling on adipose tissue in vivo remains unclear. In the current study, we generated adipose tissue-specific GIPR knockout (GIPR) mice and investigated the direct actions of GIP in adipose tissue. Under high-fat diet (HFD)-fed conditions, GIPR mice had significantly lower body weight and lean body mass compared with those in floxed GIPR (GIPR) mice, although the fat volume was not significantly different between the two groups. Interestingly, insulin resistance, liver weight, and hepatic steatosis were reduced in HFD-fed GIPR mice. Plasma levels of interleukin-6 (IL-6), a proinflammatory cytokine that induces insulin resistance, were reduced in HFD-fed GIPR mice compared with those in HFD-fed GIPR mice. Suppressor of cytokine signaling 3 (SOCS3) signaling is located downstream of the IL-6 receptor and is associated with insulin resistance and hepatic steatosis. Expression levels of SOCS3 mRNA were significantly lower in adipose and liver tissues of HFD-fed GIPR mice compared with those of HFD-fed GIPR mice. Thus, GIPR signaling in adipose tissue plays a critical role in HFD-induced insulin resistance and hepatic steatosis in vivo, which may involve IL-6 signaling.

The effect of glucose-dependent insulinotropic polypeptide (GIP) variants on visceral fat accumulation in Han Chinese populations

“…Mice maintained on a high-fat diet exhibited increased GIP mRNA expression, GIP secretion and K-cell density, and inhibition of GIP action by GIPR ablation or antagonists reversed high-fat-induced obesity and improved insulin sensitivity 7, 9, 21 Nonetheless, some other studies showed that GIPR −/− mice exhibited similar adiposity with wild-type mice on normal diet 7 and specific GIPR knockout mice in adiposity did not reduce fat volume but decreased liver weight and insulin resistance. 22 GIP in combination with hyperinsulinemia and hyperglycemia increased triacylglycerol deposition in subcutaneous fat by enhancing free fatty acid re-esterification in lean human subjects. 23 However, in obese patients, GIP did not induce changes in triacylglycerol uptake in adipose tissue during hyperinsulinemia and hyperglycemic clamping, 24 potentially due to disrupted GIP signaling in insulin-resistant and excess weight states.…”

Association of IL-6 Gene (-174 and -572 G/C) Polymorphisms with Proliferative Diabetic Retinopathy of Type 2 Diabetes in a Chinese Population

“…Therefore, deletion of IL-6 was able to eliminate myocardial fibrosis and improve the cardiac function of diabetic mice. In another study, both IL-6 and gastric inhibitory polypeptide receptor signaling was involved in high-fat diet-induced insulin resistance and hepatic steatosis in vivo [25] .…”

Gastric inhibitory polypeptide/glucose‐dependent insulinotropic polypeptide signaling in adipose tissue

“…To address this problem, we generated adipose tissue‐specific GIPR knockout (GIPR adipo−/− ) mice. Under HFD‐fed conditions, GIPR adipo−/− mice had significantly lower bodyweight and lean body mass compared with those in floxed GIPR (GIPR fl/fl ) mice, although the fat volume was not significantly different between the two groups.…”