SummaryObjectiveGastric inhibitory polypeptide plays a role in glucose and lipid metabolism and is associated with obesity and insulin resistance. The objective of this study is to confirm the anti‐obesity effects of the gastric inhibitory polypeptide receptor antagonist, SKL‐14959, on diet‐induced obesity mice.MethodDiet‐induced obesity mice at 20 weeks of age were administered with or without SKL‐14959 for 96 d. Body weight and food intake were monitored throughout the experiment. Mice were sacrificed, and physiological and biochemical markers were measured, and then histochemical and gene expression analyses were also performed. In further studies, mice were orally gavaged with [14C]‐oleic acid to investigate the excursion of digested lipids.ResultsSKL‐14959 significantly suppressed weight gain without affecting food intake, decreased triacylglycerol contents in the liver and the muscle and the intensity stained with oil‐red in the liver. It also improved plasma glutamic pyruvic transaminase and 3‐hydroxybutyrate levels in addition to notably down‐regulated relative gene expression of srebf1 and dgat1 in the liver despite not altering in the adipose tissue. Furthermore, SKL‐14959 showed remarkable inhibition of lipid uptake in the adipose tissue after the oil challenge.ConclusionSKL‐14959 inhibited lipids uptake and improved lipids metabolism, results in suppression of body‐weight gain.

These data indicate that SKL-14959 is distinguished in the physiological phenotype of GIP following direct binding to the receptor.

Introduction Glucose-dependent insulinotropic polypeptide (GIP) plays a crucial role in the regulation of lipid metabolism via lipoprotein lipase (LPL). GIP receptor antagonist, SKL-14959, suppressed the weight gain in the diet-induced obesity model. However, the mechanism is not unclear. Therefore, we aimed to give insight into the reason. Methods Mice were divided into three groups of the low-fat diet, high-fat diets mixture with or without SKL-14959 for 151 days, and were monitored body weight and food consumption through the test. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were also performed. After that, blood, liver, muscle and adipose tissue were collected. Blood samples were measured glycosylated hemoglobin A1c (HbA1c), glucose, insulin, GIP level and plasma LPL activity. Triacylglycerol (TG) contents of liver and muscles were also measured. Moreover, a simple correlation analysis was performed. Results SKL-14959 suppressed the body weight gain, decreased body mass index (BMI), HbA1c, and fasting glucose level, and trended to decline adipose tissues weight and TG contents compared with the vehicle, and inhibited plasma LPL activity. OGTT and ITT in the SKL-14959 group were not significantly changed relative to the vehicle. Additionally, upon treatment with SKL-14959 treatment, weight gain had weak correlation with lipase activity. Furthermore, lipase activity was associated with the fat mass and not white but red muscle TG contents and liver TG contents were not associated with lipase activity but HbA1c. In Conclusion SKL-14959 might direct lipids metabolism to catabolism by inhibition of plasma LPL activity, resulting in the suppression of weight gain on diets-induced obesity mice.

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