Background Dipeptidyl peptidase-Ⅳ (DPP-4) inhibitors are now used to improve postprandial glycemic control in type 2 diabetes.However,their effects on hepatic glucose production (HGP) in obesity are not clear.This study was designed to test the hypothesis that gluconeogenesis and HGP can be modulated by DPP-4 inhibitors in obesity.Methods Sprague Dawley male rats were divided into four groups,each on a different diet:general rat chow,n=10 (G);G+sitagliptin,n=10; high fat chow (obesity),n=10 (55％ fat calories,HFO); HFO+sitagliptin,n=10.After 10 weeks,the rats were fasted overnight and glucose metabolism was determined using 3-3H-glucose and 14C-glycerol as tracers.Results Glycerol rate of appearance (P＜0.00001),plasma glycerol (P＜0.05) and free fatty acid (FFA) (P＜0.05)concentrations,and HGP (P＜0.05) were decreased in HFO+sitagliptin group compared with HFO group,but there was no significant difference between G and G+sitagliptin groups (P＞0.05).Gluconeogenesis in HFO group was five times of that in G rats (P＜0.01),but was significantly declined in HFO+sitagliptin group (P＜0.0001).Conclusions Gluconeogenesis and HGP were inhibited by sitagliptin in high fat-induced obese rats due to decreased glycerol availability,which was a result of reduced glycerol release from adipose tissues.The finding suggests that sitagliptin is potentially useful for controlling fasting glucose in obesity,thereby delaying or preventing the development of diabetes.