Reduced insulin suppression of glucose appearance is related to susceptibility to dietary obesity in rats.

To examine the relationship between insulin action and body weight regulation in male rats, the following studies were performed. In study 1, rats (n = 31) were fed a low-fat diet (LFD) for 4 wk, and then glucose kinetics were estimated under basal and hyperinsulinemic conditions using the glucose clamp. After clamps, these same rats were placed on a high-fat diet (HFD) for 5 wk. In study 2, rats (n = 30) were fed an LFD for 3 wk and then a high-sucrose diet for 1 wk to produce selective hepatic insulin resistance. Clamps were then performed, and after clamps, these same rats were placed on an HFD for 5 wk. In study 3, rats (n = 30) were fed an LFD for 1 wk and then a high-sucrose diet for 3 wk to produce widespread insulin resistance. Clamps were then performed, and after clamps, these same rats were placed on an HFD for 5 wk. The rate of glucose appearance (R(a)) during the hyperinsulinemic clamps was the only pre-HFD variable that correlated (r = 0.49, P < 0.01 in study 1; r = 0.51, P < 0.001 in study 2) with weight gain on the HFD. Clamp R(a) also correlated with energy intake on the HFD in study 1 (r = 0.64, P < 0.001) and study 2 (r = 0.59, P < 0.001). Clamp R(a) and energy intake on the HFD accounted for similar portions of the variance in body weight gain on the HFD. Weight gain and fat-pad mass were increased (P < 0.05) in study 2 compared with study 1. In study 3, pre-HFD glucose kinetics were not correlated with energy intake or weight gain on the HFD. Widespread insulin resistance did not significantly reduce the rate of weight gain on the HFD. Thus insulin action on R(a) can influence body weight gain on an HFD. The effects of R(a) on body weight gain appear to be mediated via effects on energy intake. Selective hepatic insulin resistance can increase body weight gain on an HFD, but widespread insulin resistance does not significantly reduce HFD-induced weight gain.