Consumption of a high-fat diet induces central insulin resistance independent of adiposity

Abstract

Plasma insulin enters the CNS where it interacts with insulin receptors in areas that are related to energy homeostasis and elicits a decrease of food intake and body weight. Here, we demonstrate that consumption of a high-fat (HF) diet impairs the central actions of insulin. Male Long-Evans rats were given chronic (70-day) or acute (3-day) ad libitum access to HF, low-fat (LF), or chow diets. Insulin administered into the 3rd-cerebral ventricle (i3vt) decreased food intake and body weight of LF and chow rats but had no effect on HF rats in either the chronic or the acute experiment. Rats chronically pair-fed the HF diet to match the caloric intake of LF rats, and with body weights and adiposity levels comparable to those of LF rats, were also unresponsive to i3vt insulin when returned to ad libitum food whereas rats pair-fed the LF diet had reduced food intake and body weight when administered i3vt insulin. Insulin's inability to reduce food intake in the presence of the high-fat diet was associated with a reduced ability of insulin to activate its signaling cascade, as measured by pAKT. Finally, i3vt administration of insulin increased hypothalamic expression of POMC mRNA in the LF- but not the HF-fed rats. We conclude that consumption of a HF diet leads to central insulin resistance following short exposure to the diet, and as demonstrated by reductions in insulin signaling and insulin-induced hypothalamic expression of POMC mRNA.

Figure 1

Effect of i3vt saline or insulin [4 mU (a) or 8 mU (b)] on 24-hr caloric intake in rats maintained for 10 weeks on chow, the LF diet, or the HF diet. Values represent mean + SE. * = P < 0.05 compared with saline.

Figure 2

Effect of i3vt saline or insulin [4 mU (a) or 8 mU (b)] on change of body weight in rats maintained for 10 weeks on chow, the LF diet, or the HF diet. Values represent mean + SE. * = P < 0.05 compared with saline.

Figure 3

Insulin-induced increased pAKT relative to AKT in the basal medial hypothalamus of HF and LF rats following 8 mU of insulin or saline. Values represent mean percentage (± SE). * = P < 0.05 compared with 100%.

Figure 4

Effect of saline or insulin (4 mU/day) by a single daily i3vt administration on body weight (a) and food intake (c) of PLF, and body weight (b) and food intake (d) in PHF groups. Values represent mean (± SE). * = P < 0.05 compared with saline.

Figure 5

Mean percent change of hypothalamic mRNA for AgRP (a), NPY (b) and POMC (c) following i3vt saline or insulin (4 mU). * = P < 0.05 compared with saline.

Figure 6

Effect of i3vt saline or insulin (10 mU) on 24-hr caloric intake in rats maintained on LF or HF diets for 3 days. * = P < 0.05 compared with saline.