Insulin signaling in AgRP neurons regulates meal size to limit glucose excursions and insulin resistance

The importance of hypothalamic insulin signaling on feeding and glucose metabolism remains unclear. We report that insulin acts on AgRP neurons to acutely decrease meal size and thereby limit postprandial glucose and insulin excursions. The promotion of insulin signaling in AgRP neurons decreased meal size without altering total caloric intake, whereas the genetic ablation of the insulin receptor had the opposite effect. The promotion of insulin signaling also decreased the intake of sucrose-sweetened water or high-fat food over standard chow, without influencing food-seeking and hedonic behaviors. The ability of heightened insulin signaling to override the hedonistic consumption of highly palatable high-fat food attenuated the development of systemic insulin resistance, without affecting body weight. Our findings define an unprecedented mechanism by which insulin acutely influences glucose metabolism. Approaches that enhance insulin signaling in AgRP neurons may provide a means for altering feeding behavior in a nutrient-dense environment to combat the metabolic syndrome.

Automated summary

This study highlights the importance of hypothalamic insulin signaling in regulating feeding and glucose metabolism. Insulin acting on AgRP neurons can reduce meal size and limit postprandial glucose and insulin excursions, as well as prevent the development of systemic insulin resistance. Enhancing insulin signaling in AgRP neurons may be a potential approach to alter feeding behavior and combat metabolic syndrome in a nutrient-dense environment.