The pancreatic hormone insulin and the adipocyte hormone leptin have key roles in the homeostatic control of body weight and energy balance, entering the brain to act on AGRP-expressing neurons to inhibit food intake and increase energy expenditure, and also regulating hepatic glucose production (HGP) via activation of the autonomic nervous system. Central nervous system resistance to these hormones is implicated as an early contributor to weight gain and obesity. However, surprisingly, blocking either the insulin or leptin signalling pathways in the hypothalamus of mice appears to have little effect on appetite and energy homeostasis. The authors therefore set out to better understand the pathways regulating AGRP neuronal activity, with the aim of identifying novel targets for therapeutic intervention.
The authors hypothesized that both insulin and leptin pathways must be blocked simultaneously in order to influence feeding behaviour. Therefore, they decided to knock out a component integral to both pathways — FOXO1 — in AGRP-expressing neurons in mice (Agrp-Foxo1−/− mice). These mice ate less and were leaner than wild-type mice, exhibiting an 18–30% decrease in fat mass, and were protected from weight gain induced by a high-fat diet. This reduction in food intake was due to increased satiety, as the mice displayed reduced food foraging behaviour and rebound feeding after an overnight fast. Furthermore, the ablation of FOXO1 substantially reduced HGP and improved glucose homeostasis, also rendering mice more sensitive to insulin, leptin and nutrient signalling in the hypothalamus.
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