mTORC1 in AGRP neurons integrates exteroceptive and interoceptive food-related cues in the modulation of adaptive energy expenditure in mice

摘要

Losing weight through dieting can be difficult. Weight loss strategies often prove ineffective because the body works like a thermostat and couples what we eat to the number of calories we burn. When we eat less, our bodies compensate and burn fewer calories, which makes losing weight harder. The brain is the master regulator of this caloric thermostat, but it is not clear how it adjusts our energy expenditure to account for how much we have eaten. A structure deep within the brain called the hypothalamus, which helps regulate appetite, is thought to be involved in the caloric thermostat. Activating a group of neurons within the hypothalamus called the agouti-related neuropeptide (AGRP) neurons causes animals to consume large quantities of food. By contrast, inhibiting AGRP neurons causes animals to stop eating almost entirely. Burke et al. studied AGRP neurons in mice. The experiments show that artificially activating the neurons in mice that don’t have access to food increases the animals’ activity levels but reduces the rate at which they burn calories, which helps the mice to maintain their existing weight. Allowing the mice to eat, or even just to see and smell food, switches off this effect and returns energy expenditure to normal. Finally, exposing mice to a high-fat diet for several days inhibits their AGRP neurons, and causes the animals to burn calories at a faster rate. By using up excess calories, this change also helps the animals maintain their existing body weight. The findings of Burke et al. show that AGRP neurons are a key component of the caloric thermostat. By adjusting the rate at which the body burns calories, AGRP neurons can compensate for any changes in food intake and so limit changes in body weight. This work opens up the possibility of developing therapies that disconnect energy expenditure from energy intake to help maintain long-term weight loss.