Brain sensing of metabolic state regulates circulating monocytes

Changes in energy availability alter the dynamics of circulating immune cells. The existing view is that these effects are due to altered nutrient levels affecting peripheral tissue metabolism. Here, using mice and genetic approaches to manipulate the activity of distinct molecularly defined neurons, we show that the brain’s perception of hunger and satiety alone is sufficient to drive these immune changes. Hunger-promoting Agouti-related peptide (AgRP) neurons in the hypothalamus were both sufficient and necessary to reduce circulating Ly6CHi classical monocytes during fasting. Mechanistically, these neurons suppressed hepatic mammalian target of rapamycin signaling via sympathetic regulation, decreasing circulating chemokine ligand 2 and monocyte numbers. AgRP neuron–induced corticosterone release and glucocorticoid receptor activation played a permissive role in this process. These changes in monocyte dynamics can occur independently of actual nutrient levels, revealing an unexpected brain-mediated control of peripheral immunity in response to perceived variation in energy state.