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, we show that the brain's perception of hunger and satiety alone is sufficient to drive these immune changes. Hunger-promoting AgRP neurons in the hypothalamus are both sufficient and necessary for the reduction in circulating Ly6CHi classical monocytes observed during fasting. Mechanistically, these neurons suppress hepatic mTOR signaling via sympathetic regulation, decreasing circulating CCL2 and monocyte numbers. AgRP neuron-induced corticosterone release plays 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. The aim of this study was to determine whether the immunoregulatory effects of fasting are solely dependent on altered nutrient availability or if brain-initiated responses also play a role. To this end, we used genetic tools such as chemo- and optogenetics to manipulate the activity of key hypothalamic neurons encoding hunger and satiety, creating synthetic representations of these states on demand. This approach allowed us to isolate and assess the direct effects of neural activation on circulating leukocyte dynamics independently of the actual nutritional state. Male and female mice were grouped post-weaning, with transgenic and littermate control animals co-housed and receiving identical treatments to ensure a level of randomization. Experimenters were blinded to genotype, and no further blinding was necessary due to the use of objective readouts. In pharmacological experiments using only wild-type mice, experimenters were not blinded to treatments. Sample sizes were determined based on previous experiments and the availability of genetically modified animals. No outliers were excluded, and the number of replicates and individual experiments are specified in each figure legend.