While metabolic states influence the immune system, the role of brain-driven perceptions of hunger and satiety remains underestimated. A recent study published in Science Immunology employed genetic tools to selectively activate or inhibit hypothalamic neurons like hunger-promoting Agouti-related peptide (AgRP) neurons and the satiety-promoting pro-opiomelanocortin (POMC) neurons. Activating AgRP neurons mimicked fasting and altered immune function by specifically regulating circulating Ly6CHi monocytes. These neurons were both necessary and sufficient to drive immune changes through the hypothalamic-pituitary-adrenal (HPA) axis and a hypothalamic-liver circuit.
This study aimed to determine whether the immunoregulatory effects of fasting are driven exclusively by changes in nutrient availability or if brain-mediated mechanisms also contribute.
C57B1/6 mice were collected from Charles River (UK) and Envigo (UK) included in this study. AgrpCre, PomcCre, Mc4rCre, NPY-hrGFP, and Tsc1flox/flox strains mice were collected from Jackson Laboratory. Female and male mice aged 2 to 6 months old were included in this study. Drugs like clozapine-N-oxide (CNO), pretreatment of mice with pegylated amphetamine (PEGyAMPH), recombinant chemokine (C-C motif) Ligand 2 (CCL2), corticosterone and pretreatment with the GR antagonist (RU486). Different analysis methods like flow cytometry, enzyme-linked immunosorbent assay (ELISA) immunofluorescence staining, western blotting, and gene expression analysis were used. All statistical analyses were carried out by using Prism 8.0.
The effects mediated by AgRP neurons phenocopied those observed during the natural 20-hour fasting period, resulting in similar changes in circulating leukocyte levels. This phenomenon is common to both fasted humans and mice. However, a shorter 4-hour fasting period had no effect on circulating leukocyte numbers.Â
The reduction in circulating Ly6CHi monocytes brought on by fasting can be reversed by artificially stimulating hypothalamic POMC neurons. After food intake, the levels of Ly6CHi monocytes were increased in fasted mice. However, this increase was not observed in fasted mice that were fed with concurrent chemogentic activation of AgRP neurons.Â
AgRP-TeTLC mice exhibited elevated levels of Ly6CHi monocytes after a 20-hour fasting period. This indicated that AgRP neuron activity was required for the typical fasting-induced reduction in these cells. Similarly, the activity of AgRP neurons gradually increased towards the end of the diurnal rhythm.
In mice that were fed, chemogentic activation of AgRP neurons decreased plasma levels of CCL2 to levels similar to those of mice that had fasted for 20 hours. This reduction led to a decline in the circulation of Ly6CHi monocytes.
The activation of AgRP neurons reduces the expression of Ccl2 messenger ribonucleic acid (mRNA) in both the bone marrow and liver. Hepatic mammalian target of rapamycin (mTOR) was inhibited by AgRP neuron activation which frequently observed in fasting mice. This helped balance the body’s energy supply and innate immunological condition.
Administered mice with PEGyAMPH inhibited the reduction in Ly6CHi monocyte levels caused by AgRP neurons and prevented the suppression of hepatic mTOR activity. Systematic administration of RU486 also prevented the decrease in circulating Ly6CHi monocytes stimulated by AgRP neurons. Melanocortin 4 receptor (MC4R) PVN neurons were activated by POMC neurons in positive energy and blocked by AgRP neuron’s activity in fasting to maintain hunger. There was no effect on levels of Ly6CHi monocytes observed after administration of a low dose of corticosterone. However, LysMGRKO mice were mainly resistant to monocytopenia, which commonly occurred in control animals after the administration of corticosterone.
In conclusion, this research highlights that brain-driven hunger or satiety signals mimic natural effects on Ly6CHi monocytes independent of nutrient levels. This suggests immune responses to feeding or fasting were centrally mediated. Future research is necessary to understand how this top-down control could lead to new therapies for metabolic, inflammatory, psychiatric, and infectious diseases.
Reference: Cavalcanti de Albuquerque JP, Hunter J, Domingues RG, et al. Brain sensing of metabolic state regulates circulating monocytes. Sci Immunol. 2025;10(106):eadr3226. doi:10.1126/sciimmunol.adr3226
