The hypothalamus is a complex structure involved in different body functions including the control of feeding and body energy expenditure. The arcuate nucleus (ARC), in particular, is a critical nucleus involved in these processes.In the brain, the communication and the interactions between glial and neuronal cells are fundamental in maintaining the brain metabolic homeostasis1.In particular, the Triggering Receptor Expressed on Myeloid cells 2 (Trem2), an immune receptor expressed in the brain microglia, has recently emerged as central in controlling the metabolic fitness of neurons in the developing hippocampus2. Interestingly, we found that adult Trem2 heterozygous mice, maintained under normal diet, exhibit defective glucose tolerance (GTT) and insulin resistance (ITT). We thus hypothesized that Trem2 could play a pivotal role in regulating neuronal metabolism in the arcuate nucleus, and that alterations in neuronal metabolism consequent to lack of Trem2 could represent a crucial step in the development of metabolic diseases. We thus characterized the two specific antagonistic neuronal populations of the arcuate nucleus, the anorexigenic proopiomelanocortin (POMC) neurons, the orexigenic agouti-related protein and neuropeptide Y (AgRP/NPY) neurons and the associated microglia in Trem2+/+ and Trem2-/- mice in order to uncover how defective Trem2 impacts selected neuronal cell populations. Also, we are investigating how the crosstalk between hypothalamic microglia and neurons impacts local and peripheral metabolism. Paolicelli, R. C. et al. Neuron 110(21):3458-3483 (2022).Tagliatti, E., Desiato G. et al. Immunity 57, 86–105 (2024).