MICROGLIAL TREM2 AS REGULATOR OF HYPOTHALAMIC HOMEOSTASIS

Microglia are the main resident immune cells of the brain. Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is exclusively expressed by microglia in the brain and mediates microglial metabolism, survival, and phagocytic activity. Through TREM2 signalling, microglia adapt their responses to environmental cues, supporting neuronal health. Alongside their immunological functions, they are active regulators of brain development, neuronal metabolism and circuit remodelling in the hippocampus (Tagliatti, Desiato et al., 2024). Emerging evidence suggests that microglia also act as key mediators of metabolic homeostasis within the hypothalamus, which is the main brain region responsible for metabolic regulation (Valdearcos et al., 2025). Within the arcuate nucleus, specialized neuronal populations integrate peripheral cues, thanks to a unique anatomical relationship with brain barriers, to orchestrate a coordinated response that restores energy homeostasis. Our project investigates how microglial TREM2 shapes the hypothalamic environment by addressing its impact on neuronal fitness and development. To this end, we developed a cell-based platform that recapitulates key aspects of the hypothalamic milieu, using WT and Trem2^−/− mice. We employ sex-specific primary neuronal and microglial cultures. Preliminary results show a marked metabolic impairment specifically in female Trem2^−/− neurons, revealing a TREM2-related disruption in neuronal metabolism. These findings prompt to further investigation of the hypothalamic environment using “Banker” co-culture systems (Kaech & Banker, 2007). Moreover, parallel ex-vivo analyses revealed an altered microglia morphology in Trem2^−/− female mice. By integrating ex-vivo and in-vitro findings, we aim to determine how altered microglial crosstalk contributes to this metabolic dysfunction.