AN EMERGING ASTROCYTIC PLAYER IN HYPOTHALAMIC REGULATION OF ENERGY HOMEOSTASIS

Obesity and metabolic disorders represent major global challenges, yet the central mechanisms governing energy balance remain incompletely understood. While hypothalamic neurons have been extensively studied, the contribution of astrocytes to metabolic regulation is still poorly defined. This study investigates the role of FGFR3 in hypothalamic astrocytes, focusing on the arcuate nucleus (ARC), a key integrative center for energy homeostasis. Using an astrocyte-targeted mouse model, Fgfr3 expression was selectively downregulated in ARC astrocytes via intrahypothalamic delivery of shRNA-expressing adenoviruses. Mice exhibited significant metabolic alterations, including increased body weight and reduced energy expenditure, without changes in food intake or physical activity, indicating a primary defect in energy metabolism. Peripheral consequences were also observed, such as white adipocyte hypertrophy and whitening of brown adipose tissue. At the hypothalamic level, molecular and histological analyses revealed abnormal expression of the astrocytic markers GFAP and S100β, consistent with astrocyte reactivity. Complementary in vivo and in vitro experiments further demonstrated that FGFR3 is required to maintain normal astrocytic identity and morphology. Notably, immunofluorescence analyses within the ARC showed altered POMC immunoreactivity alongside a significant increase in C-Fos-positive cells, indicating sustained neuronal activation. These findings suggest that Fgfr3 downregulation disrupts astrocyte-mediated homeostatic control, leading to persistent hyperactivation of the ARC circuitry. Overall, this study demonstrates that FGFR3 signalling in hypothalamic astrocytes is essential for maintaining energy balance and body weight, highlighting astrocytes as active contributors to central metabolic regulation and providing new insight into the metabolic disturbances associated with FGFR3-related skeletal disorders.