HYPOTHALAMIC ASTROCYTES ADAPT TO A HIGH-FAT ​DIET IN A SEX-DEPENDENT MANNER

Brain function relies on dynamic interactions between neurons and glia, among which astrocytes play key roles in physiological and pathological processes. Energy balance is essential for health and is regulated by signals between the body and the brain. Notably, the hypothalamus is a central hub for orchestrating energy homeostasis, with astrocytes emerging as important regulators (Chowen et al., 2018; García-Cáceres et al., 2019). However, the signaling properties of hypothalamic astrocytes and their adaptation to metabolic environments remain poorly understood. My study investigated endogenous astrocytic calcium signaling and its adaptation to a high-fat diet in the hypothalamic paraventricular nucleus (PVN), an anorexigenic center relaying neuroendocrine signals to the autonomic outputs controlling body metabolism. Using mouse genetics, calcium imaging, and metabolic assays in lean and diet-induced obese (DIO) mice, I showed that: (1) PVN astrocytes display active, region-specific calcium signaling characterized by flexible basal activity dependent on endoplasmic reticulum calcium stores and modulated by plasma membrane fluxes; (2) because adrenergic receptors play important roles in regulating astrocyte activity, astrocyte-neuron interaction and energy metabolism, I investigated α1-adrenergic responses of PVN astrocytes. I found that activation of α1-adrenergic receptors with phenylephrine induces oscillatory calcium responses in PVN astrocytes; and (3) astrocytic α1-adrenergic response is remodeled in DIO mice in a sex-dependent manner, with opposite adaptations in males and females. Together, these findings reveal a flexible hypothalamic astrocyte network exhibiting dimorphism in response to metabolic changes, highlighting the heterogeneous contribution of astrocytes to energy homeostasis.