ADAPTATION OF NEURON-GLIA INTERACTION TO BODY METABOLISM

The brain plays a major role in maintaining energy homeostasis by integrating peripheral metabolic signals and adapting neuronal circuit activity accordingly. Disruption of this regulation, notably in response to obesogenic environments, contributes to the development of metabolic disorders such as obesity. The hypothalamic paraventricular nucleus (PVN) is an anorexigenic nucleus involved in the control of food intake and energy expenditure, yet the mechanisms underlying its adaptation to metabolic imbalance remain incompletely understood. Beyond neurons, glial cells are key modulators of neuronal activity and metabolic coupling. Astrocytes display structural and functional plasticity in response to metabolic states, including altered calcium signaling under obesogenic conditions. We investigate how neuron-glia interactions within the PVN contribute to early adaptations to obesity, with a specific focus on astrocytic interactions with somatostatin-expressing (SST) neurons that are implicated in feeding regulation. Using transgenic mouse models, dietary conditioning, calcium imaging, and electrophysiology approaches, we characterized functional, morphological, and molecular properties of PVN SST neurons in control and high-fat diet (HFD) conditions. During early HFD-induced obesity, SST neurons display a reduction in spontaneous activity, indicating adaptation to an altered metabolic state. Moreover, HFD decreases SST neuronal response latency to glutamate, reaching values comparable to those observed following pharmacological inhibition of astrocytic glutamate transporters. These findings suggest an obesity-induced impairment of astrocytic glutamate uptake, leading to elevated extracellular glutamate levels and SST neuron desensitization. We also explore the contribution of microglia to glial plasticity. This work highlights the role of glial cells in hypothalamic circuit adaptation during early obesity development.