ASTROCYTE REACTIVITY IN THE LATERAL ORBITOFRONTAL CORTEX INCREASES FOOD INTAKE AND BODY WEIGHT

Introduction: Obesity is a major public health challenge whose persistence cannot be explained by metabolic dysfunction alone. Diet-induced obesity disinhibits pyramidal neuronal activity in the lateral orbitofrontal cortex (lOFC), a region implicated in goal-directed action, biasing behaviour toward habitual food consumption. We have previously shown that an obesogenic diet also induces astrocyte hypertrophy in the lOFC. However, whether astrocyte reactivity precedes and contributes to overeating and weight gain, or instead reflects a consequence of obesity, remains unknown.
Methods: Mice were maintained on a high-fat diet (HFD) for 12 weeks to induce obesity or used in a model of astrocyte reactivity using excitatory DREADDs (AAV2/3-GFAabc1d-hDM3q) expressed in lOFC astrocytes. In the DREADD model, mice were exposed to a 21-day HFD, with chronic astrocyte activation via deschloroclozapine delivered in drinking water; control mice received water alone. Food intake and body weight were measured daily. Astrocyte reactivity was assessed using S100β, SOX9 markers, and multiplex cytokine assays. DREADD specificity and functional activation were validated using immunolabelling and calcium imaging.
Results: Diet-induced obesity and chronic astrocyte activation increased S100β and SOX9 expression and elevated pro-inflammatory cytokines in the lOFC. Diet-induced obesity increased body weight compared to chow-fed controls, and chronic astrocyte activation increased food intake and weight gain; effects absent in water-only controls.
Conclusion: Diet-induced obesity and chronic astrocyte activation induce inflammatory markers in the lOFC. Together, these findings demonstrate that astrocyte reactivity in the lOFC is sufficient to increase food intake and exacerbate weight gain, implicating lOFC astrocytes in the maintenance of obesity.