Abstract
OBJECTIVE: Despite successful weight loss, many individuals with obesity regain weight, yet cognitive factors in the weight loss state remain unclear. Here, we tested whether obesity induces deficits in cognitive flexibility, a core component of reinforcement learning (RL), after body weight normalizes. METHODS: Male and female C57BL/6J mice were exposed to high-fat diet-induced obesity followed by weight loss. Weight loss and control mice were tested on a modified probabilistic reversal learning (PRL) task to assess cognitive flexibility and a progressive-ratio (PR) task to evaluate motivation. RL modeling was applied to dissociate latent decision-making parameters. RESULTS: Post-weight-loss mice exhibited persistent impairments in PRL efficiency. Males showed reduced late-phase reversal efficiency (p < 0.001), while females showed early-phase inefficiency but later recovery (p < 0.05). RL modeling revealed reduced learning rates in both sexes, indicating impaired value updating despite intact motivation, as PR performance did not differ between groups. Across tasks, food intake remained unchanged, suggesting reduced efficiency reflected cognitive inflexibility rather than diminished appetite. CONCLUSIONS: Weight loss after obesity produced sex-specific RL deficits. These findings dissociated motivational drive from cognitive flexibility and highlighted maladaptive decision-making as a feature of the weight loss state. This demonstrates the need for targeted interventions addressing post-weight-loss cognitive barriers.