Prefrontal cortex-to-hypothalamic outputs orchestrate cue-potentiated palatable food consumption via AMPKβ2 signaling.

Cognitive factors critically influence appetite and food consumption, contributing to the increasing incidence of obesity in modern obesogenic environments. However, the cellular and molecular mechanisms underlying this phenomenon remain poorly understood. Here, using calcium imaging in freely moving mice, we found that neurons in the prelimbic cortex (PrL) underwent activity-dependent plasticity in response to learned environmental cues paired with a high-fat diet (HFD). The activity of these neurons reliably predicted the duration of food consumption. Transcriptomic analyses further revealed significant alterations in ATP metabolic processes in the PrL following HFD-associated learning. Notably, the depletion of AMPKβ2, a subunit of AMPK that senses ATP dynamics, abolished PrL plasticity during HFD associative learning and prevented the cue-driven overconsumption of palatable food. At the circuitry level, the activity of PrL(CaMKIIα+) neuronal projections to orexin neurons in the lateral hypothalamus was required for HFD overconsumption under conditioned contexts. Collectively, our findings elucidate a cellular and molecular framework in a cortical-hypothalamic pathway that regulates cue-evoked HFD overconsumption, highlighting AMPKβ2 as a promising therapeutic target for treating eating disorders.