Targeting glucose-inhibited hippocampal CCK interneurons prevents cognitive impairment in diet-induced obesity

Metabolic disorders are closely linked to increased risk of cognitive decline, with Western-style high-fat diets (HFDs) emerging as key contributors. However, the underlying cellular and molecular mechanisms remain unclear. Here, we demonstrate that short-term HFD (stHFD) consumption disrupts memory processing by inducing hyperactivity in dentate gyrus (DG) cholecystokinin-expressing interneurons (CCK-INs). We identify DG CCK-INs as glucose-inhibited neurons that become hyperactive in response to stHFD-induced reductions in DG glucose availability, coinciding with increased phosphorylation of the glycolytic enzyme pyruvate kinase M2 (PKM2). Restoring glucose availability, reducing PKM2 expression, or inhibiting PKM2 activity normalizes CCK-IN activity and rescues memory deficits. Furthermore, interventions preventing CCK-IN hyperactivity or PKM2 phosphorylation protect against long-term cognitive impairments in a diet-induced obesity mouse model. These findings reveal a previously unrecognized mechanism by which dietary metabolic stress disrupts hippocampal function and highlight DG CCK-INs and PKM2 as promising therapeutic targets for preventing cognitive decline associated with metabolic disorders.