Distinct therapeutic roles of diet control and exercise in metabolic disorder-related depression: insights from metabolic and gut microbiota signatures

Depression frequently co-occurs with metabolic disorders, yet the mechanisms linking metabolic dysfunction to depression remain incompletely understood. Using a chronic high-fat diet (HFD) feeding mouse model of metabolic disorder-related depression, we previously demonstrated that downregulation of astrocytic glutamate transporters in the ventral hippocampus drives depression-like behaviors through hyperactivation of ventral hippocampal glutamatergic projections to the nucleus accumbens. Although pharmacological restoration of these transporters rescued depression-like phenotypes, systemic glutamatergic modulation was associated with substantial mortality in chow-fed controls, highlighting the need for safer non-pharmacological strategies. Here, we showed that, compared with mice maintained on HFD for 12 weeks, switching from HFD to normal chow at week 9 ameliorated most metabolic abnormalities and anhedonia but failed to restore insulin sensitivity or alleviate behavioral despair. In contrast, initiation of mild-intensity treadmill running exercise at week 9 prevented further weight gain without improving metabolic dysfunction or depression-like behaviors. Neither intervention restored ventral hippocampal glutamate transporter expression, astrocytic structural integrity, nor hyperactivity within the ventral hippocampus-nucleus accumbens circuit. Notably, behavioral despair was strongly associated with systemic insulin resistance, but not overweight or corticosterone levels, implicating impaired insulin signaling as a key pathogenic factor and potential biomarker of this depression subtype. In parallel, we identified a distinct gut microbiota signature associated with HFD-induced depressive behaviors and astrocytic dysfunction. Together, these findings suggest that HFD-induced depression is driven by insulin resistance-linked astrocytic and circuit-level pathology and identify metabolic and microbial biomarkers with translational relevance for metabolic disorder-related depression.