KATP channel functional remodeling is associated with neuroinflammatory and dopaminergic alterations under metabolic stress in female mice.

Metabolic stress and neuroinflammation are associated with depression, but the mechanisms connecting peripheral metabolic dysfunction to reward-related circuit alterations remain incompletely understood. ATP-sensitive potassium (KATP) channels couple cellular energy state to neuronal excitability and may link metabolic and neuroimmune signaling. Here, we used female mice exposed to post-weaning isolation combined with a high-fat diet to model convergent psychosocial and metabolic stress. We tested whether KATP channel modulation is associated with behavioral, inflammatory, and dopaminergic-marker changes under this combined stress condition. Peripheral KATP channel modulation was achieved by interscapular brown adipose tissue infusion of glibenclamide, and dopaminergic neuron-specific Kir6.2 conditional knockout mice were used to assess the contribution of neuronal KATP channel signaling. Combined stress induced obesity, hyperglycemia, depression-like behavioral alterations, peripheral cytokine imbalance, increased inflammatory markers, and reduced dopaminergic activity markers in the mesolimbic pathway. Glibenclamide improved glucose tolerance, attenuated stress-associated behavioral and inflammatory-marker changes, and increased Fos expression under stress conditions, while enhancing SUR1 maturation and surface localization. Kir6.2 deletion attenuated stress-associated behavioral alterations and reduced nucleus accumbens Iba1-positive cell accumulation, whereas effects on ventral tegmental area tyrosine hydroxylase-positive cell density were more modest. Together, these findings support KATP channel functional state as a candidate link between metabolic stress, neuroimmune alterations, and dopaminergic circuit adaptations in female mice, and suggest KATP channel modulation as a potential therapeutic strategy for metabolic-associated depression.