Biliverdin reductase A deficiency reveals sex- and brain region-specific vulnerability to high-fat diet feeding.

How the brain senses and responds to early metabolic stress, and why this process fails differently across sexes and regions, remains poorly understood. Here we show that biliverdin reductase A (BVRA) loss is associated with sex- and brain region-specific effects in response to high-fat diet (HFD) feeding, impairing insulin signaling and mitochondrial responses in selected brain regions while being associated with adaptive liver remodeling and improved systemic glucose handling in female mice. Using wild-type and whole-body BVRA-deficient mice of both sexes exposed to short-term high-fat diet (HFD) followed by dietary normalization, we show that BVRA loss is sufficient to induce cortical insulin resistance within just one week, phenocopying eight weeks of HFD and preceding detectable oxidative distress or mitochondrial failure. This sequence supports a model in which dysfunctional insulin signaling may represent an early event in the cascade of brain metabolic injury. The frontal cortex is the earliest and most vulnerable brain region, whereas the hippocampus shows delayed and milder alterations, suggesting brain region-specific vulnerability to HFD. Strikingly, F mice develop cognitive impairments indistinguishable from M mice despite substantially milder molecular alterations, revealing a sex-specific dissociation between molecular severity and functional outcome. After dietary normalization, M mice show partial recovery of cortical insulin signaling, mitochondrial function, and recognition memory. In contrast, F mice exhibit progressive BVRA decline, worsening insulin signaling uncoupling, and persistent cognitive deficits that outlast dietary exposure - revealing a metabolic memory encoded at the molecular level. These findings identify BVRA loss as a potential causal and sex-biased determinant of brain metabolic vulnerability, with implications for understanding the sex-differential susceptibility to insulin resistance-related neurodegeneration.