Brca1 heterozygosity leads to hepatic steatosis in male and female mice despite sexually dimorphic effects on systemic metabolism

In contrast, male Brca1+/- mice showed modest resistance to HFD-induced weight gain and displayed improved glucose tolerance compared to WT controls. Notably, Brca1 heterozygosity led to more severe hepatic steatosis with HFD, indicating a shared susceptibility to liver lipid accumulation despite divergent systemic outcomes. In females, steatosis was associated with reduced mitochondrial respiratory complex IV activity and transcriptional remodeling that favored lipid storage.

Treatment with the dual GLP‑1/GIP receptor agonist tirzepatide ameliorated systemic metabolic dysfunction and hepatic steatosis in HFD–fed female Brca1+/− mice. These findings identify Brca1 heterozygosity as a modifier of metabolic disease risk, expanding BRCA1 biology beyond tumor suppression.