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

BACKGROUND: Carrying a germline BRCA1 mutation increases the risk of several cancers, including breast and ovarian cancer. While BRCA1 is best known for its role in DNA damage repair, emerging evidence suggests broader functions in metabolic regulation. METHODS: To determine whether heterozygous loss of Brca1, as occurs in individuals carrying a germline mutation, modifies susceptibility to diet-induced metabolic dysfunction in a sex-dependent manner, wild-type (WT) and Brca1+/- mice of both sexes were fed a low-fat diet (LFD) or high-fat diet (HFD) and underwent longitudinal metabolic phenotyping. RESULTS: Female HFD-fed Brca1+/- mice exhibited exacerbated obesity, increased adiposity, hyperinsulinemia, and impaired glucose tolerance compared with WT controls. In contrast, male Brca1+/- mice showed modest resistance to HFD-induced weight gain and improved glucose tolerance. Human genetic analyses supported an association between BRCA1 and metabolic traits, including BMI, type 2 diabetes and liver fat accumulation. Despite divergent systemic metabolic phenotypes, Brca1 heterozygosity increased susceptibility to HFD-induced hepatic steatosis in both sexes. In HFD-fed female Brca1+/- mice, steatosis was associated with transcriptional remodeling linked to lipid accumulation and oxidative stress responses, together with reduced mitochondrial respiratory complex IV activity, altered mitochondrial morphology, lower hepatic ATP levels. Treatment with the dual GLP‑1/GIP receptor agonist tirzepatide improved systemic metabolic dysfunction and hepatic steatosis in HFD-fed female Brca1+/- mice. CONCLUSIONS: These findings identify Brca1 heterozygosity as a modifier of metabolic disease susceptibility and expand the biological role of BRCA1 beyond tumor suppression to include the regulation of metabolic health.