This study aimed to compare the behavioral, metabolic, and molecular consequences of congenital/complete (aromatase knockout, AROM KO) and adult-onset/partial (ovariectomy, OVX) estrogen (E2) deficiency in female mice, aiming to validate common phenotypes for model selection and therapeutic targeting. Female AROM KO, OVX, and wild-type C57BL/6 littermates were fed a low-fat or high-fat diet for 17 weeks. Body composition, energy expenditure, physical activity, respiratory exchange ratio (RER), glucose metabolism, and gene expression (microarray and qRT-PCR) in adipose tissue and skeletal muscle were assessed. Both AROM KO and OVX mice exhibited increased adiposity, reduced physical activity (>40% reduction in ambulatory movement, ≥70% reduction in wheel running), and elevated RER. AROM KO mice displayed higher baseline body weight as well as hyperglycemia and hyperinsulinemia compared to OVX mice, reflecting more severe effects of complete estrogen loss. Transcriptomic analyses revealed downregulated metabolic pathways (e.g., TCA cycle, fatty acid metabolism) and upregulated inflammatory pathways in adipose tissue of AROM KO mice, with similar but less pronounced changes in OVX mice confirmed by qRT-PCR. Skeletal muscle showed downregulation of exercise-responsive ( Nr4a3 ), insulin-signaling ( Irs1 ), metabolic ( Pcx ), and antioxidant ( Gpx3 ) genes with E2 deficiency, implicating impaired energy metabolism and increased oxidative stress in metabolic dysfunction. Unexpectedly, total energy expenditure was comparable across groups despite reduced activity. Overall, congenital and adult-onset E2 deficiency share common phenotypes, but congenital deficiency induces more severe metabolic impairments. These findings validate both models for studying E2 deficiency and highlight potential therapeutic targets ( Nr4a3 , Gpx3 , Pcx , and Irs1 ) for mitigating E2-deficient-related metabolic dysfunction.
Al-Adhami et al. (Mon,) studied this question.