Author(s): HANDY, R., BRUNETTA, H., JUNG, A., GÓMEZ, A., RAHMAN, F., KUPRATY, A., COYLE-ASBIL, B., DESORMEAUX, G., DALTON, B., MASHOURI, P., FRANGOS, S., POWER, G., BARTELT, A., HOLLOWAY, G., Institution: UNIVERSITY OF GUELPH, Country: CANADA, Abstract-ID: 1459

INTRODUCTION:
Menopause is associated with increased cardiometabolic disease risk, which cannot be fully explained by changes in body mass or skeletal muscle function. Adipose tissue (AT) is a key regulator of systemic metabolism, yet the impact of 17B-estradiol (E2) loss on AT mitochondrial function and inflammatory remodeling remains incompletely understood. Therefore, we investigated whether ovarian failure disrupts AT mitochondrial function and redox balance, whether these impairments are directly attributable to E2 loss, and if they could be rescued by high-intensity interval training (HIIT).
METHODS:
Female CD-1 mice aged 12-15 weeks received daily intraperitoneal injections of 4-vinylcyclohexene diepoxide (VCD; 160 mg/kg) for 15 d to induce ovarian failure and subsequent ovarian E2 deficiency or remained untreated as controls. Ovarian failure was confirmed 120 d following VCD treatment by prolonged diestrus using vaginal cytology and uterine atrophy. Upon confirmation, VCD-treated mice were further allocated to receive a slow-release E2 replacement or sham treatment. A separate cohort of VCD-treated mice underwent HIIT 3x/week for 4 weeks following confirmation of ovarian failure. Whole-body metabolism was assessed using indirect calorimetry, fasting blood measures, and intraperitoneal glucose tolerance tests. Gonadal white adipose tissue (gWAT) was collected for assessment of mitochondrial respiration and reactive oxygen species (mtROS) emission, inflammatory and fibrotic remodeling, and transcriptomic profiling using bulk RNAseq.
RESULTS:
VCD-induced ovarian E2 deficiency resulted in impaired insulin sensitivity and reduced whole-body energy expenditure. In gWAT, the absence of ovarian E2 did not impair mitochondrial respiratory capacity, but markedly increased mtROS emission, indicating altered mitochondrial redox balance. These changes were accompanied by adipocyte hypertrophy, increased fibrotic remodeling, and inflammation. Transcriptomic analysis revealed coordinated enrichment of immune and inflammatory response networks following ovarian E2 loss. E2 replacement normalized mtROS emission, and attenuated inflammatory and fibrotic markers, demonstrating E2-dependent regulation of AT function. Notably, HIIT elicited comparable protective effects, rescuing adipocyte hypertrophy, reducing fibrosis and inflammation, and lowering mtROS emission despite persistent ovarian E2 deficiency.
CONCLUSION:
Ovarian failure induces mitochondrial redox imbalance and inflammatory remodeling in AT that may contribute to metabolic impairments observed after menopause. E2 replacement reverses these defects, indicating sensitivity to ovarian E2 signaling. Importantly, HIIT elicits convergent AT adaptations, normalizing mtROS emission and inflammatory remodeling without ovarian E2 restoration. These findings identify exercise training as a potent non-pharmacological strategy to preserve AT health following menopause.