Estrogen supplementation deteriorates visceral adipose function in aged postmenopausal subjects via Gas5 targeting IGF2BP1

Increased visceral fat is strongly associated with a series of metabolic complications. Postmenopausal women have an increased risk of visceral fat accumulation, metabolic disorders, and a high incidence of cardiovascular events. However, the effect of estrogen replacement therapy on visceral adipose tissue among postmenopausal women of different ages remains controversial, and the underlying mechanism remains unclear. Hence, it is important to understand when estrogen replacement therapy affects the function of visceral adipose tissue (VAT). Therefore, we collected VAT from pre- and post-menopausal females and we observed increased proinflammatory cytokines and insulin resistance-inducing factors, decreased insulin-sensitizing factors, and thermogenic factors in VAT of postmenopausal women. The analysis of adipocytes isolated from the VAT of females of different ages indicated that adiponectin and browning signature genes were significantly decreased with estrogen treatment in postmenopausal women, but were not altered in the young group. Estrogen supplementation in aged female mice (22 m) significantly prevented visceral fat accumulation. However, it deteriorated VAT function by inducing pro-inflammatory cytokines and insulin resistance-inducing factors and decreasing insulin-sensitizing and thermogenic factors. Mechanistically, estrogen induced the expression of long non-coding RNA Gas5 via binding ERa in premenopausal women, which therefore suppressed IGF2BP1 to maintain VAT function. After menopause, with the reversal of ERa/ERp ratio in VAT, estrogen supplementation mainly worked through ERp, which led to low expression levels of Gas5 and eventually caused VAT dysfunction. Our study demonstrated the adverse effects of estrogen supplementation on VAT function in aged postmenopausal population and further elucidated the involved mechanism.

Automated summary

Increased visceral fat in postmenopausal women is associated with metabolic complications and cardiovascular events. The effect of estrogen replacement therapy on visceral adipose tissue and its underlying mechanism are still controversial. This study investigated the function of visceral adipose tissue and found that estrogen supplementation in postmenopausal women led to adverse effects on visceral fat function, potentially through the ERp pathway.