Estradiol signaling mediates gender difference in visceral adiposity via autophagy.
Zhipeng TaoLouise D ZhengCayleen SmithJing LuoAlex RobinsonFabio A AlmeidaZongwei WangAria F OlumiDongmin LiuZhiyong ChengPublished in: Cell death & disease (2018)
Excessive adiposity (particularly visceral fat mass) increases the risks of developing metabolic syndrome. Women have lower deposit of visceral fat than men, and this pattern becomes diminished postmenopausally, but the underlying mechanism remains largely unknown. Here, we show that the gender difference in visceral fat distribution is controlled by an estradiol-autophagy axis. In C57BL/6J and wild-type control mice, a higher visceral fat mass was detected in the males than in the females, which was associated with lower expression of estrogen receptor α (ERα) and more active autophagy in males vs. females. However, deletion of ERα normalized autophagy activity and abolished the gender difference in visceral adiposity. In line with the adiposity-reducing effect of the ERα-autophagy axis, we found that downregulation of ERα and increased autophagy activity were required for adipogenesis, while induction of estradiol signaling dampened autophagy and drastically prevented adipogenesis. Mechanistically, the estradiol-ERα signaling activated mTOR, which phosphorylated and inhibited ULK1, thereby suppressing autophagy and adipogenesis. Together, our study suggests that the lower visceral adiposity in the females (vs. the males) arises from a more active estradiol-ERα signaling, which tunes down autophagy and adipogenesis.
Keyphrases
- estrogen receptor
- insulin resistance
- cell death
- endoplasmic reticulum stress
- signaling pathway
- high fat diet induced
- adipose tissue
- metabolic syndrome
- oxidative stress
- polycystic ovary syndrome
- mental health
- weight gain
- skeletal muscle
- breast cancer cells
- type diabetes
- cardiovascular disease
- endoplasmic reticulum
- cell proliferation
- pregnant women
- climate change
- human health