Identification of hepatic fibroblast growth factor 21 as a mediator in 17β‐estradiol‐induced white adipose tissue browning

Abstract

Both ovarian E2 and hepatic fibroblast growth factor 21 (FGF21) are critical for energy homeostasis and white adipose tissue browning. Estrogen receptor α (ERα) is abundantly expressed in liver. However, whether FGF21 has a role in E2-induced white adipose tissue browning remains uncertain. In this study, we showed that hepatic Fgf21 expression and secretion during estrus cycle changed with the tetradian oscillatory secretion of circulation E2 in adult, female mice, with their peak expressions and secretions at the proestrus. In addition, exogenous E2 robustly stimulated liver Fgf21 expression and elevated serum FGF21 concentrations, which induced browning gene expression and reduced the tissue weight in subcutaneous white adipose in mice with ovariectomies. The inhibitor of mammalian target of rapamycin (mTOR) and of ERα blocked the induction effect of E2 on the expression of Fgf21 in primary hepatocytes, which revealed that E2 might stimulate FGF21 expression via the ERα-mTOR pathway. Furthermore, FGF21 liver-specific deficiency abolished E2-induced white adipose browning in mice with ovariectomies. This study indicates that ovarian E2 increased liver FGF21 expression directly, which in turn, functioned as an endocrine signal to influence inguinal white adipose tissue browning.-Hua, L., Zhuo, Y., Jiang, D., Li, J., Huang, X., Zhu, Y., Li, Z., Yan, L., Jin, C., Jiang, X., Che, L., Fang, Z., Lin, Y., Xu, S., Li, J., Feng, B., Wu, D. Identification of hepatic fibroblast growth factor 21 as a mediator in 17β-estradiol-induced white adipose tissue browning.

Time‐restricted feeding improves the reproductive function of female mice via liver fibroblast growth factor 21

“…The FGF21 liverspecific knockout (FGF21LKO) mice have been previously characterized. 29,35 Briefly, FGF21 loxp/loxp mice from Jackson Laboratory (022361; Bar Harbor, ME, USA) were mated with Alb-Cre mice from Nanjing University (J003574; Model Animal Research Center, Nanjing, China) to generate FGF21 loxp+/-, Alb-Cre mice. And then FGF21 loxp+/-, Alb-Cre mice were mated with FGF21 loxp/loxp mice to generate FGF21 loxp/loxp, Alb-Cre .…”

“…Identification of the estrus cycle stage was performed as previously described. 29 After 8 week TRF treatment, a continuous 17-week mating protocol was used to measure the number of litters per female and litter size as previously described. 36 Confirmed fertile males and female mice were housed together (1:1) at 21:00 and were left with the females until 07:00 with randomly rotated.…”

“…RNA extraction and RT-PCR were performed as previously reported. 29,35 Briefly, RNA from ovarian was extracted by Trizol (15596018; Thermo Fisher Scientific) and purified using RNA mini-columns (RR037A; Takara Bio). RT-PCR was conducted in 10 μl of reaction volume with SYBR Green (RR820A; Takara Bio).…”

“…28 FGF21 can induce thermogenesis and energy expenditure by promoting white adipose tissue browning and the activation of brown adipose tissue. [24][25][26]29,30 Both FGFR1c and β-klotho are expressed in hypothalamic neurons 31,32 and FGF21 has shown a non-saturable, unidirectional influx across the blood-brain barrier. [31][32][33] Injection of FGF21 to rats by intracerebroventricular increased energy expenditure and insulin sensitivity.…”

Beneficial Effects of Decreased Meal Frequency on Nutrient Utilization, Secretion of Luteinizing Hormone and Ovarian Follicular Development in Gilts

“…RNA extraction and real-time PCR were performed as previously reported [16]. Brie y, RNA from ovarian was extracted by Trizol (15596018; Thermo Fisher Scienti c) and puri ed using RNA mini-columns (RR037A; Takara Bio, Kusatsu, Japan).…”