College of Life Science, Sichuan Agricultural University, Ya'an 625014, China.
Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611134, China.
Int J Mol Sci. 2023 Oct 5;24(19):14922. doi: 10.3390/ijms241914922.
Increased glucocorticoid (GC) levels act as a master contributor to central obesity in estrogen-depleted females; however, what factors cause their increased GC production is unclear. Given (1) liver fibroblast growth factor 21 (FGF21) and GCs regulate each other's production in a feed-forward loop, and (2) circulating FGF21 and GCs are parallelly increased in menopausal women and ovariectomized mice, we thus hypothesized that elevation of hepatic FGF21 secretion causes increased GGs production in estrogen-depleted females. Using the ovariectomized mice as a model for menopausal women, we found that ovariectomy (OVX) increased circulating corticosterone levels, which in turn increased visceral adipose expression, thus causing visceral obesity in females. In contrast, liver-specific FGF21 knockout (FGF21 LKO) completely reversed OVX-induced high GCs and high visceral adipose expression, thus abrogating OVX-induced obesity in females. Even though FGF21 LKO failed to rescue OVX-induced dyslipidemia, hepatic steatosis, and insulin resistance. What's worse, FGF21 LKO even further exacerbated whole-body glucose metabolic dysfunction as evidenced by more impaired glucose and pyruvate tolerance and worsened insulin resistance. Mechanically, we found that FGF21 LKO reduced circulating insulin levels, thus causing the dissociation between decreased central obesity and the improvement of obesity-related metabolic syndromes in OVX mice. Collectively, our results suggest that liver FGF21 plays an essential role in mediating OVX-induced central obesity by promoting GC production. However, lack of liver FGF21 signaling reduces insulin production and in turn causes the dissociation between decreased central obesity and the improvement of obesity-related metabolic syndromes, highlighting a detrimental role for hepatic FGF21 signals in mediating the development of central obesity but a beneficial role in preventing metabolic abnormality from further exacerbation in estrogen-depleted females.
糖皮质激素（GC）水平升高是导致雌激素耗竭女性中心性肥胖的主要因素；然而，导致其 GC 产生增加的因素尚不清楚。鉴于（1）肝成纤维细胞生长因子 21（FGF21）和 GCs 以正反馈环的方式相互调节各自的产生，以及（2）绝经女性和去卵巢小鼠中循环 FGF21 和 GCs 平行升高，我们因此假设肝 FGF21 分泌增加导致雌激素耗竭女性 GC 产生增加。我们使用去卵巢小鼠作为绝经女性的模型，发现去卵巢（OVX）增加了循环皮质酮水平，进而增加了内脏脂肪组织表达，从而导致女性内脏肥胖。相比之下，肝特异性 FGF21 敲除（FGF21 LKO）完全逆转了 OVX 诱导的高 GC 和高内脏脂肪组织表达，从而消除了 OVX 诱导的女性肥胖。尽管 FGF21 LKO 未能挽救 OVX 诱导的血脂异常、肝脂肪变性和胰岛素抵抗。更糟糕的是，FGF21 LKO 甚至进一步加重了全身葡萄糖代谢功能障碍，表现为葡萄糖和丙酮酸耐量受损更严重，胰岛素抵抗恶化。从机制上讲，我们发现 FGF21 LKO 降低了循环胰岛素水平，从而导致 OVX 小鼠中中心性肥胖减轻和肥胖相关代谢综合征改善的分离。总之，我们的结果表明，肝 FGF21 通过促进 GC 产生在介导 OVX 诱导的中心性肥胖中发挥重要作用。然而，缺乏肝 FGF21 信号会降低胰岛素的产生，从而导致中心性肥胖减轻和肥胖相关代谢综合征改善的分离，突出了肝 FGF21 信号在介导中心性肥胖发展中的有害作用，但在预防雌激素耗竭女性代谢异常进一步恶化方面具有有益作用。
