Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Endocrinology. 2022 May 1;163(5). doi: 10.1210/endocr/bqac035.
The hepatic transcription factor forkhead box O1 (FOXO1) is a critical regulator of hepatic and systemic insulin sensitivity. Previous work by our group and others demonstrated that genetic inhibition of FOXO1 improves insulin sensitivity both in genetic and dietary mouse models of metabolic disease. Mechanistically, this is due in part to cell nonautonomous control of adipose tissue insulin sensitivity. However, the mechanisms mediating this liver-adipose tissue crosstalk remain ill defined. One candidate hepatokine controlled by hepatic FOXO1 is fibroblast growth factor 21 (FGF21). Preclinical and clinical studies have explored the potential of pharmacological FGF21 as an antiobesity and antidiabetic therapy. In this manuscript, we performed acute loss-of-function experiments to determine the role of hepatocyte-derived FGF21 in glucose homeostasis and insulin tolerance both in control and mice lacking hepatic insulin signaling. Surprisingly, acute deletion of FGF21 did not alter glucose tolerance, insulin tolerance, or adipocyte lipolysis in either liver-specific FGF21KO mice or mice lacking hepatic AKT-FOXO1-FGF21, suggesting a permissive role for endogenous FGF21 in the regulation of systemic glucose homeostasis and insulin tolerance in mice. In addition, these data indicate that liver FOXO1 controls glucose homeostasis independently of liver-derived FGF21.
肝脏转录因子叉头框 O1（FOXO1）是肝脏和全身胰岛素敏感性的关键调节因子。我们小组和其他小组的先前工作表明，FOXO1 的基因抑制可改善代谢疾病的遗传和饮食性小鼠模型中的胰岛素敏感性。从机制上讲，这部分归因于脂肪组织胰岛素敏感性的细胞非自主性控制。但是，介导这种肝脏-脂肪组织串扰的机制仍未明确。受肝脏 FOXO1 控制的候选肝分泌因子是成纤维细胞生长因子 21（FGF21）。临床前和临床研究已经探索了药理 FGF21 作为抗肥胖和抗糖尿病疗法的潜力。在本文中，我们进行了急性功能丧失实验，以确定肝源性 FGF21 在控制和缺乏肝胰岛素信号的小鼠中对葡萄糖稳态和胰岛素耐量的作用。令人惊讶的是，急性缺失 FGF21 并未改变肝特异性 FGF21KO 小鼠或缺乏肝 AKT-FOXO1-FGF21 的小鼠的葡萄糖耐量、胰岛素耐量或脂肪细胞脂肪分解，表明内源性 FGF21 在调节小鼠全身葡萄糖稳态和胰岛素耐量中起许可作用。此外，这些数据表明，肝脏 FOXO1 可独立于肝源性 FGF21 控制葡萄糖稳态。
