Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, Tübingen, Germany.
German Center for Diabetes Research (DZD), Neuherberg, Germany.
Exp Clin Endocrinol Diabetes. 2020 Nov;128(11):752-770. doi: 10.1055/a-0879-2968. Epub 2019 May 20.
Human fibroblast growth factor 21 (FGF21) is primarily produced and secreted by the liver as a hepatokine. This hormone circulates to its target tissues (e. g., brain, adipose tissue), which requires two components, one of the preferred FGF receptor isoforms (FGFR1c and FGFR3c) and the co-factor beta-Klotho (KLB) to trigger downstream signaling pathways. Although targeting FGF21 signaling in humans by analogues and receptor agonists results in beneficial effects, e. g., improvements in plasma lipids and decreased body weight, it failed to recapitulate the improvements in glucose handling shown for many mouse models. FGF21's role and metabolic effects in mice and its therapeutic potential have extensively been reviewed elsewhere. In this review we focus on circulating FGF21 levels in humans and their associations with disease and clinical parameters, focusing primarily on obesity and obesity-associated diseases such as type-2 diabetes. We provide a comprehensive overview on human circulating FGF21 levels under normal physiology and metabolic disease. We discuss the emerging field of inactivating FGF21 in human blood by fibroblast activation protein (FAP) and its potential clinical implications.
人成纤维细胞生长因子 21（FGF21）主要由肝脏作为肝源细胞因子产生和分泌。这种激素循环到其靶组织（例如脑、脂肪组织），需要两种成分，首选的成纤维细胞生长因子受体同工型（FGFR1c 和 FGFR3c）之一和辅助因子β-Klotho（KLB）来触发下游信号通路。尽管通过类似物和受体激动剂靶向人类的 FGF21 信号会产生有益的效果，例如改善血浆脂质和降低体重，但它未能重现许多小鼠模型中显示的葡萄糖处理改善。FGF21 在小鼠中的作用及其代谢效应及其治疗潜力已在其他地方广泛综述。在这篇综述中，我们重点关注人类循环 FGF21 水平及其与疾病和临床参数的关联，主要关注肥胖症和肥胖症相关疾病，如 2 型糖尿病。我们提供了正常生理学和代谢疾病下人类循环 FGF21 水平的综合概述。我们讨论了在人类血液中通过成纤维细胞激活蛋白（FAP）失活 FGF21 的新兴领域及其潜在的临床意义。
