Fibroblast growth factor 21 night watch: advances and uncertainties in the field

Abstract

Abstract. Kharitonenkov A, DiMarchi R (Indiana University Bloomington, Bloomington, IN, USA). Fibroblast growth factor 21 night watch: advances and uncertainties in the field (Review). J Intern Med 2017; 281: 233-246.Fibroblast growth factor (FGF) 21 belongs to a hormone-like subgroup within the FGF superfamily. The members of this subfamily, FGF19, FGF21 and FGF23, are characterized by their reduced binding affinity for heparin that enables them to be transported in the circulation and function in an endocrine manner. It is likely that FGF21 also acts in an autocrine and paracrine fashion, as multiple organs can produce this protein and its plasma concentration seems to be below the level necessary to induce a pharmacological effect. FGF21 signals via FGF receptors, but for efficient receptor engagement it requires a cofactor, membrane-spanning bKlotho (KLB). The regulation of glucose uptake in adipocytes was the initial biological activity ascribed to FGF21, but this hormone is now recognized to stimulate many other pathways in vitro and display multiple pharmacological effects in metabolically compromised animals and humans. Understanding of the precise physiology of FGF21 and its potential medicinal role has evolved exponentially over the last decade, yet numerous aspects remain to be defined and others are a source of debate. Here we provide a historical overview of the advances in FGF21 biology focusing on the uncertainties in the mechanism of action as well as the differing viewpoints relating to this intriguing protein.

FGF19, FGF21, and an FGFR1/β-Klotho-Activating Antibody Act on the Nervous System to Regulate Body Weight and Glycemia

“…Fibroblast growth factors (FGFs) 19 and 21 are members of an atypical subfamily of FGFs that can circulate as hormones (Fisher and Maratos-Flier, 2016; Kharitonenkov and DiMarchi, 2017; Owen et al, 2015). FGF19 is induced by postprandial bile acids in small intestine and represses bile acid synthesis and induces glycogen and protein synthesis in the liver.…”

Dietary carbohydrates impair the protective effect of protein restriction against diabetes in NZO mice used as a model of type 2 diabetes

“…FGF21 targets organs through a cell-surface receptor complex composed of the traditional FGF receptor, FGFR1c, and the necessary FGF co-receptor β-Klotho [8]. Administration of FGF21 to mice induces activation of brown adipose tissue (BAT), and increases energy expenditure and insulin sensitivity [9][10][11]. The nervous system is the direct target of FGF21, whereas β-Klotho in adipose tissue and liver is dispensable for FGF21 effects on weight loss [12].…”

A common allele in FGF21 associated with preference for sugar consumption lowers body fat in the lower body and increases blood pressure

“…We used a well-validated and freely available R package called GGIR (v1. [5][6][7][8][9][10][11][12] to process these files, made available to researchers, in order to extract measures of physical activity and sleep. For this study, we used three derived measures of activity and one measure of sleep timing (L5 time).…”

“…Pre-clinical evidence of FGF21's potential role in metabolism includes resistance to diet induced obesity in mice overexpressing FGF21 [3] and improved glucose tolerance in obese mice through administration of recombinant FGF21 [3]. Subsequent studies have confirmed these findings in mice [10] and shown similar effects in non human primates, including improvement of glucose tolerance and slight weight loss in diabetic rhesus monkeys [11], but other studies are less conclusive [5].…”

“…These features and several other lines of evidence have prompted the development of FGF21 based therapies as potential treatments for obesity and type 2 diabetes, with consistent effects on triglyceride lowering, some effects on weight loss but little effect on glucose tolerance [5,6]. An early trial showed lipid lowering effects in people with type 2 diabetes and obesity but there was only suggestive evidence for effects on weight and glucose tolerance [7].…”