Metabolic Messengers: FGF21 - PubMed (original) (raw)

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Metabolic Messengers: FGF21

Kyle H Flippo et al. Nat Metab. 2021 Mar.

Abstract

As a non-canonical fibroblast growth factor, fibroblast growth factor 21 (FGF21) functions as an endocrine hormone that signals to distinct targets throughout the body. Interest in therapeutic applications for FGF21 was initially sparked by its ability to correct metabolic dysfunction and decrease body weight associated with diabetes and obesity. More recently, new functions for FGF21 signalling have emerged, thus indicating that FGF21 is a dynamic molecule capable of regulating macronutrient preference and energy balance. Here, we highlight the major physiological and pharmacological effects of FGF21 related to nutrient and energy homeostasis and summarize current knowledge regarding FGF21’s pharmacodynamic properties. In addition, we provide new perspectives and highlight critical unanswered questions surrounding this unique metabolic messenger.

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Competing interests

The authors declare no competing interests.

Figures

Fig. 1

Fig. 1. Discovery of FGF21 as a metabolic messenger.

After the discovery of FGF21 in the year 2000, insight into FGF21’s function has advanced rapidly. FGF21 was first identified as a regulator of body weight and an insulin-independent modulator of glucose uptake (2005). Subsequent work revealed that FGF21 signals through a unique receptor complex (KLB–FGFR) (2007) and has potent insulin-sensitizing effects in obese rodents (2009). Physiological roles in which FGF21 regulates fasting (2007) and macronutrient intake (2013 and 2016) were later revealed, thus underscoring its function in energy and nutrient homeostasis. Important cellular targets, specifically the CNS (2014) and adipose tissues (2017), were then identified as direct targets mediating distinct aspects of FGF21’s metabolic effects. Clinical studies have revealed the therapeutic potential of FGF21 analogues in the treatment of diabetes and obesity (2013) and NASH (2019–2020). Most recently, direct central targets of FGF21’s actions have been shown to underlie its effects on neuronal function to suppress simple-sugar intake (2020).

Fig. 2

Fig. 2. Target tissues and metabolic activities of FGF21.

The metabolic effects of FGF21 in regulating body weight, hepatic triglycerides and macronutrient preference are conserved. However, species-specific differences in FGF21’s glucose-lowering effects have been observed. Most of FGF21’s metabolic effects are mediated through direct signalling to the brain and adipose tissues. Although FGF21 signalling to other tissues indirectly affects hepatic metabolism, whether FGF21 analogues signal directly to the liver is unclear. Evidence in rodents suggests FGF21’s abilities to regulate macronutrient preference, decrease body weight and hepatic triglycerides, and secondarily increase insulin sensitivity (associated with weight loss) are mediated through direct FGF21 signalling to the central nervous system. FGF21’s acute insulin-sensitizing effects are mediated through direct signalling to adipose tissues. ER, endoplasmic reticulum.

Fig. 3

Fig. 3. FGF21 modulates signals, thus regulating energy and nutrient homeostasis.

a, In rodents, pharmacological administration of recombinant human FGF21 (rhFGF21) signals to unknown regions in the brain and invokes the primary (1°) energy-expending effects of FGF21 in decreasing body weight and liver triglycerides. However, in rodents lacking thermogenic adipose tissues, or in primates and humans, which have lower thermogenic adipose capacity than rodents, secondary (2°) and tertiary (3°) mechanisms increase physical activity and decrease caloric intake, thereby decreasing body weight. Direct actions of FGF21 on the liver in humans are unclear. b, FGF21’s ability to regulate glucose homeostasis is bimodal. FGF21 production from the liver is increased in a ChREBP- and PPARα-dependent transcriptional response to excess hepatic carbohydrate levels. Once secreted, FGF21 signals to the CNS and consequently enhances the excitability of glucose-excited (GE) neurons in the VMH in response to glucose. This increase in glucose sensitivity signals the suppression of simple-sugar intake. To complement FGF21’s effects on simple-sugar consumption, FGF21 also promotes carbohydrate disposal by enhancing insulin sensitivity in adipose tissues. c, FGF21 is produced by the liver in response to amino acid restriction through transcriptional regulation mediated by ATF4 and PPARα. Liver-derived FGF21 then enters the circulation and signals the brain to modulate macronutrient preference and energy expenditure. FGF21 signalling to the brain suppresses sugar intake, which secondarily promotes the intake of other macronutrients (such as protein). The brain regions mediating FGF21’s effects on thermogenesis and physical activity during amino acid dilution remain to be identified. BAT, brown adipose tissue; WAT, white adipose tissue; VLDL, very low-density lipoprotein.

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