Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis

Abstract

Fibroblast growth factor 21 (FGF21) is an endocrine hormone derived from the liver that exerts pleiotropic effects on the body to maintain overall metabolic homeostasis. During the past decade, there has been an enormous effort made to understand the physiological roles of FGF21 in regulating metabolism and to identify the mechanism for its potent pharmacological effects to reverse diabetes and obesity. Through both human and rodent studies, it is now evident that FGF21 levels are dynamically regulated by nutrient sensing, and consequently FGF21 functions as a critical regulator of nutrient homeostasis. In addition, recent studies using new genetic and molecular tools have provided critical insight into the actions of this endocrine factor. This review examines the numerous functions of FGF21 and highlights the therapeutic potential of FGF21-targeted pathways for treating metabolic disease.

Keywords: FGF21; adipose; alcohol; macronutrient; thermogenesis; β-klotho.

Figure 1

The role of fibroblast growth factor 21 (FGF21) during fasting and refeeding. During fasting, FGF21 expression is induced by peroxisome proliferator–activated receptor-α (PPARα) in the liver. Circulating FGF21 then activates the hypothalamic–pituitary–adrenal (HPA) axis to increase glucocorticoid release and increase gluconeogenesis. When nutrients become available during refeeding, insulin is released from the pancreas, and while both FGF21 and insulin are in circulation, FGF21 functions to enhance insulin-stimulated glucose uptake in peripheral tissues.

Figure 2

Nutritional regulation of FGF21 production. The production of circulating levels of FGF21 is regulated by PPARα and ChREBP in response to high carbohydrate levels and by ATF4 and PPARαin response to amino acid starvation in the liver. NUPR1 is also critical for protein dilution–mediated increases in hepatic FGF21. In response to these nutritional cues, circulating FGF21 decreases carbohydrate intake through actions on the central nervous system. In addition, FGF21 enhances carbohydrate disposal by direct action on brown adipose tissue, and increases energy expenditure through central nervous system–mediated regulation of adipose tissue function. Abbreviations: ATF4, activating transcription factor 4; ChREBP, carbohydrate-response element-binding protein; FGF21, fibroblast growth factor 21; NUPR1, nuclear protein 1; PPARα, peroxisome proliferator–activated receptor-α; SNA, sympathetic nerve activity.

Figure 3

Fibroblast growth factor 21 (FGF21) coordinates adipose tissue thermogenesis during acute cold. Two models are shown for the physiological regulation of energy homeostasis by FGF21 during acute cold exposure. (a) Exposure to cold stimulates sympathetic nerve activity (SNA) to adipose tissues. Increased SNA to brown adipose tissue increases thermogenesis and the production of FGF21, which enhances thermogenesis. Increased SNA to white adipose tissue stimulates FGF21 to act in an autocrine fashion on adipose tissue to induce the production of the cytokine CCL11. CCL11 recruits eosinophils and macrophages to promote the beiging of subcutaneous white adipose tissue and increase adipose tissue thermogenesis. (b) During acute cold exposure, FGF21 production from the liver is increased through an unknown mechanism, but it may involve central nervous system (CNS)–mediated sympathetic output to the liver (❶). Elevated circulating levels of FGF21 (❷) then act centrally to increase sympathetic nerve output to drive brown adipose tissue thermogenesis (❸).

Figure 4

Dissociation of the pharmacological actions of fibroblast growth factor 21 (FGF21). FGF21 has acute and chronic effects on metabolism. Primary, or direct targets, and secondary sites of FGF21 action are indicated. The acute insulin-sensitizing effects are mediated through direct signaling to adipose tissue in the presence of insulin signaling, but do not require adiponectin (red X). FGF21 signaling to brown adipose tissue is primarily responsible for the acute glucose-lowering effect of FGF21. The chronic effects of FGF21 are mediated through direct signaling in the central nervous system (CNS). The activation of specific FGFR1 and β-klotho neurons by FGF21 leads to increased energy expenditure through increased sympathetic nerve activity (SNA) to brown adipose tissue and the beiging of white adipose tissue. These effects result in decreased body weight and a secondary improvement in insulin sensitivity. figure adapted from Reference 11.