FGF21 as an Endocrine Regulator in Lipid Metabolism: From Molecular Evolution to Physiology and Pathophysiology

Abstract

The FGF family comprises twenty-two structurally related proteins with functions in development and metabolism. The Fgf21 gene was generated early in vertebrate evolution. FGF21 acts as an endocrine regulator in lipid metabolism. Hepatic Fgf21 expression is markedly induced in mice by fasting or a ketogenic diet. Experiments with Fgf21 transgenic mice and cultured cells indicate that FGF21 exerts pharmacological effects on glucose and lipid metabolism in hepatocytes and adipocytes via cell surface FGF receptors. However, experiments with Fgf21 knockout mice indicate that FGF21 inhibits lipolysis in adipocytes during fasting and attenuates torpor induced by a ketogenic diet but maybe not a physiological regulator for these hepatic functions. These findings suggest the pharmacological effects to be distinct from the physiological roles. Serum FGF21 levels are increased in patients with metabolic diseases having insulin resistance, indicating that FGF21 is a metabolic regulator and a biomarker for these diseases.

Figure 1

The evolutionary lineage of deuterostome organisms and the evolutionary history of endocrine Fgf genes. (a) The Fgf gene family expanded in two major phases (I and II) during deuterostome evolution. Phase I occurred after the separation of protostomes and deuterostomes. Phase II occurred early in the emergence of vertebrates. (b) Fgf13-like is the ancestral gene of the Fgf gene family. Fgf4-like was generated from Fgf13-like by gene duplication during invertebrate evolution. Fgf15/19-like was also generated from Fgf4-like by local gene duplication early in the emergence of vertebrates. Later, Fgf19, Fgf21, and Fgf23 were generated via two genome duplication events in phase II.

Figure 2

Mechanism of action and regulatory mechanism of the gene expression of FGF21. (a) Hepatic Fgf21 expression is induced by the activation of PPARα. NEFA binds to and activates PPARα. The ligand-bound PPARα forms a heterodimer with RXRs and induces the expression of Fgf21. The FGF21 inhibits lipolysis in adipocytes. In cultured adipocytes, FGF21 signaling is transduced by activating the βKlotho-FGFR1c complex. However, FGF21 signaling can be transduced in βKlotho knockout mice, indicating the existence of a βKlotho-independent FGF21 signaling pathway. The regulatory process forms a negative feedback loop in the control of lipolysis by FGF21. (b) Feeding with a ketogenic diet (KD) mimics the metabolic conditions of chronic starvation. KD induces hepatic Fgf21 expression and torpor. FGF21 attenuates torpor induced by KD.