The FGF metabolic axis

Abstract

Members of the fibroblast growth factor (FGF) family play pleiotropic roles in cellular and metabolic homeostasis. During evolution, the ancestor FGF expands into multiple members by acquiring divergent structural elements that enable functional divergence and specification. Heparan sulfate-binding FGFs, which play critical roles in embryonic development and adult tissue remodeling homeostasis, adapt to an autocrine/paracrine mode of action to promote cell proliferation and population growth. By contrast, FGF19, 21, and 23 coevolve through losing binding affinity for extracellular matrix heparan sulfate while acquiring affinity for transmembrane α-Klotho (KL) or β-KL as a coreceptor, thereby adapting to an endocrine mode of action to drive interorgan crosstalk that regulates a broad spectrum of metabolic homeostasis. FGF19 metabolic axis from the ileum to liver negatively controls diurnal bile acid biosynthesis. FGF21 metabolic axes play multifaceted roles in controlling the homeostasis of lipid, glucose, and energy metabolism. FGF23 axes from the bone to kidney and parathyroid regulate metabolic homeostasis of phosphate, calcium, vitamin D, and parathyroid hormone that are important for bone health and systemic mineral balance. The significant divergence in structural elements and multiple functional specifications of FGF19, 21, and 23 in cellular and organismal metabolism instead of cell proliferation and growth sufficiently necessitate a new unified and specific term for these three endocrine FGFs. Thus, the term “FGF Metabolic Axis,” which distinguishes the unique pathways and functions of endocrine FGFs from other autocrine/paracrine mitogenic FGFs, is coined.

Keywords

FGF19 / FGF21 / FGF23 / FGFR / metabolism / endocrine / Klotho

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Acknowledgements

I would like to acknowledge the long-term contributions of many members of my Wenzhou FGF team to the FGF field research as I cited in the text that made the idea of “The FGF Metabolic Axis” possible. I thank Dr. Yongde Luo for the expert assistance on the conceptual and practical aspects of the manuscript and Dr. Jin-San Zhang and Dr. Jian Xiao for their assistance. I apologize to those whose works have not been cited here due to the limited discussion scope on this evolving field. This work is supported by the National Key R&D Program of China (No. 2017YFA0506000, Xiaokun Li).

Compliance with ethics guidelines

Xiaokun Li declares no conflict of interests. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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