Hormone-like (endocrine) Fgfs: their evolutionary history and roles in development, metabolism, and disease

Aug 24, 2010Cell and tissue research

Hormone-like Fgfs: their evolution and roles in growth, metabolism, and disease

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Abstract

The human Fgf gene family consists of 22 members classified into three groups: canonical, intracellular, and hormone-like Fgf genes.

Hormone-like Fgfs, including Fgf15/19, Fgf21, and Fgf23, are specific to vertebrates and evolved from a gene duplication of canonical Fgfs.
Canonical Fgfs function as local signaling factors, while hormone-like Fgfs operate as endocrine factors affecting distant tissues.
Fgf15/19 and Fgf23 require specific cofactors (βKlotho and αKlotho, respectively) for their functions, while Fgf21 does not appear to need them.
Hormone-like Fgfs are involved in metabolic regulation during postnatal stages and also contribute to developmental processes during embryonic stages.
Fgf15/19 influences bile acid metabolism, Fgf21 regulates lipid metabolism in white adipose tissue, and Fgf23 manages serum phosphate and active vitamin D levels.
Metabolic disorders can lead to increased serum levels of Fgf19 or Fgf21, highlighting their association with metabolic health.

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Fibroblast growth factors (Fgfs) are proteins with diverse functions in development, repair, and metabolism. The human Fgf gene family with 22 members can be classified into three groups, canonical, intracellular, and hormone-like Fgf genes. In contrast to canonical and intracellular Fgfs identified in invertebrates and vertebrates, hormone-like Fgfs, Fgf15/19, Fgf21, and Fgf23, are vertebrate-specific. The ancestral gene of hormone-like Fgfs was generated from the ancestral gene of canonical Fgfs by gene duplication early in vertebrate evolution. Later, Fgf15/19, Fgf21, and Fgf23 were generated from the ancestral gene by genome duplication events. Canonical Fgfs act as autocrine/paracrine factors in an Fgf receptor (Fgfr)-dependent manner. In contrast, hormone-like Fgfs act as endocrine factors in an Fgfr-dependent manner. Canonical Fgfs have a heparin-binding site necessary for the stable binding of Fgfrs and local signaling. In contrast, hormone-like Fgfs acquired endocrine functions by reducing their heparin-binding affinity during their evolution. Fgf15/19 and Fgf23 require βKlotho and αKlotho as cofactors, respectively. However, Fgf21 might physiologically require neither. Hormone-like Fgfs play roles in metabolism at postnatal stages, although they also play roles in development at embryonic stages. Fgf15/19 regulates bile acid metabolism in the liver. Fgf21 regulates lipid metabolism in the white adipose tissue. Fgf23 regulates serum phosphate and active vitamin D levels. Fgf23 signaling disorders caused by hereditary diseases or tumors result in metabolic disorders. In addition, serum Fgf19 or Fgf21 levels are significantly increased by metabolic disorders. Hormone-like Fgfs are newly emerging and quite unique in their evolution and function.

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Hormone-like (endocrine) Fgfs: their evolutionary history and roles in development, metabolism, and disease

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