Editors' ChoiceCell growth

Starved into Action

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Science Signaling  08 Jul 2008:
Vol. 1, Issue 27, pp. ec246
DOI: 10.1126/scisignal.127ec246

Stimulation of cell growth by growth hormone (GH) involves the phosphorylation and activation of the signal transducer and activator of transcription (STAT) proteins STAT5A and STAT5B. These proteins translocate to the nucleus and activate the transcription of target genes, including that encoding insulin-like growth factor 1 (IGF-1), the main mediator of the effects of GH. Under fasting conditions, GH signaling is inhibited by an unknown mechanism. Production of the hormone fibroblast growth factor 21 (FGF21) is stimulated during fasting, which led Inagaki et al. to investigate its role in inhibiting GH signaling. The authors generated FGF21-transgenic mice, which had constitutively higher serum concentrations of FGF21 than did wild-type mice. The FGF21-transgenic mice were smaller and lighter than wild-type mice even though they did not eat any less. The serum concentration of IGF-1 and the abundance of IGF-1 mRNA in the liver were lower in FGF21-transgenic mice than in wild-type mice. This was also true for acid-labile subunit (ALS), which binds to and stabilizes IGF-1 in the circulation. In contrast, the abundance of mRNA of IGF-1 binding protein (IGFBP-1), an inhibitor of IGF-1 signaling, was higher in the liver of FGF21-transgenic mice compared to that in wild-type mice. The abundance of phosphorylated, but not total, STAT5A and STAT5B was lower in FGF21-transgenic mice than in wild-type mice. In addition, the mRNA of suppressor of cytokine signaling 2 (SOCS2), an inhibitor of GH receptor signaling, was more abundant in the FGF21-transgenic animals. Finally, administration of recombinant FGF21 to wild-type mice reduced the abundance of phosphorylated STAT5 in the liver and the serum concentration of IGF-1, suggesting an important role for FGF21 in inhibiting GH signaling during fasting.

T. Inagaki, V. Y. Lin, R. Goetz, M. Mohammadi, D. J. Mangelsdorf, S. A. Kliewer, Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metab. 8, 77-83 (2008). [PubMed]