Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2008 Jul;8(1):77-83.
doi: 10.1016/j.cmet.2008.05.006.

Inhibition of growth hormone signaling by the fasting-induced hormone FGF21

Takeshi Inagaki  1 , Vicky Y Lin, Regina Goetz, Moosa Mohammadi, David J Mangelsdorf, Steven A Kliewer
Affiliations

Inhibition of growth hormone signaling by the fasting-induced hormone FGF21

Takeshi Inagaki et al. Cell Metab. 2008 Jul.

Abstract

Starvation blocks the actions of growth hormone (GH) and inhibits growth through mechanisms that are not well understood. In this report, we demonstrate that fibroblast growth factor 21 (FGF21), a hormone induced by fasting, causes GH resistance. In liver, FGF21 reduces concentrations of the active form of signal transducer and activator of transcription 5 (STAT5), a major mediator of GH actions, and causes corresponding decreases in the expression of its target genes, including insulin-like growth factor 1 (IGF-1). FGF21 also induces hepatic expression of IGF-1 binding protein 1 and suppressor of cytokine signaling 2, which blunt GH signaling. Chronic exposure to FGF21 markedly inhibits growth in mice. These data suggest a central role for FGF21 in inhibiting growth as part of its broader role in inducing the adaptive response to starvation.

PubMed Disclaimer

Figures

Figure 1
Figure 1
FGF21 inhibits growth. (A) Plasma FGF21 concentrations were measured in wild type (WT) and FGF21-transgenic (Tg) mice in either the fed state or after a 24 hour fast. n = 5 male mice/group. **, P<0.01 compared to WT, fed group. (B) Male and female WT and Tg mice are shown. (C) Body weights are shown for male (squares) and female (circles) WT (open symbols) and Tg mice (closed symbols). n = 5 mice/group. *, P<0.05; **, P<0.01; ***, P<0.001 compared to WT mice of same sex. (D) Tibia length was measured in male and female WT and Tg mice. n = 4 mice/group. **, P<0.01. In this and all other figures, error bars represent the mean ± SEM.
Figure 2
Figure 2
FGF21 inhibits IGF-1. (A) GH and IGF-1 concentrations in plasma from wild type (WT) and FGF21-transgenic (Tg) mice. n = 8 male mice/WT group, 11 male mice/Tg group. (B) mRNA levels of the indicated genes were measured by RT-qPCR in livers from WT and Tg mice. *, P<0.05; **, P<0.01; ***, P<0.001.
Figure 3
Figure 3
FGF21 reduces STAT5 phosphorylation. (A) Phosphorylated STAT5 (P-STAT5), total STAT5, STAT5A, STAT5B, phosphorylated JAK2 (P-JAK2), and total JAK2 protein levels were measured by immunoblotting in hepatic whole-cell extracts (WCE) or nuclear extracts (NE) from wild type (WT) or FGF21-transgenic (Tg) mice. β-Actin and Lamin B were used as loading controls. Immunoblotting was done with equal amounts of protein pooled from 4 male mice. Quantification by densitometry is indicted below each band. (B) SOCS2 mRNA and protein levels were measured by RT-qPCR and immunoblotting, respectively, in livers from WT and Tg mice. n = 7 male mice/group. **, P<0.01.
Figure 4
Figure 4
FGF21, PPARα activation, and fasting have similar effects on the IGF-1 pathway. Mice were administered vehicle (Veh) or Wy14643 (Wy) for 10 days (left panels); vehicle (Veh) or FGF21 for 1 or 3 days (middle panels); or were fed or fasted for 24 hours (right panels). Plasma IGF-1 concentrations, hepatic IGF-1, ALS, and IGFBP-1 mRNA levels, hepatic phosphorylated STAT5 (P-STAT5) and SOCS2 protein levels and plasma insulin levels were measured. n = 4-6 mice/group except for 1 day FGF21 treatment group, where n = 3. Male mice were used in the FGF21 and fasting experiments and female mice in the Wy14643 experiment. *, P<0.05; **, P<0.01; ***, P<0.001. For the middle panels, the presence of different lowercase letters indicates statistical significance (P<0.05) between groups.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic Fibroblast Growth Factor 21 Is Regulated by PPARalpha and Is a Key Mediator of Hepatic Lipid Metabolism in Ketotic States. Cell Metab. 2007;5:426–437. - PubMed
    1. Baxter RC, Martin JL. Binding proteins for the insulin-like growth factors: structure, regulation and function. Prog Growth Factor Res. 1989;1:49–68. - PubMed
    1. Beauloye V, Willems B, de Coninck V, Frank SJ, Edery M, Thissen JP. Impairment of liver GH receptor signaling by fasting. Endocrinology. 2002;143:792–800. - PubMed
    1. Bornfeldt KE, Arnqvist HJ, Enberg B, Mathews LS, Norstedt G. Regulation of insulin-like growth factor-I and growth hormone receptor gene expression by diabetes and nutritional state in rat tissues. J Endocrinol. 1989;122:651–656. - PubMed
    1. Clemmons DR. Role of insulin-like growth factor in maintaining normal glucose homeostasis. Horm Res. 2004;62 Suppl 1:77–82. - PubMed

Publication types

-