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Loss of fibroblast growth factor 21 action induces insulin resistance, pancreatic islet hyperplasia and dysfunction in mice.

So WY, Cheng Q, Xu A, Lam KS, Leung PS - Cell Death Dis (2015)

Bottom Line: Twenty-four-week-old male global FGF21-KO mice were used in this study.Expression of genes and proteins related to islet function and underlying mechanisms were also examined.This phenotype probably results from enhanced growth hormone (GH) sensitivity in FGF21-KO mouse islets.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.

ABSTRACT
Fibroblast growth factor (FGF) 21 is an endocrine factor that normalizes glucose homeostasis and reduces insulin resistance in diabetes. Although the pancreas is an FGF21 target organ, its role in pancreatic islets remains obscure. This study aimed to elucidate the physiological role of FGF21 in pancreatic islets using FGF21-knockout (FGF21-KO) mice. Twenty-four-week-old male global FGF21-KO mice were used in this study. Glucose and insulin tolerance were assessed. Expression of genes and proteins related to islet function and underlying mechanisms were also examined. Islet morphology and insulin-secreting capacity were further evaluated. FGF21-KO mice exhibited insulin resistance while being normoglycemic, associated with increases in beta-cell proliferation and insulin synthesis, acting as compensatory responses. This phenotype probably results from enhanced growth hormone (GH) sensitivity in FGF21-KO mouse islets. In addition, ex vivo FGF21 treatment in normal C57BL/6J mouse islets reduced GH signaling, probably via upregulation of peroxisome proliferator-activated receptor gamma (PPARγ) and cytokine-inducible SH-2 containing (CIS) protein, whereas KO mouse islets displayed reduced PPARγ and CIS expression. FGF21 treatment also reversed GH-induced insulin expression, beta-cell proliferation and GH-impaired glucose-stimulated insulin secretion (GSIS) in islets. Furthermore, distorted islet morphology and impaired GSIS were observed in KO mice, suggestive of islet dysfunction, whereas the enhanced insulin expression and impaired GSIS in FGF21-KO mouse islets could be reversed by blockade of GH signaling. Our data indicate that FGF21 is important in the regulation of beta-cell proliferation and insulin synthesis, probably via modulation of GH signaling. These findings provide evidence that FGF21 is an obligatory metabolic regulator in pancreatic islets and shed new light onto the role of endogenous FGF21 in the pathogenesis of insulin resistance and islet dysfunction.

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FGF21 inhibits GH signaling in islets. (a) Phosphorylated and total JAK2, and (b) phosphorylated and total STAT5 in FGF21-KO and WT mouse islets treated with GH for 15 min. *P<0.05, **P<0.01, ***P<0.001 versus 0 ng/ml (n=3–4). (c) Phosphorylated and total JAK2, and (d) phosphorylated and total STAT5 in normal mouse islets pre-treated with FGF21 (0–2 μg/ml) for 72 h, followed by GH (100 ng/ml) treatment for 15 min. *P<0.05, **P<0.01, ***P<0.001 versus Vehicle; †P<0.05, ††P<0.01, †††P<0.001 versus GH (n=3). Data are mean±SE
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fig4: FGF21 inhibits GH signaling in islets. (a) Phosphorylated and total JAK2, and (b) phosphorylated and total STAT5 in FGF21-KO and WT mouse islets treated with GH for 15 min. *P<0.05, **P<0.01, ***P<0.001 versus 0 ng/ml (n=3–4). (c) Phosphorylated and total JAK2, and (d) phosphorylated and total STAT5 in normal mouse islets pre-treated with FGF21 (0–2 μg/ml) for 72 h, followed by GH (100 ng/ml) treatment for 15 min. *P<0.05, **P<0.01, ***P<0.001 versus Vehicle; †P<0.05, ††P<0.01, †††P<0.001 versus GH (n=3). Data are mean±SE

Mentions: To study the cross-talk between FGF21 and GH, serum GH levels in WT and FGF21-KO mice were measured in fed and overnight-fasted states. FGF21 deficiency had no effect on the production of GH in either fasting or fed state (Supplementary Figure S4A). GH action in islets was examined by determining GHR expression in both FGF21-KO and WT mouse islets. In 24-week-old mice, GHR mRNA was higher in FGF21-KO than WT mouse islets (Supplementary Figure S4B). However, significant change in GHR protein levels was not detected (Supplementary Figure S4C) while exogenous FGF21 treatment in normal mouse islets did not affect GHR expression (Supplementary Figures S4D and E). Isolated islet responses to GH were then studied by measuring JAK2 and STAT5 phosphorylation. After treatment with recombinant GH (0, 25, 50, or 100 ng/ml) for 15 min, FGF21-KO mouse islets showed enhanced phosphorylation of JAK2 and STAT5 compared with that in WT mouse islets (Figures 4a and b). To investigate the direct effects of FGF21 on GH action in islets, islets isolated from normal mice were pre-treated with recombinant FGF21 (0, 0.5, 1, or 2 μg/ml) before GH-induced signaling was examined. After 72 h treatment, both JAK2 and STAT5 phosphorylation induced by GH (100 ng/ml) was reduced in a dose-dependent manner, in which the greatest effect was found at 2 μg/ml of FGF21 (Figures 4c and d).


Loss of fibroblast growth factor 21 action induces insulin resistance, pancreatic islet hyperplasia and dysfunction in mice.

So WY, Cheng Q, Xu A, Lam KS, Leung PS - Cell Death Dis (2015)

FGF21 inhibits GH signaling in islets. (a) Phosphorylated and total JAK2, and (b) phosphorylated and total STAT5 in FGF21-KO and WT mouse islets treated with GH for 15 min. *P<0.05, **P<0.01, ***P<0.001 versus 0 ng/ml (n=3–4). (c) Phosphorylated and total JAK2, and (d) phosphorylated and total STAT5 in normal mouse islets pre-treated with FGF21 (0–2 μg/ml) for 72 h, followed by GH (100 ng/ml) treatment for 15 min. *P<0.05, **P<0.01, ***P<0.001 versus Vehicle; †P<0.05, ††P<0.01, †††P<0.001 versus GH (n=3). Data are mean±SE
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385948&req=5

fig4: FGF21 inhibits GH signaling in islets. (a) Phosphorylated and total JAK2, and (b) phosphorylated and total STAT5 in FGF21-KO and WT mouse islets treated with GH for 15 min. *P<0.05, **P<0.01, ***P<0.001 versus 0 ng/ml (n=3–4). (c) Phosphorylated and total JAK2, and (d) phosphorylated and total STAT5 in normal mouse islets pre-treated with FGF21 (0–2 μg/ml) for 72 h, followed by GH (100 ng/ml) treatment for 15 min. *P<0.05, **P<0.01, ***P<0.001 versus Vehicle; †P<0.05, ††P<0.01, †††P<0.001 versus GH (n=3). Data are mean±SE
Mentions: To study the cross-talk between FGF21 and GH, serum GH levels in WT and FGF21-KO mice were measured in fed and overnight-fasted states. FGF21 deficiency had no effect on the production of GH in either fasting or fed state (Supplementary Figure S4A). GH action in islets was examined by determining GHR expression in both FGF21-KO and WT mouse islets. In 24-week-old mice, GHR mRNA was higher in FGF21-KO than WT mouse islets (Supplementary Figure S4B). However, significant change in GHR protein levels was not detected (Supplementary Figure S4C) while exogenous FGF21 treatment in normal mouse islets did not affect GHR expression (Supplementary Figures S4D and E). Isolated islet responses to GH were then studied by measuring JAK2 and STAT5 phosphorylation. After treatment with recombinant GH (0, 25, 50, or 100 ng/ml) for 15 min, FGF21-KO mouse islets showed enhanced phosphorylation of JAK2 and STAT5 compared with that in WT mouse islets (Figures 4a and b). To investigate the direct effects of FGF21 on GH action in islets, islets isolated from normal mice were pre-treated with recombinant FGF21 (0, 0.5, 1, or 2 μg/ml) before GH-induced signaling was examined. After 72 h treatment, both JAK2 and STAT5 phosphorylation induced by GH (100 ng/ml) was reduced in a dose-dependent manner, in which the greatest effect was found at 2 μg/ml of FGF21 (Figures 4c and d).

Bottom Line: Twenty-four-week-old male global FGF21-KO mice were used in this study.Expression of genes and proteins related to islet function and underlying mechanisms were also examined.This phenotype probably results from enhanced growth hormone (GH) sensitivity in FGF21-KO mouse islets.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.

ABSTRACT
Fibroblast growth factor (FGF) 21 is an endocrine factor that normalizes glucose homeostasis and reduces insulin resistance in diabetes. Although the pancreas is an FGF21 target organ, its role in pancreatic islets remains obscure. This study aimed to elucidate the physiological role of FGF21 in pancreatic islets using FGF21-knockout (FGF21-KO) mice. Twenty-four-week-old male global FGF21-KO mice were used in this study. Glucose and insulin tolerance were assessed. Expression of genes and proteins related to islet function and underlying mechanisms were also examined. Islet morphology and insulin-secreting capacity were further evaluated. FGF21-KO mice exhibited insulin resistance while being normoglycemic, associated with increases in beta-cell proliferation and insulin synthesis, acting as compensatory responses. This phenotype probably results from enhanced growth hormone (GH) sensitivity in FGF21-KO mouse islets. In addition, ex vivo FGF21 treatment in normal C57BL/6J mouse islets reduced GH signaling, probably via upregulation of peroxisome proliferator-activated receptor gamma (PPARγ) and cytokine-inducible SH-2 containing (CIS) protein, whereas KO mouse islets displayed reduced PPARγ and CIS expression. FGF21 treatment also reversed GH-induced insulin expression, beta-cell proliferation and GH-impaired glucose-stimulated insulin secretion (GSIS) in islets. Furthermore, distorted islet morphology and impaired GSIS were observed in KO mice, suggestive of islet dysfunction, whereas the enhanced insulin expression and impaired GSIS in FGF21-KO mouse islets could be reversed by blockade of GH signaling. Our data indicate that FGF21 is important in the regulation of beta-cell proliferation and insulin synthesis, probably via modulation of GH signaling. These findings provide evidence that FGF21 is an obligatory metabolic regulator in pancreatic islets and shed new light onto the role of endogenous FGF21 in the pathogenesis of insulin resistance and islet dysfunction.

Show MeSH
Related in: MedlinePlus