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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-KO mice display impaired GSIS. (a) Islet insulin secretion in WT and FGF21-KO mice. *P<0.05, ***P<0.001 versus 1.6 mmol/l; †P<0.05 versus WT 16.7 mmol/l. (b) Islet insulin secretion was expressed as % of low glucose. *P<0.05 versus WT (n=4–6 mice/batch; four batches). (c) Islet insulin secretion in normal mouse islets pre-treated with GH (100 ng/ml) with or without FGF21 (2 μg/ml) for 72 h. *P<0.05, ***P<0.001 versus 1.6 mmol/l; †P<0.05 versus vehicle 1.6 mmol/l. (d) Islet insulin secretion was expressed as % of low glucose. *P<0.05 versus vehicle; †P<0.05 versus GH (n=4). Data are mean±SE
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fig7: FGF21-KO mice display impaired GSIS. (a) Islet insulin secretion in WT and FGF21-KO mice. *P<0.05, ***P<0.001 versus 1.6 mmol/l; †P<0.05 versus WT 16.7 mmol/l. (b) Islet insulin secretion was expressed as % of low glucose. *P<0.05 versus WT (n=4–6 mice/batch; four batches). (c) Islet insulin secretion in normal mouse islets pre-treated with GH (100 ng/ml) with or without FGF21 (2 μg/ml) for 72 h. *P<0.05, ***P<0.001 versus 1.6 mmol/l; †P<0.05 versus vehicle 1.6 mmol/l. (d) Islet insulin secretion was expressed as % of low glucose. *P<0.05 versus vehicle; †P<0.05 versus GH (n=4). Data are mean±SE

Mentions: For islet insulin-secreting capacity, high-glucose challenge induced insulin secretion in both WT and FGF21-KO mouse islets (Figure 7a). However, the insulin secretion upon glucose challenge was significantly reduced in FGF21-KO mouse islets, as shown by the reduced % of low glucose (Figure 7b; WT=676.23±140.4; KO=292.36±48.66% of low glucose). To test whether enhanced GH signaling impairs GSIS in FGF21-KO mice, isolated islets from normal mice were treated with GH, with or without FGF21 prior to GSIS assessment. As shown in Figure 7c, GH (100 ng/ml, 72 h) increased basal insulin secretion (in 1.6 mmol/l low glucose) as compared with vehicle. Insulin release in response to high glucose was, however, reduced by GH treatment, but co-treatment with FGF21 (2 μg/ml) reversed the inhibitory effect of GH on GSIS (Figure 7d; Vehicle=366.78±63.87; GH=161.76±18.61; GH+FGF21=311.44±32.29% of low glucose).


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-KO mice display impaired GSIS. (a) Islet insulin secretion in WT and FGF21-KO mice. *P<0.05, ***P<0.001 versus 1.6 mmol/l; †P<0.05 versus WT 16.7 mmol/l. (b) Islet insulin secretion was expressed as % of low glucose. *P<0.05 versus WT (n=4–6 mice/batch; four batches). (c) Islet insulin secretion in normal mouse islets pre-treated with GH (100 ng/ml) with or without FGF21 (2 μg/ml) for 72 h. *P<0.05, ***P<0.001 versus 1.6 mmol/l; †P<0.05 versus vehicle 1.6 mmol/l. (d) Islet insulin secretion was expressed as % of low glucose. *P<0.05 versus vehicle; †P<0.05 versus GH (n=4). Data are mean±SE
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig7: FGF21-KO mice display impaired GSIS. (a) Islet insulin secretion in WT and FGF21-KO mice. *P<0.05, ***P<0.001 versus 1.6 mmol/l; †P<0.05 versus WT 16.7 mmol/l. (b) Islet insulin secretion was expressed as % of low glucose. *P<0.05 versus WT (n=4–6 mice/batch; four batches). (c) Islet insulin secretion in normal mouse islets pre-treated with GH (100 ng/ml) with or without FGF21 (2 μg/ml) for 72 h. *P<0.05, ***P<0.001 versus 1.6 mmol/l; †P<0.05 versus vehicle 1.6 mmol/l. (d) Islet insulin secretion was expressed as % of low glucose. *P<0.05 versus vehicle; †P<0.05 versus GH (n=4). Data are mean±SE
Mentions: For islet insulin-secreting capacity, high-glucose challenge induced insulin secretion in both WT and FGF21-KO mouse islets (Figure 7a). However, the insulin secretion upon glucose challenge was significantly reduced in FGF21-KO mouse islets, as shown by the reduced % of low glucose (Figure 7b; WT=676.23±140.4; KO=292.36±48.66% of low glucose). To test whether enhanced GH signaling impairs GSIS in FGF21-KO mice, isolated islets from normal mice were treated with GH, with or without FGF21 prior to GSIS assessment. As shown in Figure 7c, GH (100 ng/ml, 72 h) increased basal insulin secretion (in 1.6 mmol/l low glucose) as compared with vehicle. Insulin release in response to high glucose was, however, reduced by GH treatment, but co-treatment with FGF21 (2 μg/ml) reversed the inhibitory effect of GH on GSIS (Figure 7d; Vehicle=366.78±63.87; GH=161.76±18.61; GH+FGF21=311.44±32.29% of low glucose).

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