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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 islet hyperplasia and increased beta-cell proliferation. (a) Representative photomicrographs of islets stained with hematoxylin and eosin, and (b) measurement of islet area. (c) Representative immunostaining of islets labeled for insulin (green), DAPI (blue) and Ki-67 (red). (d) Beta-cell proliferation was analyzed by counting the Ki-67-positive beta-cell number divided by total beta-cell number (% Ki-67-positive beta cells). (e) Islets per section. Scale bar=100 μm. **P<0.01 versus WT (n=4–6 mice/batch; three batches). Data are mean±SE
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fig2: FGF21-KO mice display islet hyperplasia and increased beta-cell proliferation. (a) Representative photomicrographs of islets stained with hematoxylin and eosin, and (b) measurement of islet area. (c) Representative immunostaining of islets labeled for insulin (green), DAPI (blue) and Ki-67 (red). (d) Beta-cell proliferation was analyzed by counting the Ki-67-positive beta-cell number divided by total beta-cell number (% Ki-67-positive beta cells). (e) Islets per section. Scale bar=100 μm. **P<0.01 versus WT (n=4–6 mice/batch; three batches). Data are mean±SE

Mentions: FGF21-KO mouse islets were larger than those of WT mice (Figures 2a and b; WT=12311.36±884.54 μm2; KO=19321±2290.51  μm2), as shown by hematoxylin–eosin staining. FGF21-KO mice also had increased beta-cell proliferation (Figure 2c), as evidenced by immunostaining results. In islets from 24-week-old WT mice, the cell proliferation marker Ki-67 was virtually absent, but was easily detectable in FGF21-KO mice. Ki-67 staining was co-localized to the nuclei (labeled by DAPI) of beta cells (stained by insulin), indicating increased beta-cell proliferation (Figure 2d; WT=0.27±0.17; KO=0.72±0.39% Ki-67-positive beta cells). A slight, but statistically insignificant increase in islet number per pancreatic section was detected in FGF21-KO mouse islets (Figure 2e; WT=5.33±0.80; KO=8.01±1.08 islets per section). In addition, FGF21 deficiency did not affect islet apoptosis as shown in Supplementary Figure S1, suggesting that islet hyperplasia in FGF21-KO mice was mainly due to increased beta-cell proliferation.


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 islet hyperplasia and increased beta-cell proliferation. (a) Representative photomicrographs of islets stained with hematoxylin and eosin, and (b) measurement of islet area. (c) Representative immunostaining of islets labeled for insulin (green), DAPI (blue) and Ki-67 (red). (d) Beta-cell proliferation was analyzed by counting the Ki-67-positive beta-cell number divided by total beta-cell number (% Ki-67-positive beta cells). (e) Islets per section. Scale bar=100 μm. **P<0.01 versus WT (n=4–6 mice/batch; three batches). Data are mean±SE
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig2: FGF21-KO mice display islet hyperplasia and increased beta-cell proliferation. (a) Representative photomicrographs of islets stained with hematoxylin and eosin, and (b) measurement of islet area. (c) Representative immunostaining of islets labeled for insulin (green), DAPI (blue) and Ki-67 (red). (d) Beta-cell proliferation was analyzed by counting the Ki-67-positive beta-cell number divided by total beta-cell number (% Ki-67-positive beta cells). (e) Islets per section. Scale bar=100 μm. **P<0.01 versus WT (n=4–6 mice/batch; three batches). Data are mean±SE
Mentions: FGF21-KO mouse islets were larger than those of WT mice (Figures 2a and b; WT=12311.36±884.54 μm2; KO=19321±2290.51  μm2), as shown by hematoxylin–eosin staining. FGF21-KO mice also had increased beta-cell proliferation (Figure 2c), as evidenced by immunostaining results. In islets from 24-week-old WT mice, the cell proliferation marker Ki-67 was virtually absent, but was easily detectable in FGF21-KO mice. Ki-67 staining was co-localized to the nuclei (labeled by DAPI) of beta cells (stained by insulin), indicating increased beta-cell proliferation (Figure 2d; WT=0.27±0.17; KO=0.72±0.39% Ki-67-positive beta cells). A slight, but statistically insignificant increase in islet number per pancreatic section was detected in FGF21-KO mouse islets (Figure 2e; WT=5.33±0.80; KO=8.01±1.08 islets per section). In addition, FGF21 deficiency did not affect islet apoptosis as shown in Supplementary Figure S1, suggesting that islet hyperplasia in FGF21-KO mice was mainly due to increased beta-cell proliferation.

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