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Insulin sensitizes FGF21 in glucose and lipid metabolisms via activating common AKT pathway

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Abstract

Previous studies reveal that fibroblast growth factor 21 (FGF21) sensitizes insulin to achieve a synergy in regulating glucose metabolism. Here, we report that insulin sensitizes FGF21 in regulating both glucose and lipid metabolisms. db/db diabetic mice were subcutaneously administrated once a day for 6 weeks. Effective dose of insulin (1 U) could control blood glucose level of the db/db mice for maximum of 2 h, increased the body weight of the db/db mice and did not improve serum lipid parameters. In contrast, effective dose of FGF21 (0.5 mg/kg) could maintain blood glucose of the db/db mice at normal level for at least 24 h, repressed the weight gain of the mice and significantly improved lipid parameters. Ineffective doses of FGF21 (0.125 mg/kg) and insulin had no effect on blood glucose level of the db/db mice after 24 h administration, body weight or lipid parameters. However, combination of the two ineffective doses could maintain blood glucose level of the db/db mice for at least 24 h, suppressed weight gain and significantly improved lipid parameters. These results suggest that insulin sensitizes FGF21 in regulating both glucose and lipid metabolism. The results aimed to study the molecular basis of FGF21 sensitization indicates that combination of the two ineffective doses increased the mRNA expression of glut1, glut4, β-Klotho, sirt1, pgc-1α, ucp-1 and AKT phosphorylation, decreased fasn. The results demonstrate that insulin sensitizes FGF21 through elevating the phosphorylation of common gene Akt and amplifying FGF21 downstream signaling, including increasing expression of glut1 sirt1, pgc-1α, ucp-1, and decreasing fasn expression. In summary, we reports herein for the first time that insulin sensitizes FGF21 to achieve a synergy in regulating glucose and lipid metabolism. Along with previous studies, we conclude that the synergistic effect between FGF21 and insulin is realized through mutual sensitization.

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Abbreviations

FGF21:

Fibroblast growth factor 21

AKT:

Protein kinase B

glut1/4 :

Glucose transport1/4

fasn :

Fatty acid synthase

sirt1:

Silent mating type information regulation 2 homolog 1

pgc-1a:

Peroxisome proliferator-activated receptor gamma coactivator-1α

ucp-1:

Uncoupling protein -1

hASC:

Human adipose stem cell derived cells

IR:

Insulin resistant

GHb:

Glycosylated hemoglobin or glycated hemoglobin

TG:

Triacylglycerol

TC:

Total Cholesterol

LDL:

Low-Density Lipoprotein

HDL:

High density lipoprotein

OGTT:

Oral glucose tolerance test

BCA:

Bicinchonini\c acid

DTT:

Dithiothreitol

g6pase :

Glucose-6-phosphatase

pepck :

Phosphoenolpyruvate carboxykinase

FGFR:

Fibroblast growth factor receptor

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Acknowledgments

Yu Dan, Deshan Li, and Guiping Ren conceived and designed the experiments. Xianlong Ye, Qiang Wu, Shujie Li, et al. performed the experiments. Yu Dan, Deshan Li, and Guiping Ren analyzed the data. Yu Dan wrote the paper. Deshan Li and Guiping Ren revised the paper.

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    Authors and Affiliations

    1. Biopharmaceutical Lab, Life Science College, Northeast Agricultural University, Harbin, 150030, China

      Dan Yu, Shujie Li, Yongbi Yang, Jinjiao He, Qingyan Yuan, Mingyao Liu, Deshan Li & Guiping Ren

    2. School of Life Science, Henan Normal University, Xinxiang, 453007, China

      Xianlong Ye

    3. Key Laboratory of Agricultural Biological Functional Gene, Northeast Agricultural University, Harbin, 150030, China

      Qiang Wu, Yunye Liu, Xiaoyu Zhang, Deshan Li & Guiping Ren

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    1. Dan Yu
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    Both Deshan Li and Guiping Ren contributed equally to the design and supervision of the research for this article.

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    Yu, D., Ye, X., Wu, Q. et al. Insulin sensitizes FGF21 in glucose and lipid metabolisms via activating common AKT pathway. Endocrine 52, 527–540 (2016). https://doi.org/10.1007/s12020-015-0801-9

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