title: Canine Fibroblast Growth Factor 21 Ameliorates Hyperglycemia Associated with Inhibiting Hepatic Gluconeogenesis and Improving Pancreatic Beta-Cell Survival in Diabetic Mice and Dogs.
abstract: Diabetes mellitus is a common endocrinopathy in dog. Fibroblast growth factor 21 (FGF-21) is a secreted protein, which is involved in glucose homeostasis. We speculate that the recombinant canine FGF-21 (cFGF-21) has the potential to become a powerful therapeutics to treat canine diabetes. The cFGF-21 gene was cloned and expressed in E. coli Rosetta (DE3). After purification, a cFGF-21 protein with the purity exceeding 95% was obtained. Mouse 3T3-L1 adipocytes and type 1 diabetic mice/dogs induced by STZ were used to examine the biological activity of cFGF-21 in vitro and in vivo, respectively. Results showed that cFGF-21 stimulated glucose uptake in adipocytes significantly in a dose-dependent manner, and reduced plasma glucose significantly in diabetic mice/dogs. After treatment with cFGF-21, the serum insulin level, glycosylated hemoglobin (HbA1c) level and the expressions of the hepatic gluconeogenesis genes (glucose-6-phosphatase, G6Pase and phosphoenolpyruvate carboxykinase, PCK) of the diabetic mice/dogs were attenuated significantly. In the mouse experiment, we also found that the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the expression of suppressor of cytokine signaling 3 (SOCS3) were up-regulated significantly in the livers after treatment. Histopathological and immunohistochemical results showed that treatment with cFGF-21 promoted recovery of pancreatic islets from STZ-induced apoptosis. Besides, we also found that treatment with cFGF-21 protected liver against STZ or hyperglycemia induced damage and the mechanism of this action associated with inhibiting oxidative stress. In conclusion, cFGF-21 represents a promising candidate for canine diabetes therapeutics. The mechanism of cFGF-21 ameliorates hyperglycemia associated with inhibiting hepatic gluconeogenesis by regulation of STAT3 signal pathway and improving pancreatic beta-cell survival.
authors.affiliation: Biopharmaceutical Lab, School of Life Science, Northeast Agricultural University, Harbin, P.R. China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Xu
authors.affiliation: Biopharmaceutical Lab, School of Life Science, Northeast Agricultural University, Harbin, P.R. China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Biopharmaceutical Lab, School of Life Science, Northeast Agricultural University, Harbin, P.R. China.
authors.forename: Xinghao
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Biopharmaceutical Lab, School of Life Science, Northeast Agricultural University, Harbin, P.R. China.
authors.forename: Junyan
authors.initials: J
authors.lastname: Li
authors.affiliation: Biopharmaceutical Lab, School of Life Science, Northeast Agricultural University, Harbin, P.R. China.
authors.forename: Liying
authors.initials: L
authors.lastname: Song
authors.affiliation: Biopharmaceutical Lab, School of Life Science, Northeast Agricultural University, Harbin, P.R. China.
authors.forename: Mir Hasson
authors.initials: MH
authors.lastname: Khoso
authors.affiliation: Biopharmaceutical Lab, School of Life Science, Northeast Agricultural University, Harbin, P.R. China.
authors.forename: Yunye
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Biopharmaceutical Lab, School of Life Science, Northeast Agricultural University, Harbin, P.R. China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Biopharmaceutical Lab, School of Life Science, Northeast Agricultural University, Harbin, P.R. China.
authors.forename: Guiping
authors.initials: G
authors.lastname: Ren
authors.affiliation: Biopharmaceutical Lab, School of Life Science, Northeast Agricultural University, Harbin, P.R. China.
authors.forename: Deshan
authors.initials: D
authors.lastname: Li
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015153:Blotting, Western; D004285:Dogs; D005346:Fibroblast Growth Factors / Q000627:therapeutic use*; D005943:Gluconeogenesis / Q000187:drug effects*; D006943:Hyperglycemia / Q000188:drug therapy* / Q000378:metabolism*; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017382:Reactive Oxygen Species; C414620:fibroblast growth factor 21; D008315:Malondialdehyde; D005346:Fibroblast Growth Factors; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase