Rapid increase in fibroblast growth factor 21 in protein malnutrition and its impact on growth and lipid metabolism.
Protein malnutrition promotes hepatic steatosis, decreases insulin-like growth factor (IGF)-I production and retards growth. To identify new molecules involved in such changes, we conducted DNA microarray analysis on liver samples from rats fed an isoenergetic low-protein diet for 8 h. We identified the fibroblast growth factor 21 gene (Fgf21) as one of the most strongly up-regulated genes under conditions of acute protein malnutrition (P<0·05, false-discovery rate<0·001). In addition, amino acid deprivation increased Fgf21 mRNA levels in rat liver-derived RL-34 cells (P<0·01). These results suggested that amino acid limitation directly increases Fgf21 expression. FGF21 is a polypeptide hormone that regulates glucose and lipid metabolism. FGF21 also promotes a growth hormone-resistance state and suppresses IGF-I in transgenic mice. Therefore, to determine further whether Fgf21 up-regulation causes hepatic steatosis and growth retardation after IGF-I decrease in protein malnutrition, we fed an isoenergetic low-protein diet to Fgf21-knockout (KO) mice. Fgf21-KO did not rescue growth retardation and reduced plasma IGF-I concentration in these mice. Fgf21-KO mice showed greater epididymal white adipose tissue weight and increased hepatic TAG and cholesterol levels under protein malnutrition conditions (P<0·05). Overall, the results showed that protein deprivation directly increased Fgf21 expression. However, growth retardation and decreased IGF-I were not mediated by increased FGF21 expression in protein malnutrition. Furthermore, FGF21 up-regulation rather appears to have a protective effect against obesity and hepatic steatosis in protein-malnourished animals.
1Department of Agricultural Chemistry,School of Agriculture,Meiji University,Kawasaki,Kanagawa 214-8571,Japan.
Yori
Y
Ozaki
2Corporate Sponsored Research Program 'Food for Life',Organization for Interdisciplinary Research Projects,The University of Tokyo,Bunkyo,Tokyo 113-8657,Japan.
Kenji
K
Saito
2Corporate Sponsored Research Program 'Food for Life',Organization for Interdisciplinary Research Projects,The University of Tokyo,Bunkyo,Tokyo 113-8657,Japan.
Kyoko
K
Nakazawa
3Department of Microbial Chemistry,Kobe Pharmaceutical University,Kobe,Hyogo 658-8558,Japan.
Morichika
M
Konishi
4Department of Genetic Biochemistry,Kyoto University Graduate School of Pharmaceutical Sciences,Sakyo,Kyoto 606-8501,Japan.
Nobuyuki
N
Itoh
5Department of Animal Sciences and Applied Biological Chemistry,Graduate School of Agriculture and Life Sciences,The University of Tokyo,Bunkyo,Tokyo 113-8657,Japan.
Fumihiko
F
Hakuno
5Department of Animal Sciences and Applied Biological Chemistry,Graduate School of Agriculture and Life Sciences,The University of Tokyo,Bunkyo,Tokyo 113-8657,Japan.
Shin-Ichiro
S
Takahashi
2Corporate Sponsored Research Program 'Food for Life',Organization for Interdisciplinary Research Projects,The University of Tokyo,Bunkyo,Tokyo 113-8657,Japan.
Hisanori
H
Kato
1Department of Agricultural Chemistry,School of Agriculture,Meiji University,Kawasaki,Kanagawa 214-8571,Japan.
Asako
A
Takenaka
D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D018753:Diet, Protein-Restricted; D005234:Fatty Liver / Q000235:genetics; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D013006:Growth Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity; D020411:Oligonucleotide Array Sequence Analysis; D011502:Protein-Energy Malnutrition / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation
D012333:RNA, Messenger; D014280:Triglycerides; C414620:fibroblast growth factor 21; C548904:insulin-like growth factor-1, rat; D005346:Fibroblast Growth Factors; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D002784:Cholesterol
DNA microarray analysis; Epi-WAT epididymal white adipose tissue; FGF fibroblast growth factor; Fibroblast growth factor 21; GH growth hormone; IGF insulin-like growth factor; IGFBP insulin-like growth factor binding protein; KO knockout; Low-protein diets; Protein malnutrition: Fgf21; TKB total ketone body; Tg transgenic; WT wild-type