British Journal of Nutrition 2015 Nov 14;114(9):1410-18.
Rapid increase in fibroblast growth factor 21 in protein malnutrition and its impact on growth and lipid metabolism
Yori Ozaki1, Kenji Saito2, Kyoko Nakazawa2, Morichika Konishi3, Nobuyuki Itoh4, Fumihiko Hakuno5, Shin-Ichiro Takahashi5, Hisanori Kato2 and Asako Takenaka1*
1 Department of Agricultural Chemistry, School of Agriculture, Meiji University, Kawasaki, Kanagawa 214-8571, Japan.
2 Corporate Sponsored Research Program ‘Food for Life’, Organization for Interdisciplinary Research Projects, The University of Tokyo, Bunkyo, Tokyo, 113-8657, Japan.
3 Department of Microbial Chemistry, Kobe Pharmaceutical University, Kobe, Hyogo, 658-8558, Japan.
4 Department of Genetic Biochemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Sakyo, Kyoto, 606-8501, Japan.
5 Department of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo, Tokyo, 113-8657, Japan.
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.
Erratum of Fig.2 legend in Br J Nutr. 2015 Nov 14;114(9):1535-6 (PMID: 26400728).
Protein malnutrition inhibits animal growth and is accompanied by down-regulation of IGF-I and up- regulation of IGF binding protein (IGFBP)-1, which sequesters IGF-I action (1, 2) (Fig. 1). With suppressed protein anabolism, animals fed a low protein diet develop hepatosteatosis with marked accumulation of triglycerides. Such a phenotype is typically observed in kwashiorkor, a form of severe protein malnutrition in infants and children (3, 4), and we have previously showed that reduction of IGF-1 and increase of hepatic triglyceride accumulation occurs very rapidly (within 1 day) after the onset of feeding a low protein diet to growing rats (5). In the present study, in order to identify new molecules involved in such changes, we first conducted DNA microarray analysis, and identified FGF21 as one of the most strongly up-regulated genes in the liver from rats fed an isoenergetic low-protein diet for 8 h (Fig. 2a). In agreement with the up-regulation of FGF21 gene expression, these animals showed marked increase in plasma FGF21 levels (Fig. 2b). Protein deprivation seemed to directly increase FGF21 in the liver because amino acid deprivation from the culture media increased FGF21 gene expression in rat liver-derived RL-34 cells (Fig. 2c). We further investigated whether the up-regulation of FGF21 in protein malnutrition is responsible for growth retardation or liver steatosis, by feeding an isoenergetic low-protein diet to Fgf21-KO mice. Unexpectedly, we showed that growth retardation, decreased IGF-I and increased IGFBP-1 are not mediated by increased FGF21 under conditions of protein malnutrition (Fig. 3). Besides, Fgf21-KO mice fed a low-protein diet showed greater epi-WAT weight as well as marked increase in hepatic TAG and cholesterol levels (Fig. 4 a, b and c). Thus, we concluded that FGF21 up-regulation has a protective effect against obesity and hepatic steatosis under protein malnutrition conditions (Fig. 5).
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