Section of Endocrinology and Diabetes, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, Pennsylvania 19134, USA.
Endocrinology. 2012 May;153(5):2287-95. doi: 10.1210/en.2011-1909. Epub 2012 Feb 28.
Reduced caloric intake in mammals causes reduced skeletal growth and GH insensitivity. However, the underlying molecular mechanisms are not fully elucidated. The aim of this study was to determine whether the increased activity of fibroblast growth factor 21 (FGF21) during chronic undernutrition in mice causes GH insensitivity and growth failure. After 4 wk of food restriction, fgf21 knockout (KO) mice exhibited greater body and tibial growth than their wild-type (WT) littermates. Daily injections of recombinant human FGF21 in a subgroup of food-restricted fgf21 KO mice prevented these differences in body and tibial growth. At the end of the 4-wk food restriction, GH binding and GH receptor expression were reduced in the liver and in the growth plate of food-restricted WT mice (compared to WT mice fed ad libitum), whereas they were similar between food-restricted and ad libitum KO mice. In addition, a single injection of GH induced greater liver signal transducer and activator of transcription 5 phosphorylation and IGF-I mRNA in food-restricted KO mice than in WT mice. Lastly, in the tibial growth plate of food-restricted WT mice, FGF21 mRNA and protein expression was greater than that of WT mice fed ad libitum. In contrast, the IGF-I mRNA and protein expression was smaller. Our findings support a causative role for FGF21 in the inhibition of skeletal growth during prolonged undernutrition. Such role may be mediated by the antagonistic effect of FGF21 on GH action in the liver and, possibly, in the growth plate.
哺乳动物热量摄入减少会导致骨骼生长减少和 GH 不敏感。然而，其潜在的分子机制尚未完全阐明。本研究旨在确定在慢性营养不良期间，成纤维细胞生长因子 21（FGF21）活性增加是否会导致 GH 不敏感和生长障碍。在限制食物 4 周后，fgf21 敲除（KO）小鼠的体重和胫骨生长大于其野生型（WT）同窝小鼠。在一小部分限制食物的 fgf21 KO 小鼠中，每天注射重组人 FGF21 可防止体重和胫骨生长的这些差异。在限制食物 4 周结束时，与自由进食的 WT 小鼠相比，限制食物的 WT 小鼠肝脏和生长板中的 GH 结合和 GH 受体表达减少，而限制食物和自由进食的 KO 小鼠之间相似。此外，GH 的单次注射在限制食物的 KO 小鼠中诱导的肝脏信号转导和转录激活物 5 磷酸化和 IGF-I mRNA 大于 WT 小鼠。最后，在限制食物的 WT 小鼠的胫骨生长板中，FGF21 mRNA 和蛋白表达大于自由进食的 WT 小鼠。相比之下，IGF-I mRNA 和蛋白表达较小。我们的研究结果支持 FGF21 在长期营养不良期间抑制骨骼生长中起因果作用。这种作用可能是通过 FGF21 在肝脏中对 GH 作用的拮抗作用介导的，可能在生长板中也是如此。
