Role of Fibroblast Growth Factor 21 (FGF21) in Undernutrition-Related Attenuation of Growth in Mice

Abstract

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.

Increased Expression of Fibroblast Growth Factor 21 (FGF21) during Chronic Undernutrition Causes Growth Hormone Insensitivity in Chondrocytes by Inducing Leptin Receptor Overlapping Transcript (LEPROT) and Leptin Receptor Overlapping Transcript-like 1 (LEPROTL1) Expression

“…Transgenic mice overexpressing FGF21 exhibit shorter body length and tibiae when compared with wild-type mice (6). We have previously demonstrated that FGF21 expression is increased in the liver and in the growth plate of food-restricted wild-type mice (17). In food-restricted Fgf21 knock-out mice, the attenuated reduction of tibial growth and tibial growth plate thickness (compared with food-restricted wild-type mice) indicates that the increased expression of systemic FGF21 in food-restricted wild-type mice is causally related to the suppressed growth plate chondrogenesis and, in turn, suppressed longitudinal bone growth.…”

“…In a previous study we demonstrated that mice undergoing 4 weeks of food restriction exhibited increased expression of Fgf21 (both in the liver and in the growth plate), growth hormone (GH) 3 insensitivity, and a concomitant reduction of their body linear growth and growth plate chondrogenesis (17). Interest-ingly, food-restricted Fgf21 knock-out mice experienced an attenuated reduction of their linear growth, tibial growth, and tibial growth plate thickness when compared with food-restricted wild-type mice.…”

FGF21 is an endocrine signal of protein restriction

“…The effect appears to be mediated in part by FGF21-dependent inhibition of growth hormone (GH) signaling in the liver, resulting in reduced hepatic IGF1 secretion (49)(50)(51). A separate study indicates that FGF21 contributes to the attenuation of growth during undernutrition (52). Our results support and extend these data and demonstrate that FGF21 plays an essential role in linking dietary protein intake to body growth and composition.…”

The starvation hormone, fibroblast growth factor-21, extends lifespan in mice

“…Transgenic (Tg) mice overexpressing FGF21 are markedly smaller than wild-type mice and have a corresponding decrease in circulating IGF-1 concentrations despite having elevated growth hormone (GH) levels (Inagaki et al, 2008). Conversely, FGF21-knockout mice grow more than wild-type mice under conditions of nutrient deprivation (Kubicky et al, 2012). In liver, FGF21 inhibits the GH signaling pathway by blocking JAK2-mediated phosphorylation and nuclear translocation of the transcription factor, STAT5.…”