Defining the role of Fibroblast growth factor 21 (FGF21) in the pathogenesis of growth hormone resistance and subsequent growth failure in chronic childhood conditions

Abstract

Fibroblast growth factor 21 (FGF21) is an essential metabolic regulator, adapting to changes in nutritional status. Excessive undernutrition is suggested to elevate FGF21 levels, developing Growth hormone (GH) resistance and subsequent linear growth attenuation through unknown mechanisms. The aim of this PhD was to unravel in vitro the mechanistic interplay of FGF21 on GH receptor (GHR) signalling, further determining the association between nutrition induced chronic FGF21 using postnatal growth failure of very pre-term (VPT) infants as a model. FGF21 and receptor complex (FGFR1/-IIIC/β-Klotho) expression was evaluated in newly established HEK-293 stably expressing human/ mouse GHR. Human growth plate tissue was examined for the localisation of FGF21 and co-receptors within growth plate zonation. Cell lines and/or human growth plate explants were tested for GHR half-life and key GHR signalling mediators; STAT5, SOCS2 and IGF-1 in the presence/ absence of recombinant GH and FGF21. Serially measured FGF21/ IGF-1 levels and nutritional intake were assessed for the association with linear growth trends in VPT infants. The molecular integrity of GHR signalling and expression of FGF21 and receptors; FGFR1/-IIIC/β-KLOTHO was confirmed in stable lines. FGF21 and co-receptors were localised within the proliferative and pre-hypertrophic zones of human growth plate tissue. FGF21 increased GH-induced GHR turnover and SOCS2 expression; leading to the inhibition of downstream GHR signalling events including; pSTAT5 and IGF-1 expression. VPT infants displayed an immediate growth failure after birth followed by catch-up. FGF21 levels were elevated during growth deflection compared to catch-up (p<0.001). A positive association of fat (β=8.83, p=0.004) and carbohydrate (β=4.11, p=0.006) intake after birth was associated with the change in SD score for length catch-up growth. Chronic FGF21 inhibited GHR signalling events, playing a central role in GH resistance and growth failure. Nutrition did not regulate hormonal levels, having a direct effect on linear growth catch-up in VPT infants.