Serum FGF21 in boys with idiopathic short stature: relationship to lipid profile, onset of puberty and growth *

Fibroblast growth factor 21 (FGF21) is an important metabolic regulator that in rodents appears to mediate multiple processes related to metabolic adaptation, reproduction and growth. In mice, for example, FGF21 seems to regulate glucose tolerance, hepatic lipid metabolism and adaptation to starvation by inducing lipolysis and ketogenesis. In humans, serum FGF21 levels are highly variable, and increased levels have been reported in obesity and obesityrelated conditions. FGF21 levels correlated positively with serum triglyceride and negatively with HDL-cholesterol levels in overweight subjects; it is not currently known if FGF21 levels are associated to lipid or lipoprotein levels in children. We investigated circulating FGF21 levels in peripubertal boys with idiopathic short stature (ISS) and correlated them to lipid and lipoprotein levels and measures reflecting body composition and growth. Boys with ISS participated in a double-blind, randomized, placebo-controlled trial investigating the efficacy and safety of aromatase inhibitor therapy in the treatment of short stature. Twenty-nine boys were examined. At the start, their mean age was 11Æ1 (SD 1Æ5) years, height standard deviation score (SDS) )2Æ3 (0Æ3), BMI 16Æ4 (1Æ7) kg/m, BMI Z-score )0Æ8 (range )2Æ0 to +1Æ2) and the median Tanner genital stage 1 (range 1–3). Longitudinal serum FGF21 levels were measured in 14 boys, constituting the placebo group of the study, who were followed up every 6 months for 2 years and finally 3 years after the start. Of the 14 subjects followed longitudinally, seven (50%) showed physical signs of puberty progression during the follow-up and the rest remained prepubertal. Venous blood samples were obtained between 07 : 30 and 10 : 00 after an overnight fast. The serum samples for FGF21 analysis were prepared by centrifugation after blood collection and stored at )80 C until analysed. FGF21 concentrations were measured by ELISA kit (Fibroblast Growth Factor-21 Human ELISA; BioVendor GmbH, Heidelberg, Germany) according to manufacturer’s instructions. In statistical analyses, the values below the sensitivity of the assay were assigned a value 7 pg/mL. Intra-assay CV was 4Æ4%, and inter-assay CV was 16%. Serum FGF21 levels ranged from <7 to 3321 pg/ml. Two boys displayed exceptionally high levels (531 and 3321 pg/ml), and therefore, the data were log-transformed to normality prior to correlation analyses. Log-transformed circulating FGF21 levels correlated strongly with triglyceride (r = 0Æ50, n = 29, P < 0Æ01), HDL2-cholesterol (r = )0Æ37, P < 0Æ005), HDL3-cholesterol (r = )0Æ48, P < 0Æ01) and apolipoprotein AI (ApoA1) levels (r = )0Æ56, P < 0Æ005), but not with apolipoprotein AII (ApoA2), apolipoprotein B (ApoB), total cholesterol, LDL or homeostasis model of insulin resistance (HOMA-IR) (data not shown). Log FGF21 levels did not correlate with height, growth velocity, weight, Tanner G stage, BMI, BMI Z-score, body fat percentage as measured by skinfold measurements, serum testosterone or IGF-1 levels (data not shown). In boys followed up for 3 years, there were no significant changes in serum FGF21 levels (Fig. 1a). There were no consistent changes in FGF21 levels preceding the onset of puberty (Fig. 1b). In humans, FGF21 levels are modulated by prolonged starvation and agonists of the PPARa, including free fatty acids. In the current work, serum FGF21 in boys associated negatively with ApoA1 levels. Indeed, Wang et al. recently showed that the fgf21 gene is under the regulation of the retinoic acid receptor–related receptor a (RORa) that also regulates the apoA1 expression and that the