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.
During calorie restriction in mice, increased expression of FGF21 causes growth attenuation and growth hormone (GH) insensitivity. Previous evidence also indicates that fasting-associated increased expression of leptin receptor overlapping transcript (LEPROT) and LEPROT-like 1 (LEPROTL1) (two proteins that regulate intracellular protein trafficking) reduces GH receptor cell-surface expression in the liver. Thus, we hypothesized that FGF21 causes GH insensitivity through regulation of LEPROT and/or LEPROTL1 expression. After 4 weeks of food restriction, LEPROT and LEPROTL1 mRNA expression in the liver and in the tibial growth plate of wild-type (WT) mice was increased compared with WT mice fed ad libitum. In Fgf21 knock-out (KO) mice, LEPROT and LEPROTL1 mRNA expression in food-restricted and fed ad libitum was similar, with the exception of a subgroup of food-restricted Fgf21 KO mice treated with recombinant human (rh) FGF21 that experienced increased LEPROT and LEPROTL1 mRNA expression compared with untreated food-restricted Fgf21 KO mice. In cultured growth plate chondrocytes, FGF21 stimulated LEPROT and LEPROTL1 mRNA expression, with such effect being prevented in chondrocytes transfected with FGFR1 siRNA or ERK1 siRNA. In cells transfected with control siRNA, GH increased [(3)H]thymidine incorporation, collagen X, and IGF-1 mRNA expression, with all effects being prevented by rhFGF21. In addition, rhFGF21 decreased (125)I-GH binding. In LEPROT siRNA- and/or LEPROTL1 siRNA-transfected cells, rhFGF21 did not prevent the GH stimulatory effects on thymidine incorporation, collagen X, and IGF-1 expression; furthermore, rhFGF21 did not prevent (125)I-GH binding. Consistent with the effects of rhFGF21, LEPROT overexpression in chondrocytes resulted in the inhibition of GH action. Our findings indicate that the increased expression of FGF21 during chronic undernutrition inhibits GH action on chondrocytes by activating LEPROT and LEPROTL1.
Section of Endocrinology and Diabetes, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, Pennsylvania 19134; First Affiliated Hospital of Medical School of Xi'an Jiaotong University, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Medical School of Xi'an Jiaotong University, Xi'an 710061 China.
Shufang
S
Wu
Section of Endocrinology and Diabetes, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, Pennsylvania 19134.
Tal
T
Grunwald
Lilly Research Laboratories, Indianapolis, Indiana.
Alexei
A
Kharitonenkov
INSERM, U1016, Institut Cochin, Paris 75014, France; CNRS UMR 8104, Paris 75014, France; Université Paris Descartes, Sorbonne Paris Cite, Paris 75270, France.
Julie
J
Dam
INSERM, U1016, Institut Cochin, Paris 75014, France; CNRS UMR 8104, Paris 75014, France; Université Paris Descartes, Sorbonne Paris Cite, Paris 75270, France.
Ralf
R
Jockers
Section of Endocrinology and Diabetes, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, Pennsylvania 19134. Electronic address: francesco.deluca@drexelmed.edu.
Francesco
F
De Luca
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D002908:Chronic Disease; D005346:Fibroblast Growth Factors / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D005786:Gene Expression Regulation; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D044342:Malnutrition / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000096:biosynthesis / Q000235:genetics
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C484581:Obrgrp protein, mouse; D012333:RNA, Messenger; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D048052:Mitogen-Activated Protein Kinase 3
Chondrocytes; Chondrogenesis; Fibroblast Growth Factor (FGF); Growth Hormone; Growth Plate; Nutrition