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Journal article
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
The Journal of biological chemistry, v 288(38), pp 27375-27383
20 Sep 2013
PMID: 23940039
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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 [3H]thymidine incorporation, collagen X, and IGF-1 mRNA expression, with all effects being prevented by rhFGF21. In addition, rhFGF21 decreased 125I-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 125I-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.
Background: FGF21 causes GH insensitivity.
Results: Increased FGF21 expression induces LEPROT and LEPROTL1 expression. Inhibition of LEPROT or LEPROTL1 in growth plate chondrocytes prevents the FGF21-mediated inhibition of the GH stimulatory effects on chondrocyte function and IGF-1 expression.
Conclusion: FGF21 prevents the GH effects on chondrocytes by activating LEPROT and LEPROTL1.
Significance: LEPROT and LEPROTL1 mediate the FGF21 inhibition of GH action.
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Details
- Title
- 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
- Creators
- Shufang Wu - Xi'an Jiaotong UniversityTal Grunwald - St. Christopher's Hospital for ChildrenAlexei Kharitonenkov - Eli LillyJulie Dam - French National Centre for Scientific ResearchRalf Jockers - French National Centre for Scientific ResearchFrancesco De Luca - St. Christopher's Hospital for Children
- Publication Details
- The Journal of biological chemistry, v 288(38), pp 27375-27383
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pediatrics; College of Medicine
- Web of Science ID
- WOS:000330597300033
- Scopus ID
- 2-s2.0-84884580553
- Other Identifier
- 991019168331404721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology