Expression of the growth hormone receptor isoforms and its correlation with the metabolic profile in morbidly obese subjects.
Adipose tissue
Exon 3 GHR
GH
GH Receptor
Metabolic syndrome
Morbid obesity
Journal
Endocrine
ISSN: 1559-0100
Titre abrégé: Endocrine
Pays: United States
ID NLM: 9434444
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
28
06
2018
accepted:
15
10
2018
pubmed:
27
10
2018
medline:
28
4
2020
entrez:
27
10
2018
Statut:
ppublish
Résumé
Given the lipolytic effect of GH and its potential role in determining adipose tissue distribution, we evaluated the expression of the GH hormone receptor (GHR) isoforms in patients with morbid obesity seeking associations with metabolic parameters. 262 morbidly obese subjects (mean age 42.5 ± 11 years, 75% women) underwent PCR-genotyping of the exon 3 GHR polymorphism. In 17 of these subjects, who proved to be heterozygous for the exon 3 genotype (+3/-3), subcutaneous and visceral adipose tissue was obtained during bariatric surgery; total RNA was extracted, reversely transcribed, and the different isoforms of the GHR (exon 3 containing and lacking flGHR as well as the trGHR) were PCR-amplified using specific primers. 27% were +3/+3 homozygous, 20% -3/-3 homozygous and 53% were +3/-3 heterozygous. Compared to subjects homozygous for the +3 genotype, homozygous and heterozygous carriers of the -3 genotype were significantly heavier and tended to have a higher HOMA 2-IR. Expression of the flGHR and trGHR mRNA was demonstrated in all evaluated samples of subcutaneous and visceral adipose tissue from the 17 patients. The exon 3+ isoform was expressed in all adipose tissue samples, whereas only six subjects expressed the 3- isoform as well. The only distinctive feature of these six patients was a higher HbA1c. The heterozygous GHR +3/-3 genotype is more prevalent in subjects with morbid obesity. Patients expressing the exon +3 and exon -3 isoforms in adipose tissue had a higher HbA1c, than those expressing only the exon -3 isoform.
Sections du résumé
BACKGROUND AND AIM OF THE STUDY
Given the lipolytic effect of GH and its potential role in determining adipose tissue distribution, we evaluated the expression of the GH hormone receptor (GHR) isoforms in patients with morbid obesity seeking associations with metabolic parameters.
METHODS
262 morbidly obese subjects (mean age 42.5 ± 11 years, 75% women) underwent PCR-genotyping of the exon 3 GHR polymorphism. In 17 of these subjects, who proved to be heterozygous for the exon 3 genotype (+3/-3), subcutaneous and visceral adipose tissue was obtained during bariatric surgery; total RNA was extracted, reversely transcribed, and the different isoforms of the GHR (exon 3 containing and lacking flGHR as well as the trGHR) were PCR-amplified using specific primers.
RESULTS
27% were +3/+3 homozygous, 20% -3/-3 homozygous and 53% were +3/-3 heterozygous. Compared to subjects homozygous for the +3 genotype, homozygous and heterozygous carriers of the -3 genotype were significantly heavier and tended to have a higher HOMA 2-IR. Expression of the flGHR and trGHR mRNA was demonstrated in all evaluated samples of subcutaneous and visceral adipose tissue from the 17 patients. The exon 3+ isoform was expressed in all adipose tissue samples, whereas only six subjects expressed the 3- isoform as well. The only distinctive feature of these six patients was a higher HbA1c.
CONCLUSIONS
The heterozygous GHR +3/-3 genotype is more prevalent in subjects with morbid obesity. Patients expressing the exon +3 and exon -3 isoforms in adipose tissue had a higher HbA1c, than those expressing only the exon -3 isoform.
Identifiants
pubmed: 30361972
doi: 10.1007/s12020-018-1794-y
pii: 10.1007/s12020-018-1794-y
doi:
Substances chimiques
Protein Isoforms
0
Receptors, Somatotropin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
573-581Subventions
Organisme : Instituto Mexicano del Seguro Social
ID : R-2013-3601-227 and R-2015-785-015
Pays : International
Références
M.J. Waters, The growth hormone receptor. Growth Horm. IGF Res. 28, 6–10 (2016)
doi: 10.1016/j.ghir.2015.06.001
pubmed: 26059750
M.J. Waters, A.J. Brooks, JAK2 activation by growth hormone and other cytokines. Biochem. J. 466, 1–11 (2015)
doi: 10.1042/BJ20141293
pubmed: 25656053
pmcid: 4325515
C.G. Goodyer, R.M. Figueiredo, S. Krackovitch, et al., Characterization of the growth hormone receptor in human dermal fibroblasts and liver during development. Am. J. Physiol. Endocrinol. Metab. 281, E1213–1220 (2001)
doi: 10.1152/ajpendo.2001.281.6.E1213
pubmed: 11701436
C.G. Goodyer, G. Zogopoulos, G. Schwartzbauer, H. Zheng, G.N. Hendy, R.K. Menon, Organization and evolution of the human growth hormone receptor gene 5’-flanking region. Endocrinology 142, 1923–1934 (2001)
doi: 10.1210/endo.142.5.8170
pubmed: 11316758
M. Ballesteros, K.C. Leung, R.J. Ross, et al., Distribution and abundance of messenger ribonucleic acid for growth hormone receptor isoforms in human tissues. J. Clin. Endocrinol. Metab. 85, 2865–2871 (2000)
pubmed: 10946895
R.J. Ross, N. Esposito, X.Y. Shen, et al., A short isoform of the human growth hormone receptor functions as a dominant negative inhibitor of the full-length receptor and generates large amounts of binding protein. Mol. Endocrinol. 11, 265–273 (1997)
doi: 10.1210/mend.11.3.9901
pubmed: 9058373
F. Baş, F. Darendeliler, Z. Aycan, et al., The exon 3-deleted/full-length growth hormone receptor polymorphism and response to growth hormone therapy in growth hormone deficiency and Turner syndrome: A multicenter study. Horm. Res. Paediatr. 77, 85–93 (2012)
doi: 10.1159/000335172
pubmed: 22456308
M.L. Sobrier, P. Duquesnoy, B. Duriez, S. Amselem, M. Goossens, Expression and binding properties of two isoforms of the human growth hormone receptors. FEBS Lett. 319, 16–20 (1993)
doi: 10.1016/0014-5793(93)80028-S
pubmed: 8454051
C. Dos Santos, L. Essioux, C. Teinturier, et al., A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone. Nat. Genet. 36, 720–724 (2004)
doi: 10.1038/ng1379
pubmed: 15208626
M. Mercado, N. Dávila, J.F. McLeod, et al., Distribution of growth hormone receptor messenger ribonucleic acid containing and lacking exon 3 in human tissues. J. Clin. Endocrinol. Metab. 78, 731–735 (1994)
pubmed: 8126150
J. Pantel, K. Machinis, M.L. Sobrier, et al., Species-specific alternative splice mimicry at the growth hormone receptor locus revealed by the lineage of retroelements during primate evolution. J. Biol. Chem. 275, 18664–18669 (2000)
doi: 10.1074/jbc.M001615200
pubmed: 10764769
L. Audí, C. Esteban, A. Carrascosa, et al., Exon 3-deleted/full-length growth hormone receptor polymorphism genotype frequencies in Spanish short small-for-gestational-age (SGA) children and adolescents (n = 247) and in an adult control population (n = 289) show increased fl/fl in short SGA. J. Clin. Endocrinol. Metab. 91, 5038–5043 (2006)
doi: 10.1210/jc.2006-0828
pubmed: 17003087
M. Mercado, B. Gonz lez, C. Sandoval, et al., Clinical and biochemical impact of the d3 growth hormone receptor genotype in acromegaly. J. Clin. Endocrinol. Metab. 93, 3411–3415 (2008)
doi: 10.1210/jc.2008-0391
pubmed: 18611972
G. Binder, B. Trebar, F. Baur, R. Schweizer, M.B. Ranke, Homozygocity of the d3-growth hormone receptor polymorphism is associated with a high total effect of GH on growth and a high BMI in girls with Turner syndrome. Clin. Edocrinol. 68, 567–572 (2008)
doi: 10.1111/j.1365-2265.2007.03090.x
G. Binder, B. Trebar, F. Baur, R. Schweizer, M.B. Ranke, The d3-growth hormone (GH) receptor polymorphism is associated with increased responsiveness to GH in Turner syndrome and short small-for-gestational-age children. J. Clin. Endocrinol. Metab. 91, 659–664 (2006)
doi: 10.1210/jc.2005-1581
pubmed: 16291706
A.A. Jorge, F.G. Marchissotti, L.R. Montenegro, L.R. Carvalho, B.B. Mendonca, I.J. Arnhold, Growth hormone (GH) pharmacogenetics: influence of GH receptor exon 3 retention or deletion on first year growth response and final height in patients with severe GH deficiency. J. Clin. Endocrinol. Metab. 91, 1076–1080 (2006)
doi: 10.1210/jc.2005-2005
pubmed: 16291702
L. Audi, A. Carrascosa, C. Esteban, M. Fernandez-Cancio, P. Andaluz, D. Yeste, R. Eespadero, M.L. Granada, H. Wollmann, L. Dryklund, The exón 3-deleted/full-length growth hormone receptor polymorphism does not influence the effect of puberty or growth hormone therapy on glcose homeostasis in short, non-growth hormone deficient small-for-gestationla-age children: Results from a two-year controlled prospective study. J. Clin. Endocrinol. Metab. 93, 2709–2715 (2008)
doi: 10.1210/jc.2008-0150
pubmed: 18445665
W.F. Blum, K. Machinis, E.P. Shavrikova, A. Keller, H. Stobbe, R.W. Pfaefle, S. Amselem, The growth response to growth hormone (GH) treatment in children with isolated GH deficiency is independent of the exon-3 minus isoform of the GHR receptor. J. Clin. Endocrinol. Metab. 91, 4171–4174 (2006)
doi: 10.1210/jc.2006-0063
pubmed: 16868057
M. Mormando, S. Chiloiro, A. Bianchi, A. Giampetro, F. Angelini, L. Tartaglione, L. Nasto, D. Milardi, A.M. Formenti, A. Giustina, L. De Marinis, Growth hormone receptor isoforms and fracture risk in adult-onset growth hormone deficient patients. Clin. Endocrinol. 85, 717–724 (2016)
doi: 10.1111/cen.13161
A. Bianchi, A. Giustina, V. Cimino, R. Pola, F. Angelini, A. Pontecorvi, L. De Marinis, Influence of the growth hormone receptor d3 and full-length isoforms on biochemical treatment outcomes in acromegaly. J. Clin. Endocrinol. Metab. 94, 2015–2022 (2009)
doi: 10.1210/jc.2008-1337
pubmed: 19336510
N. Møller, J.O. Jørgensen, Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr. Rev. 30, 152–177 (2009)
doi: 10.1210/er.2008-0027
pubmed: 19240267
D.E. Berryman, C.A. Glad, E.O. List, et al., The GH/IGF-1 axis in obesity: Pathophysiology and therapeutic considerations. Nat. Rev. Endocrinol. 9, 346–356 (2013)
doi: 10.1038/nrendo.2013.64
pubmed: 23568441
C. Beauregard, A.L. Utz, A.E. Schaub, et al., Growth hormone decreases visceral fat and improves cardiovascular risk markers in women with hypopituitarism: A randomized, placebo-controlled study. J. Clin. Endocrinol. Metab. 93, 2063–2071 (2008)
doi: 10.1210/jc.2007-2371
pubmed: 18381581
pmcid: 2435650
K.C. Mekala, N.A. Tritos, Effects of recombinant human growth hormone therapy in obesity in adults: A meta analysis. J. Clin. Endocrinol. Metab. 94, 130–137 (2009)
doi: 10.1210/jc.2008-1357
pubmed: 18940879
A. Erman, A. Veilleux, A. Tchernof, et al., Human growth hormone receptor (GHR) expression in obesity: I. GHR mRNA expression in omental and subcutaneous adipose tissues of obese women. Int. J. Obes. 35, 1511–1519 (2011)
doi: 10.1038/ijo.2011.23
American Diabetes Association, Classification and diagnosis of diabetes: Standards of medical care in diabetes-2018. Diabetes Care 41(Suppl. 1), S13–S27 (2018)
doi: 10.2337/dc18-S002
K.G. Alberti, P. Zimmet, J. Shaw, IDF Epidemiology Task Force Consensus Group. The metabolic syndrome—a new worldwide definition. Lancet 366, 1059–1062 (2005)
doi: 10.1016/S0140-6736(05)67402-8
pubmed: 16182882
D.E. Berryman, E.O. List, Growth hormone’s effect on adipose tissue: Quality versus quantity. Int. J. Mol. Sci. 18, 1621 (2017)
doi: 10.3390/ijms18081621
pmcid: 5578013
L. Gao, Z. Zheng, L. Cao, et al., The growth hormone receptor (GHR) exon 3 polymorphism and its correlation with metabolic profiles in obese Chinese children. Pediatr. Diabetes 12, 429–434 (2011)
doi: 10.1111/j.1399-5448.2010.00747.x
pubmed: 21470351
R.J. Strawbridge, L. Kärvestedt, C. Li, et al., GHR exon 3 polymorphism: Association with type 2 diabetes mellitus and metabolic disorder. Growth Horm. IGF Res. 17, 392–398 (2007)
doi: 10.1016/j.ghir.2007.04.005
pubmed: 17537658
C.A. Glad, L.M. Carlsson, O. Melander, et al., The GH receptor exon 3 deleted/full-length polymorphism is associated with central adiposity in the general population. Eur. J. Endocrinol. 172, 123–8 (2015)
doi: 10.1530/EJE-14-0723
pubmed: 25391539
S. Fisker, B. Hansen, J. Fuglsang et al. Gene expression of the GH receptor in subcutaneous and intraabdominal fat in healthy females: relationship to GH-binding protein. Eur. J. Endocrinol. 150, 773–777 (2004)
doi: 10.1530/eje.0.1500773
pubmed: 15191346
R.B. Wickelgren, K.L. Landin, C. Ohlsson et al. Expression of exon 3-retaining and exon 3-excluding isoforms of the human growth hormone-receptor is regulated in an interindividual, rather than a tissue-specific manner. J. Clin. Endocrinol. Metab. 80, 2154–2157 (1995)
pubmed: 7608270