Abstract
Background
To study the associations of Protein Tyrosine Phosphatase-N1 (PTPN1) polymorphisms with obesity-related phenotypes in European adolescents, and the influence of physical activity on these relationships.
Methods
Five polymorphisms of PTPN1 were genotyped in 1057 European adolescents (12–18 years old). We measured several phenotypes related to obesity, such as adiposity markers, and biochemical and clinical parameters. Physical activity was objectively measured by accelerometry.
Results
The T, A, T, T and G alleles of the rs6067472, rs10485614, rs2143511, rs6020608 and rs968701 polymorphisms, respectively, were associated with lower levels of obesity-related phenotypes (i.e., body mass index, body fat percentage, hip circumference, fat mass index, systolic blood pressure and leptin) in European adolescents. In addition, the TATTG haplotype was associated with lower body fat percentage and fat mass index compared to the AACCA haplotype. Finally, when physical activity levels were considered, alleles of the rs6067472, rs2143511, rs6020608 and rs968701 polymorphisms were only associated with lower adiposity in active adolescents.
Conclusions
PTPN1 polymorphisms were associated with adiposity in European adolescents. Specifically, alleles of these polymorphisms were associated with lower adiposity only in physically active adolescents. Therefore, meeting the recommendations of daily physical activity may reduce obesity risk by modulating the genetic predisposition to obesity.
Impact
-
Using gene-phenotype and gene*environment analyses, we detected associations between polymorphisms of the Protein Tyrosine Phosphatase-N1 (PTPN1) gene and obesity-related phenotypes, suggesting a mechanism that can be modulated by physical activity.
-
This study shows that genetic variability of PTPN1 is associated with adiposity, while physical activity seems to modulate the genetic predisposition.
-
This brings insights about the mechanisms by which physical activity positively influences obesity.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Data availability
In order to maintain a low risk of re-identification and compliance with the EU General Data Protection Regulation, the clinical and genetic raw data used in this study cannot be public. Interested parties can request the Risk Analysis Assessment approved by the funding agency that includes full explanations about the security measures and their justification.
References
GBD 2015 Obesity Collaborators. Health effects of overweight and obesity in 195 countries over 25 years. N. Engl. J. Med. 377, 13–27 (2017).
Xu, B. & Xie, X. Neurotrophic factor control of satiety and body weight. Nat. Rev. Neurosci. 17, 282–292 (2016).
Abdalla, M. M. I. Central and peripheral control of food intake. Endocr. Regul. 51, 52–70 (2017).
Loos, R. J. F. & Yeo, G. S. H. The genetics of obesity: from discovery to biology. Nat. Rev. Genet. 23, 120–133 (2022).
Farooqi, I. S. & O’Rahilly, S. Genetics of obesity in humans. Endocr. Rev. 27, 710–718 (2006).
Sheikh, A. B. et al. The interplay of genetics and environmental factors in the development of obesity. Cureus 9, e1435 (2017).
Ruiz, J. R. et al. Attenuation of the effect of the FTO rs9939609 polymorphism on total and central body fat by physical activity in adolescents: the HELENA study. Arch. Pediatr. Adolesc. Med. 164, 328–333 (2010).
Pascual-Gamarra, J. M. et al. Association between UCP1, UCP2, and UCP3 gene polymorphisms with markers of adiposity in European adolescents: the HELENA study. Pediatr. Obes. 14, e12504 (2019).
Tanisawa, K., Tanaka, M. & Higuchi, M. Gene-exercise interactions in the development of cardiometabolic diseases. J. Phys. Fit. Sport. Med. 5, 25–36 (2016).
Smith, J. K. Exercise and atherogenesis. Exerc. Sport Sci. Rev. 29, 49–53 (2001).
Graff, M. et al. Genome-wide physical activity interactions in adiposity ― a meta-analysis of 200,452 adults. PLoS Genet 13, 1–26 (2017).
Ruiz, J. R. et al. Objectively measured physical activity and sedentary time in European adolescents. Am. J. Epidemiol. 174, 173–184 (2011).
Salazar‐Tortosa, D. F. et al. Association between lipoprotein lipase gene polymorphisms and cardiovascular disease risk factors in European adolescents: The Healthy Lifestyle in Europe by Nutrition in Adolescence study. Pediatr. Diabetes 21, 747–757 (2020).
Cho, H. Protein tyrosine phosphatase 1B (PTP1B) and obesity. Vitam. Horm. 91, 405–424 (2013).
Elchebly, M. et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283, 1544–1548 (1999).
Zabolotny, J. M. et al. PTP1B regulates leptin signal transduction in vivo. Dev. Cell 2, 489–495 (2002).
Cheng, A. et al. Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev. Cell 2, 497–503 (2002).
Klaman, L. D. et al. Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in Protein-Tyrosine Phosphatase 1B-deficient mice. Mol. Cell. Biol. 20, 5479–5489 (2000).
Tsou, R. C. & Bence, K. K. The genetics of PTPN1 and obesity: Insights from mouse models of tissue-specific PTP1B deficiency. J. Obes. 2012, 1–8 (2012).
Moreno, L. A. et al. Assessing, understanding and modifying nutritional status, eating habits and physical activity in European adolescents: the HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) Study. Public Health Nutr. 11, 288–299 (2007).
Moreno, L. A. et al. Design and implementation of the Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study. Int. J. Obes. 32, S4–S11 (2008).
Béghin, L. et al. Quality assurance of ethical issues and regulatory aspects relating to good clinical practices in the HELENA Cross-Sectional Study. Int. J. Obes. 32, S12–S18 (2008).
Nagy, E. et al. Harmonization process and reliability assessment of anthropometric measurements in a multicenter study in adolescents. Int. J. Obes. 32, S58–S65 (2008).
Cole, T. J., Bellizzi, M. C., Flegal, K. M. & Dietz, W. H. Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ 320, 1240–1243 (2000).
Slaughter, M. et al. Skinfold equations for estimation of body fatness in children and youth. Hum. Biol. 60, 709–723 (1998).
González-Gross, M. et al. Sampling and processing of fresh blood samples within a European multicenter nutritional study: evaluation of biomarker stability during transport and storage. Int. J. Obes. 32, S66–S75 (2008).
R Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/. (2017).
Sham, P. C. & Purcell, S. M. Statistical power and significance testing in large-scale genetic studies. Nat. Rev. Genet. 15, 335–346 (2014).
Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. 57, 289–300 (1995).
Qu, H.-Q., Tien, M. & Polychronakos, C. Statistical significance in genetic association studies. Clin. Investig. Med. 33, E266–E270 (2010).
Sinnwell, J. P. & Schaid, D. J. haplo.stats: statistical analysis of haplotypes with traits and covariates when linkage phase is ambiguous. https://cran.r-project.org/package=haplo.stats (2016).
González, J. R. et al. SNPassoc: an R package to perform whole genome association studies. Bioinformatics 23, 644–645 (2007).
Wang, N. et al. Distribution of recombination crossovers and the origin of haplotype blocks: the interplay of population history, recombination, and mutation. Am. J. Hum. Genet. 71, 1227–1234 (2002).
Sterne, J. A. C. & Smith, G. D. Sifting the evidence-what’s wrong with significance tests? BMJ 322, 226–231. https://www.bmj.com/content/322/7280/226.1 (2001).
Palmer, N. D. et al. Association of protein tyrosine phosphatase 1B gene polymorphisms with measures of glucose homeostasis in Hispanic Americans: The Insulin Resistance Atherosclerosis Study (IRAS) family study. Diabetes 53, 3013–3019 (2004).
Spencer-Jones, N. J. et al. Protein tyrosine phosphatase-1B gene PTPN1: selection of tagging single nucleotide polymorphisms and association with body fat, insulin sensitivity, and the metabolic syndrome in a normal female population. Diabetes 54, 3296–3304 (2005).
Cheyssac, C. et al. Analysis of common PTPN1 gene variants in type 2 diabetes, obesity and associated phenotypes in the French population. BMC Med. Genet. 7, 1–10 (2006).
Bento, J. L. et al. Association of protein tyrosine phosphatase 1B gene polymorphisms with type 2 diabetes. Diabetes 53, 3007–3012 (2004).
Bauer, F. et al. PTPN1 polymorphisms are associated with total and low-density lipoprotein cholesterol. Eur. J. Prev. Cardiol. 17, 28–34 (2010).
Florez, J. C. et al. Association testing of the protein tyrosine phosphatase 1B gene (PTPN1) with type 2 diabetes in 7,883 people. Diabetes 54, 1884–1891 (2005).
Bauer, F. et al. No association of PTPN1 polymorphisms with macronutrient intake and measures of adiposity. Obesity 16, 2767–2771 (2008).
Meshkani, R. et al. Polymorphisms within the protein tyrosine phosphatase IB (PTPN1) gene promoter: functional characterization and association with type 2 diabetes and related metabolic traits. Clin. Chem. 53, 1585–1592 (2007).
Traurig, M. et al. Protein tyrosine phosphatase 1B is not a major susceptibility gene for type 2 diabetes mellitus or obesity among Pima Indians. Diabetologia 50, 985–989 (2007).
EMBL-EBI. GWAS Catalogue: PTPN1. https://www.ebi.ac.uk/gwas/genes/PTPN1 (2022).
The International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).
Geraldes, P. Protein phosphatases and podocyte function. Curr. Opin. Nephrol. Hypertens. 27, 49–55 (2018).
Delibegovic, M. et al. Improved glucose homeostasis in mice with muscle-specific deletion of protein-tyrosine phosphatase 1B. Mol. Cell. Biol. 27, 7727–7734 (2007).
Ramachandran, C. & Kennedy, B. P. Protein tyrosine phosphatase 1B: a novel target for type 2 diabetes and obesity. Curr. Top. Med. Chem. 3, 749–757 (2003).
White, C. L. et al. HF diets increase hypothalamic PTP1B and induce leptin resistance through both leptin-dependent and -independent mechanisms. Am. J. Physiol. Endocrinol. Metab. 296, E291–E299 (2009).
Ahima, R. S. & Flier, J. S. Leptin. Annu. Rev. Physiol. 62, 413–437 (2000).
Bence, K. K. et al. Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat. Med. 12, 917–924 (2006).
Banno, R. et al. PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice. J. Clin. Invest. 120, 720–734 (2010).
Bruder-Nascimento, T. et al. Ptp1b deletion in pro-opiomelanocortin neurons increases energy expenditure and impairs endothelial function via TNF-α dependent mechanisms. Clin. Sci. 130, 881–893 (2016).
Bruder-Nascimento, T. et al. Deletion of protein tyrosine phosphatase 1b in proopiomelanocortin neurons reduces neurogenic control of blood pressure and protects mice from leptin- and sympatho-mediated hypertension. Pharmacol. Res. 102, 235–244 (2015).
Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359, http://physrev.physiology.org/cgi/doi/10.1152/physrev.00015.2003 (2004).
Minokoshi, Y. et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415, 339–343 (2002).
Xue, B. et al. Neuronal Protein Tyrosine Phosphatase 1B deficiency results in Inhibition of hypothalamic AMPK and isoform-specific activation of AMPK in peripheral tissues. Mol. Cell. Biol. 29, 4563–4573 (2009).
de Jonghe, B. C. et al. Deficiency of PTP1B in POMC neurons leads to alterations in energy balance and homeostatic response to cold exposure. Am. J. Physiol. Endocrinol. Metab. 300, E1002–E1011 (2011).
Miranda, S. et al. Beneficial effects of PTP1B deficiency on brown adipocyte differentiation and protection against apoptosis induced by pro- and anti-inflammatory stimuli. Cell. Signal. 22, 645–659 (2010).
Matsuo, K. et al. Regulation of brown fat adipogenesis by protein tyrosine phosphatase 1B. PLoS One 6, e16446 (2011).
Vanevski, F. & Xu, B. Molecular and neural bases underlying roles of BDNF in the control of body weight. Front. Neurosci. 7, 1–10 (2013).
Ozek, C. et al. Protein-tyrosine phosphatase 1B (PTP1B) is a novel regulator of central brain-derived neurotrophic factor and tropomyosin receptor kinase B (TrkB) signaling. J. Biol. Chem. 289, 31682–31692 (2014).
de Moura, L. P. et al. Acute exercise decreases PTP-1B protein level and improves insulin signaling in the liver of old rats. Immun. Ageing 10, 1–9 (2013).
Ropelle, E. R. et al. Reversal of diet-induced insulin resistance with a single bout of exercise in the rat: the role of PTP1B and IRS-1 serine phosphorylation. J. Physiol. 577, 997–1007 (2006).
Guerra, B. et al. Leptin signaling in skeletal muscle after bed rest in healthy humans. Eur. J. Appl. Physiol. 114, 345–357 (2014).
Sun, C. et al. SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell Metab. 6, 307–319 (2007).
Pauli, J. R. et al. Acute exercise reverses aged-induced impairments in insulin signaling in rodent skeletal muscle. Mech. Ageing Dev. 131, 323–329 (2010).
Dinoff, A., Herrmann, N., Swardfager, W. & Lanctôt, K. L. The effect of acute exercise on blood concentrations of brain-derived neurotrophic factor (BDNF) in healthy adults: a meta-analysis. Eur. J. Neurosci. 46, 1635–1646 (2017).
Valgas da Silva, C. P., Hernández-Saavedra, D., White, J. D. & Stanford, K. I. Cold and exercise: therapeutic tools to activate brown adipose tissue and combat obesity. Biology 8, 1–29 (2019).
GTEx Consortium. GTEx v8 eQTLs: rs10485614 PTPN1. https://www.gtexportal.org/home/snp/rs10485614 (2021).
GTEx Consortium. GTEx v8 eQTLs: rs2143511 PTPN1. https://www.gtexportal.org/home/snp/rs2143511 (2021).
Acknowledgements
We wish to thank Rosa Maria Torres, Petra Pickert, and Anke Berchtold for their contribution to laboratory work.
Funding
The HELENA Study was supported by contract FOOD-CT-2005-007034 from the European Community Sixth RTD Framework Programme. The present study was also supported by a Marie S. Curie Global Fellowship within the European Union research and innovation framework programme (2014–2020; ClimAHealth; https://doi.org/10.3030/101030971), by a grant from the Spanish Ministry of Science and Innovation (AGL2007-29784-E), by Redes Temáticas de Investigación Cooperativa RETIC grant (Red SAMID RD16/0022), by the University of Granada Plan Propio de Investigación (Excellence actions: Unit of Excellence on Exercise and Health [UCEES]), by the Junta de Andalucía, Consejería de Economía, Conocimiento, Empresas y Universidad (refs. P18–624 RT-4455, SOMM17/6107/UGR), and by grants from the Public University of Navarra, “Ayudas a Grupos de Investigación (2019)”. The content of this article reflects only the authors’ views, and the European Community is not liable for any use that may be made of the information contained therein.
Author information
Authors and Affiliations
Contributions
I.L., M.G.-G., M.S.-C., L.A.M., A.G.Z., K.W., A.M., D.E., D.F.S.-T. and J.R.R. designed the study. D.F.S.-T. performed all analyses. D.F.S.-T. and J.R.R. wrote the initial draft and all co-authors significantly contributed to the final version.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Consent to participate
As indicated in the Methods section, adolescents and corresponding parents/guardians were fully informed about aims and methods of the study and signed an informed written consent.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Salazar-Tortosa, D.F., Labayen, I., González-Gross, M. et al. Association between PTPN1 polymorphisms and obesity-related phenotypes in European adolescents: influence of physical activity. Pediatr Res 93, 2036–2044 (2023). https://doi.org/10.1038/s41390-022-02377-1
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41390-022-02377-1


