AccScience Publishing / GPD / Online First / DOI: 10.36922/GPD025070011
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PERSPECTIVE ARTICLE

Genetic pleiotropy between birth weight and adipose tissue regulation in determining the risk of childhood obesity

Gianvincenzo Zuccotti1,2 ,  Valeria Calcaterra2,3*
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1 Department of Biomedical and Clinical Science, Faculty of Medicine and Surgery, University of Milano, Milano, Italy
2 Department of Pediatric, Buzzi Children’s Hospital, Milano, Italy
3 Department of Internal Medicine and Therapeutics, Faculty of Medicine and Surgery, University of Pavia, Pavia, Italy
GPD, 025070011 https://doi.org/10.36922/GPD025070011
Received: 10 February 2025 | Revised: 23 April 2025 | Accepted: 6 May 2025 | Published online: 28 May 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Although obesity primarily stems from an imbalance between energy intake and expenditure, recent research over the past years has highlighted the role of various other contributing factors, including fetal growth and birth weight. Although the link between birth weight and adult body mass index remains unclear, some genomic alterations are thought to influence both fetal growth and post-natal body mass. Specifically, potential involvement of gene variants and epigenetic modifications associated with both birth weight and adipose tissue regulation could be proposed, suggesting that a genetic pleiotropy may modify growth efficiency during the fetal stage, contributing to the development of diseases later in life and serving as a link between birth weight and obesity. Given the dual role of the insulin-like growth factor 1/insulin axis, insulin-like growth factor 2, and peroxisome proliferator-activated receptors in fetal growth and adipogenesis, the potential involvement of a pleiotropic genetic effect in the relationship between birth weight and obesity warrants further consideration. Understanding the genetic interplay between birth weight and adipose tissue regulation offers valuable insights into the developmental origins of childhood obesity. These findings highlight the critical importance of prioritizing both maternal and fetal health during pregnancy. Future research should aim to integrate genetic, epigenetic, and environmental factors to develop early, targeted interventions for high-risk populations, ultimately helping to alleviate the global obesity burden.

Graphical abstract
Keywords
Birth weight
Fetal growth
Adipose tissue
Adipogenesis
Childhood obesity
Funding
None.
Conflict of interest
The authors declare they have no competing interests.
References
  1. Koliaki C, Dalamaga M, Liatis S. Update on the obesity epidemic: After the sudden rise, is the upward trajectory beginning to flatten? Curr Obes Rep. 2023;12(4):514-527. doi: 10.1007/s13679-023-00533-0

 

  1. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in underweight and obesity from 1990 to 2022: A pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults. Lancet. 2024;403(10431):1027-1050. doi: 10.1016/S0140-6736(23)02750-2

 

  1. GBD 2021 US Obesity Forecasting Collaborators. National-level and state-level prevalence of overweight and obesity among children, adolescents, and adults in the USA, 1990-2021, and forecasts up to 2050. Lancet. 2024;404(10469):2278-2298. doi: 10.1016/S0140-6736(24)01548-4

 

  1. Zhang X, Liu J, Ni Y, et al. Global prevalence of overweight and obesity in children and adolescents: A systematic review and meta-analysis. JAMA Pediatr. 2024;178(8):800-813. doi: 10.1001/jamapediatrics.2024.1576

 

  1. Schwartz MW, Seeley RJ, Zeltser LM, et al. Obesity pathogenesis: An endocrine society scientific statement. Endocr Rev. 2017;38(4):267-296. doi: 10.1210/er.2017-00111

 

  1. Lister NB, Baur LA, Felix JF, et al. Child and adolescent obesity. Nat Rev Dis Primers. 2023;9(1):24. doi: 10.1038/s41572-023-00435-4

 

  1. Gantenbein KV, Kanaka-Gantenbein C. Highlighting the trajectory from intrauterine growth restriction to future obesity. Front Endocrinol (Lausanne). 2022;13:1041718. doi: 10.3389/fendo.2022.1041718

 

  1. Magkos F, Sørensen TIA, Raubenheimer D, et al. On the pathogenesis of obesity: Causal models and missing pieces of the puzzle. Nat Metab. 2024;6(10):1856-1865. doi: 10.1038/s42255-024-01106-8

 

  1. Stinson SE, Kromann Reim P, Lund MAV, et al. The interplay between birth weight and obesity in determining childhood and adolescent cardiometabolic risk. EBioMedicine. 2024;105:105205. doi: 10.1016/j.ebiom.2024.105205

 

  1. Hansen AL, Thomsen RW, Brøns C, et al. Birthweight is associated with clinical characteristics in people with recently diagnosed type 2 diabetes. Diabetologia. 2023;66(9):1680-1692. doi: 10.1007/s00125-023-05936-1

 

  1. Zhao Y, Wang SF, Mu M, Sheng J. Birth weight and overweight/obesity in adults: A meta-analysis. Eur J Pediatr. 2012;171(12):1737-1746. doi: 10.1007/s00431-012-1701-0

 

  1. Qiao Y, Ma J, Wang Y, Li W, et al. Birth weight and childhood obesity: A 12-country study. Int J Obes Suppl. 2015;5(Suppl 2):S74-S79. doi: 10.1038/ijosup.2015.23

 

  1. Talge NM, Holzman C, Senagore PK, et al. Biological indicators of the in-utero environment and their association with birth weight for gestational age. J Dev Orig Health Dis. 2011;2(5):280-290. doi: 10.1017/S2040174411000298

 

  1. Belbasis L, Savvidou MD, Kanu C, Evangelou E, Tzoulaki I. Birth weight in relation to health and disease in later life: An umbrella review of systematic reviews and meta-analyses. BMC Med. 2016;14(1):147. doi: 10.1186/s12916-016-0692-5

 

  1. Hoffman DJ, Powell TL, Barrett ES, Hardy DB. Developmental origins of metabolic diseases. Physiol Rev. 2021;101(3):739-795. doi: 10.1152/physrev.00002.2020

 

  1. Kemp MW, Kallapur SG, Jobe AH, Newnham JP. Obesity and the developmental origins of health and disease. J Paediatr Child Health. 2012;48(2):86-90. doi: 10.1111/j.1440-1754.2010.01940.x

 

  1. Oestreich AK, Moley KH. Developmental and transmittable origins of obesity-associated health disorders. Trends Genet. 2017;33(6):399-407. doi: 10.1016/j.tig.2017.03.008

 

  1. Kaku K, Osada H, Seki K, Sekiya S. Insulin-like growth factor 2 (IGF2) and IGF2 receptor gene variants are associated with fetal growth. Acta Paediatr. 2007;96(3):363-367. doi: 10.1111/j.1651-2227.2006.00120.x

 

  1. Thompson WD, Beaumont RN, Kuang A, et al. Fetal alleles predisposing to metabolically favorable adiposity are associated with higher birth weight. Hum Mol Genet. 2022;31(11):1762-1775. doi: 10.1093/hmg/ddab356

 

  1. Osada H. Association between polymorphisms in genes related to common adult diseases and fetal growth. Clin Med Pediatr. 2009;3:11-18. doi: 10.4137/cmped.s2154

 

  1. Baxter RC. Signaling pathways of the insulin-like growth factor binding proteins. Endocr Rev. 202344(5):753-778. doi: 10.1210/endrev/bnad008

 

  1. Zhou J, Shi Y, Dong M. Influence of growth hormone-insulin-like growth factor I axis on normal pregnancy. Chin Med J (Engl). 2001;114(9):988-990.

 

  1. Abuzzahab MJ, Schneider A, Goddard A, et al. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med. 2003;349(23):2211-2222. doi: 10.1056/NEJMoa010107

 

  1. LeRoith D, Yakar S. Mechanisms of disease: Metabolic effects of growth hormone and insulin-like growth factor 1. Nat Clin Pract Endocrinol Metab. 2007;3(3):302-310. doi: 10.1038/ncpendmet0427

 

  1. Murray PG, Clayton PE. Endocrine control of growth. Am J Med Genet C Semin Med Genet. 2013;163C(2):76-85. doi: 10.1002/ajmg.c.31357

 

  1. Kajantie E, Dunkel L, Rutanen EM, et al. IGF-I, IGF binding protein (IGFBP)-3, phosphoisoforms of IGFBP-1, and postnatal growth in very low birth weight infants. J Clin Endocrinol Metab. 2002;87(5):2171-2179. doi: 10.1210/jcem.87.5.8457

 

  1. Chiesa C, Osborn JF, Haass C, et al. Ghrelin, leptin, IGF-1, IGFBP-3, and insulin concentrations at birth: Is there a relationship with fetal growth and neonatal anthropometry? Clin Chem. 2008;4(3):550-558. doi: 10.1373/clinchem.2007.095299

 

  1. Zhang S, Zhai G, Wang J, Shi W, Zhang R, Chen C. IGF‐II expression and methylation in small for gestational age infants. J Pediatr Endocrinol Metab. 2015;28:613-618. doi: 10.1515/jpem-2014-0269

 

  1. Napoli F, Di Iorgi N, Bagnasco F, et al. Growth factors and metabolic markers in cord blood: Relationship to birth weight and length. J Biol Regul Homeost Agents. 2014;28:237-249.

 

  1. Ashton IK, Zapf J, Einschenk I, MacKenzie IZ. Insulin‐like growth factors (IGF) 1 and 2 in human foetal plasma and relationship to gestational age and foetal size during midpregnancy. Acta Endocrinol (Copenh). 1985;110:558-563. doi: 10.1530/acta.0.1100558

 

  1. Lassarre C, Hardouin S, Daffos F, et al. Serum insulin‐like growth factors and insulin‐like growth factor binding proteins in the human fetus. Relationships with growth in normal subjects and in subjects with intrauterine growth retardation. Pediatr Res. 1991;29:219-225.

 

  1. DiPrisco B, Kumar A, Kalra B, et al. Placental proteases PAPP-A and PAPP-A2, the binding proteins they cleave (IGFBP-4 and -5), and IGF-I and IGF-II: Levels in umbilical cord blood and associations with birth weight and length. Metabolism. 2019;100:153959. doi: 10.1016/j.metabol.2019.153959

 

  1. Blüher S, Kratzsch J, Kiess W. Insulin-like growth factor I, growth hormone and insulin in white adipose tissue. Best Pract Res Clin Endocrinol Metab. 2005;19:577-587. doi: 10.1016/j.beem.2005.07.011

 

  1. Poulos SP, Hausman DB, Hausman GJ. The development and endocrine functions of adipose tissue. Mol Cell Endocrinol. 2010;323:20-34. doi: 10.1016/j.mce.2009.12.011

 

  1. Moreno-Mendez E, Quintero-Fabian S, Fernandez-Mejia C, Lazo-de-la-Vega-Monroy ML. Early-life programming of adipose tissue. Nutr Res Rev. 2020;33(2):244-259. doi: 10.1017/S0954422420000037

 

  1. Symonds ME, Pope M, Sharkey D, Budge H. Adipose tissue and fetal programming. Diabetologia. 2012;55(6):1597-1606. doi: 10.1007/s00125-012-2505-5

 

  1. Spalding KL, Arner E, Westermark PO, et al. Dynamics of fat cell turnover in humans. Nature. 2008;453:783-787. doi: 10.1038/nature06902

 

  1. Rigamonti A, Brennand K, Lau F, Lau F, Cowan CA. Rapid cellular turnover in adipose tissue. PLoS One. 2011;6:e17637. doi: 10.1371/journal.pone.0017637

 

  1. Ambele MA, Dhanraj P, Giles R, Pepper MS. Adipogenesis: A complex interplay of multiple molecular determinants and pathways. Int J Mol Sci. 2020;21(12):4283. doi: 10.3390/ijms21124283

 

  1. Ali AT, Hochfeld WE, Myburgh R, Pepper MS. Adipocyte and adipogenesis. Eur J Cell Biol. 2013;2(6-7):229-236. doi: 10.1016/j.ejcb.2013.06.001

 

  1. White U. Adipose tissue expansion in obesity, health, and disease. Front Cell Dev Biol. 2023;11:1188844. doi: 10.3389/fcell.2023.1188844

 

  1. Arner P, Bernard S, Salehpour M, et al. Dynamics of human adipose lipid turnover in health and metabolic disease. Nature. 2011;478(7367):110-113. doi: 10.1038/nature10426

 

  1. Boucher J, Softic S, El Ouaamari A, et al. Differential roles of insulin and IGF-1 receptors in adipose tissue development and function. Diabetes. 2016;65(8):2201-2213. doi: 10.2337/db16-0212

 

  1. Lee KY, Russell SJ, Ussar S, et al. Lessons on conditional gene targeting in mouse adipose tissue. Diabetes. 2013;62(3):864-874. doi: 10.2337/db12-1089

 

  1. Kentistou KA, Lim BEM, Kaisinger LR, et al. Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling. Nat Commun. 2025;16(1):648. doi: 10.1038/s41467-024-55761-2

 

  1. Kempf E, Landgraf K, Vogel T, et al. Associations of GHR, IGF-1 and IGFBP-3expression in adipose tissue cells with obesity-related alterations in corresponding circulating levels and adipose tissue function in children. Adipocyte. 2002;11(1):630-642. doi: 10.1080/21623945.2022.2148886

 

  1. Dunger DB, Ong KK, Huxtable SJ, et al. Association of the INS VNTR with size at birth. ALSPAC study team. Avon longitudinal study of pregnancy and childhood. Nat Genet. 1998;19(1):98-100. doi: 10.1038/ng0598-98

 

  1. Le Stunff C, Fallin D, Bougnères P. Paternal transmission of the very common class I INS VNTR alleles predisposes to childhood obesity. Nat Genet. 2001;29(1):96-99. doi: 10.1038/ng707

 

  1. Santoro N, Cirillo G, Amato A, et al. Insulin gene variable number of tandem repeats (INS VNTR) genotype and metabolic syndrome in childhood obesity. J Clin Endocrinol Metab. 2006;91(11):4641-4644. doi: 10.1210/jc.2005-2705

 

  1. Kadakia R, Josefson J. The relationship of insulin-like growth factor 2 to fetal growth and adiposity. Horm Res Paediatr. 2016;85(2):75-82. doi: 10.1159/000443500

 

  1. Alfares MN, Perks CM, Hamilton-Shield JP, et al. Insulin-like growth factor-II in adipocyte regulation: Depot-specific actions suggest a potential role limiting excess visceral adiposity. Am J Physiol Endocrinol Metab. 2018;315(6):E1098-E1107. doi: 10.1152/ajpendo.00409.2017

 

  1. Zhang K, Wang F, Huang J, et al. Insulin-like growth factor 2 promotes the adipogenesis of hemangioma-derived stem cells. Exp Ther Med. 2019;17(3):1663-1669. doi: 10.3892/etm.2018.7132

 

  1. St-Pierre J, Hivert MF, Perron P, et al. IGF2 DNA methylation is a modulator of newborn’s fetal growth and development. Epigenetics. 2012;7(10):1125-1132. doi: 10.4161/epi.21855

 

  1. Faienza MF, Santoro N, Lauciello R, et al. IGF2 gene variants and risk of hypertension in obese children and adolescents. Pediatr Res. 2010;67(4):340-344. doi: 10.1203/PDR.0b013e3181d22757

 

  1. Lazou A, Barlaka E. Peroxisome proliferator-activated receptor (PPAR). In: Choi S, editor. Encyclopedia of Signaling Molecules. New York: Springer; 2016. doi: 10.1007/978-1-4614-6438-9_101829-1

 

  1. Wieser F, Waite L, Depoix C, Taylor RN. PPAR action in human placental development and pregnancy and its complications. PPAR Res. 2008;2008:527048. doi: 10.1155/2008/527048

 

  1. Guo J, Wu J, He Q, Zhang M, Li H, Liu Y. The potential role of PPARs in the fetal origins of adult disease. Cells. 2022;11(21):3474. doi: 10.3390/cells11213474

 

  1. O’Callaghan JL, Clifton VL, Prentis P, Ewing A, Miller YD, Pelzer ES. Modulation of placental gene expression in small-for-gestational-age infants. Genes (Basel). 2020;11(1):80. doi: 10.3390/genes11010080

 

  1. Díaz M, Bassols J, López-Bermejo A, Gómez-Roig MD, De Zegher F, Ibáñez L. Placental expression of peroxisome proliferator-activated receptor γ (PPARγ): Relation to placental and fetal growth. J Clin Endocrinol Metab. 2012;97(8):E1468-E1472. doi: 10.1210/jc.2012-1064

 

  1. Vidal-Puig AJ, Considine RV, Jimenez-Liñan M, et al. Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids. J Clin Invest. 1997;99(10):2416-2422. doi: 10.1172/JCI119424

 

  1. Stienstra R, Duval C, Müller M, et al. PPARs, obesity, and inflammation. PPAR Res. 2007;2007:95974. doi: 10.1155/2007/95974

 

  1. Choi SH, Chung SS, Park KS. Re-highlighting the action of PPARγ in treating metabolic diseases. F1000Res. 2018;7:F1000 Faculty Rev:1127. doi: 10.12688/f1000research.14136.1

 

  1. Li X, Ren Y, Chang K, Wu W, Griffiths HR, Lu S, Gao D. Adipose tissue macrophages as potential targets for obesity and metabolic diseases. Front Immunol. 2023;4:1153915. doi: 10.3389/fimmu.2023.1153915

 

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