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Metabolic programming in the offspring after gestational overfeeding in the mother: toward neonatal rescuing with metformin in a swine model

International Journal of Obesity volume 46, pages 1018–1026 (2022)Cite this article

Subjects

Abstract

Objectives

Maternal overfeeding during gestation may lead to adverse metabolic programming in the offspring mediated by epigenetic alterations. Potential reversal, in early life, of these alterations may help in the prevention of future cardio-metabolic conditions. In this context, our aims were: (1) to study the effects of maternal overfeeding on the metabolic and epigenetic programming of offspring’s adipose tissue; and (2) to test the potential of postnatal metformin treatment to reverse these changes.

Methods

We used a swine animal model where commercial production sows were either overfed or kept under standard diet during gestation, and piglets at birth were randomly assigned to metformin (n = 16 per group) or vehicle treatment during lactation (n = 16 per group).

Results

Piglets born to overfed sows showed a worse metabolic profile (higher weight, weight gain from birth and abdominal circumference; all p < 0.05) together with altered serological markers (increased HOMA-IR, fructosamine, total cholesterol, C-Reactive Protein and lower HMW adiponectin; all p < 0.05). The visceral adipose tissue also showed altered morphology (increased adipocyte area, perimeter and diameter; all p < 0.05), as well as changes in gene expression (higher CCL2 and INSR, lower DLK1; all p < 0.05), and in DNA methylation (96 hypermethylated and 99 hypomethylated CpG sites; FDR < 0.05). Metformin treatment significantly ameliorated the abnormal metabolic profile, decreasing piglets’ weight, weight gain from birth, abdominal circumference and fructosamine (all p < 0.05) and reduced adipocyte area, perimeter, and diameter in visceral adipose tissue (all p < 0.05). In addition, metformin treatment potentiated several associations between gene expression in visceral adipose tissue and the altered metabolic markers.

Conclusions

Maternal overfeeding during gestation leads to metabolic abnormalities in the offspring, including adipose tissue alterations. Early metformin treatment mitigates these effects and could help rescue the offspring’s metabolic health.

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Fig. 1: Histology of the piglet’s visceral adipose tissue.
Fig. 2: Scatter plots showing the associations between GDI2 and CDK2AP1 gene expression and metabolic parameters at weaning in metformin-treated piglets.

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Acknowledgements

SX-T holds a Sara Borrell contract from Carlos III National Institute of Health (ISCIII; CD15–00162). BM-P holds a contract from Generalitat de Catalunya (SLT002/16/00065). GC-B holds a Sara Borrell contract from Carlos III National Institute of Health (ISCIII; CD19-00172). JB is Miguel Servet investigator (ISCIII; CPII17/00013). LI is a Clinical Investigator of CIBERDEM (Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders), from ISCIII. AL-B is an I3 investigator (Spanish Ministry of Economy and Competitiveness). This study was supported by grants from the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III (ISCIII), Madrid, Spain (PI17/00557 to JB, and PI16/01335 and PI19/00451to AL-B), projects co-funded by FEDER (Fondo Europeo de Desarrollo Regional).

Author information

Author notes

  1. These authors contributed equally: Sílvia Xargay-Torrent, Berta Mas-Parés

  2. These authors jointly supervised this work: Judit Bassols, López-bermejo

  3. Deceased: Esther Lizárraga-Mollinedo.

Authors and Affiliations

  1. Pediatric Endocrinology, [Girona Biomedical Research Institute] IDIBGI, Salt, Spain

    Sílvia Xargay-Torrent, Gemma Carreras-Badosa, Esther Lizárraga-Mollinedo & Abel López-Bermejo

  2. Endocrinology, Fundació Sant Joan de Déu, University of Barcelona, Esplugues de Llobregat, Spain

    Sílvia Xargay-Torrent & Lourdes Ibáñez

  3. Materno-Fetal Metabolism Research Group, [Girona Biomedical Research Institute] IDIBGI, Salt, Spain

    Berta Mas-Parés, Estíbaliz Platero-Gutierrez & Judit Bassols

  4. Benestar Animal, Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Monells, Spain

    Joan Tibau

  5. Selecció Batallé, Riudarenes, Spain

    Josep Reixach

  6. Department of Physical Therapy, EUSES University of Girona, Girona, Spain

    Anna Prats-Puig

  7. Department of Development & Regeneration, University of Leuven, Leuven, Belgium

    Francis De Zegher

  8. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain

    Lourdes Ibáñez

  9. Pediatrics, Hospital Dr. Josep Trueta, Girona, Spain

    Abel López-Bermejo

  10. Department of Medical Sciences, University of Girona, Girona, Spain

    Abel López-Bermejo

Authors
  1. Sílvia Xargay-Torrent
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  2. Berta Mas-Parés
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Contributions

SX-T designed research study, conducted experiments, analyzed the data and wrote the first draft of the manuscript. BM-P conducted experiments, analyzed the data and wrote the first draft of the manuscript. GC-B, EL-M, JT, JR, EP-G, AP-P conducted experiments, acquired data and reviewed the manuscript, FDZ, LI reviewed the manuscript. JB, AL-B designed research study and reviewed the manuscript.

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Correspondence to Judit Bassols or Abel López-Bermejo.

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Xargay-Torrent, S., Mas-Parés, B., Carreras-Badosa, G. et al. Metabolic programming in the offspring after gestational overfeeding in the mother: toward neonatal rescuing with metformin in a swine model. Int J Obes 46, 1018–1026 (2022). https://doi.org/10.1038/s41366-022-01076-5

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