Sílvia Xargay-Torrent1,2, Berta Mas-Parés3, Gemma Carreras-Badosa1, Esther Lizárraga-Mollinedo1, Joan Tibau4, Josep Reixach5, Estíbaliz Platero-Gutierrez3, Anna Prats-Puig6, Francis De Zegher7, Lourdes Ibáñez2,8, Judit Bassols9, Abel López-Bermejo10,11,12. 1. Pediatric Endocrinology, [Girona Biomedical Research Institute] IDIBGI, Salt, Spain. 2. Endocrinology, Fundació Sant Joan de Déu, University of Barcelona, Esplugues de Llobregat, Spain. 3. Materno-Fetal Metabolism Research Group, [Girona Biomedical Research Institute] IDIBGI, Salt, Spain. 4. Benestar Animal, Institut de Recerca i Tecnologia Agroalimentàries (IRTA), Monells, Spain. 5. Selecció Batallé, Riudarenes, Spain. 6. Department of Physical Therapy, EUSES University of Girona, Girona, Spain. 7. Department of Development & Regeneration, University of Leuven, Leuven, Belgium. 8. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain. 9. Materno-Fetal Metabolism Research Group, [Girona Biomedical Research Institute] IDIBGI, Salt, Spain. jbassols@idibgi.org. 10. Pediatric Endocrinology, [Girona Biomedical Research Institute] IDIBGI, Salt, Spain. alopezbermejo@idibgi.org. 11. Pediatrics, Hospital Dr. Josep Trueta, Girona, Spain. alopezbermejo@idibgi.org. 12. Department of Medical Sciences, University of Girona, Girona, Spain. alopezbermejo@idibgi.org.
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.
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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