CONTEXT: Low birth weight (LBW) and unhealthy diets are risk factors of metabolic disease including type 2 diabetes (T2D). Genetic, nongenetic, and epigenetic data propose a role of the key metabolic regulator peroxisome proliferator-activated receptor gamma, coactivator 1alpha (PPARGC1A) in the development of T2D. OBJECTIVE: Our objective was to investigate gene expression and DNA methylation of PPARGC1A and coregulated oxidative phosphorylation (OXPHOS) genes in LBW and normal birth weight (NBW) subjects during control and high-fat diets. DESIGN, SUBJECTS, AND MAIN OUTCOME MEASURES: Twenty young healthy men with LBW and 26 matched NBW controls were studied after 5 d high-fat overfeeding (+50% calories) and after a control diet in a randomized manner. Hyperinsulinemic-euglycemic clamps were performed and skeletal muscle biopsies excised. DNA methylation and gene expression were measured using bisulfite sequencing and quantitative real-time PCR, respectively. RESULTS: When challenged with high-fat overfeeding, LBW subjects developed peripheral insulin resistance and reduced PPARGC1A and OXPHOS (P < 0.05) gene expression. PPARGC1A methylation was significantly higher in LBW subjects (P = 0.0002) during the control diet. However, PPARGC1A methylation increased in only NBW subjects after overfeeding in a reversible manner. DNA methylation of PPARGC1A did not correlate with mRNA expression. CONCLUSIONS:LBW subjects developed peripheral insulin resistance and decreased gene expression of PPARGC1A and OXPHOS genes when challenged with fat overfeeding. The extent to which our finding of a constitutively increased DNA methylation in the PPARGC1A promoter in LBW subjects may contribute needs to be determined. We provide the first experimental support in humans that DNA methylation induced by overfeeding is reversible.
RCT Entities:
CONTEXT: Low birth weight (LBW) and unhealthy diets are risk factors of metabolic disease including type 2 diabetes (T2D). Genetic, nongenetic, and epigenetic data propose a role of the key metabolic regulator peroxisome proliferator-activated receptor gamma, coactivator 1alpha (PPARGC1A) in the development of T2D. OBJECTIVE: Our objective was to investigate gene expression and DNA methylation of PPARGC1A and coregulated oxidative phosphorylation (OXPHOS) genes in LBW and normal birth weight (NBW) subjects during control and high-fat diets. DESIGN, SUBJECTS, AND MAIN OUTCOME MEASURES: Twenty young healthy men with LBW and 26 matched NBW controls were studied after 5 d high-fat overfeeding (+50% calories) and after a control diet in a randomized manner. Hyperinsulinemic-euglycemic clamps were performed and skeletal muscle biopsies excised. DNA methylation and gene expression were measured using bisulfite sequencing and quantitative real-time PCR, respectively. RESULTS: When challenged with high-fat overfeeding, LBW subjects developed peripheral insulin resistance and reduced PPARGC1A and OXPHOS (P < 0.05) gene expression. PPARGC1A methylation was significantly higher in LBW subjects (P = 0.0002) during the control diet. However, PPARGC1A methylation increased in only NBW subjects after overfeeding in a reversible manner. DNA methylation of PPARGC1A did not correlate with mRNA expression. CONCLUSIONS: LBW subjects developed peripheral insulin resistance and decreased gene expression of PPARGC1A and OXPHOS genes when challenged with fat overfeeding. The extent to which our finding of a constitutively increased DNA methylation in the PPARGC1A promoter in LBW subjects may contribute needs to be determined. We provide the first experimental support in humans that DNA methylation induced by overfeeding is reversible.
Authors: Linn Gillberg; Alexander Perfilyev; Charlotte Brøns; Martin Thomasen; Louise G Grunnet; Petr Volkov; Fredrik Rosqvist; David Iggman; Ingrid Dahlman; Ulf Risérus; Tina Rönn; Emma Nilsson; Allan Vaag; Charlotte Ling Journal: Diabetologia Date: 2016-01-11 Impact factor: 10.122
Authors: Guillermo A Silva-Martínez; Dalia Rodríguez-Ríos; Yolanda Alvarado-Caudillo; Alejandro Vaquero; Manel Esteller; F Javier Carmona; Sebastian Moran; Finn C Nielsen; Marie Wickström-Lindholm; Katarzyna Wrobel; Kazimierz Wrobel; Gloria Barbosa-Sabanero; Silvio Zaina; Gertrud Lund Journal: Epigenetics Date: 2016-04-18 Impact factor: 4.528
Authors: Jill M Maples; Jeffrey J Brault; Carol A Witczak; Sanghee Park; Monica J Hubal; Todd M Weber; Joseph A Houmard; Brian M Shewchuk Journal: Am J Physiol Endocrinol Metab Date: 2015-06-09 Impact factor: 4.310
Authors: Christa Broholm; Anders H Olsson; Alexander Perfilyev; Ninna S Hansen; Maren Schrölkamp; Klaudia S Strasko; Camilla Scheele; Rasmus Ribel-Madsen; Brynjulf Mortensen; Sine W Jørgensen; Charlotte Ling; Allan Vaag Journal: Diabetologia Date: 2016-09-14 Impact factor: 10.122
Authors: Stine C Jacobsen; Linn Gillberg; Jette Bork-Jensen; Rasmus Ribel-Madsen; Ester Lara; Vincenzo Calvanese; Charlotte Ling; Agustin F Fernandez; Mario F Fraga; Pernille Poulsen; Charlotte Brøns; Allan Vaag Journal: Diabetologia Date: 2014-02-26 Impact factor: 10.122
Authors: S C Jacobsen; C Brøns; J Bork-Jensen; R Ribel-Madsen; B Yang; E Lara; E Hall; V Calvanese; E Nilsson; S W Jørgensen; S Mandrup; C Ling; A F Fernandez; M F Fraga; P Poulsen; A Vaag Journal: Diabetologia Date: 2012-09-08 Impact factor: 10.122