TY - JOUR

T1 - Fasting unmasks differential fat and muscle transcriptional regulation of metabolic gene sets in low versus normal birth weight men

AU - Gillberg, Linn

AU - Rönn, Tina

AU - Jørgensen, Sine Wanda

AU - Perfilyev, Alexander

AU - Hjort, Line

AU - Nilsson, Emma

AU - Brøns, Charlotte

AU - Vaag, Allan

AU - Ling, Charlotte

PY - 2019

Y1 - 2019

N2 - BACKGROUND: Individuals born with low birth weight (LBW) have an increased risk of metabolic diseases when exposed to diets rich in calories and fat but may respond to fasting in a metabolically preferential manner. We hypothesized that impaired foetal growth is associated with differential regulation of gene expression and epigenetics in metabolic tissues in response to fasting in young adulthood.METHODS: Genome-wide expression and DNA methylation were analysed in subcutaneous adipose tissue (SAT) and skeletal muscle from LBW and normal birth weight (NBW) men after 36 h fasting and after an isocaloric control study using microarrays.FINDINGS: Transcriptome analyses revealed that expression of genes involved in oxidative phosphorylation (OXPHOS) and other key metabolic pathways were lower in SAT from LBW vs NBW men after the control study, but paradoxically higher in LBW vs NBW men after 36 h fasting. Thus, fasting was associated with downregulated OXPHOS and metabolic gene sets in NBW men only. Likewise, in skeletal muscle only NBW men downregulated OXPHOS genes with fasting. Few epigenetic changes were observed in SAT and muscle between the groups.INTERPRETATION: Our results provide insights into the molecular mechanisms in muscle and adipose tissue governing a differential metabolic response in subjects with impaired foetal growth when exposed to fasting in adulthood. The results support the concept of developmental programming of metabolic diseases including type 2 diabetes. FUND: The Swedish Research Council, the Danish Council for Strategic Research, the Novo Nordisk foundation, the Swedish Foundation for Strategic Research, The European Foundation for the Study of Diabetes, The EU 6th Framework EXGENESIS grant and Rigshospitalet.

AB - BACKGROUND: Individuals born with low birth weight (LBW) have an increased risk of metabolic diseases when exposed to diets rich in calories and fat but may respond to fasting in a metabolically preferential manner. We hypothesized that impaired foetal growth is associated with differential regulation of gene expression and epigenetics in metabolic tissues in response to fasting in young adulthood.METHODS: Genome-wide expression and DNA methylation were analysed in subcutaneous adipose tissue (SAT) and skeletal muscle from LBW and normal birth weight (NBW) men after 36 h fasting and after an isocaloric control study using microarrays.FINDINGS: Transcriptome analyses revealed that expression of genes involved in oxidative phosphorylation (OXPHOS) and other key metabolic pathways were lower in SAT from LBW vs NBW men after the control study, but paradoxically higher in LBW vs NBW men after 36 h fasting. Thus, fasting was associated with downregulated OXPHOS and metabolic gene sets in NBW men only. Likewise, in skeletal muscle only NBW men downregulated OXPHOS genes with fasting. Few epigenetic changes were observed in SAT and muscle between the groups.INTERPRETATION: Our results provide insights into the molecular mechanisms in muscle and adipose tissue governing a differential metabolic response in subjects with impaired foetal growth when exposed to fasting in adulthood. The results support the concept of developmental programming of metabolic diseases including type 2 diabetes. FUND: The Swedish Research Council, the Danish Council for Strategic Research, the Novo Nordisk foundation, the Swedish Foundation for Strategic Research, The European Foundation for the Study of Diabetes, The EU 6th Framework EXGENESIS grant and Rigshospitalet.

KW - Adipose Tissue/metabolism

KW - Adult

KW - Binding Sites

KW - Biomarkers

KW - Birth Weight

KW - DNA Methylation

KW - Energy Metabolism/genetics

KW - Fasting

KW - Gene Expression Profiling

KW - Gene Expression Regulation

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Models, Biological

KW - Muscle, Skeletal/metabolism

KW - Nucleotide Motifs

KW - Protein Binding

KW - Sex Factors

KW - Transcription Factors

KW - Transcription, Genetic

KW - Young Adult

U2 - 10.1016/j.ebiom.2019.08.017

DO - 10.1016/j.ebiom.2019.08.017

M3 - Journal article

C2 - 31439477

VL - 47

SP - 341

EP - 351

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

ER -