Altered promoter methylation of PDK4, IL1 B, IL6, and TNF after Roux-en Y gastric bypass.
BACKGROUND
Early benefits of Roux-en Y gastric bypass (RYGB) are partly mediated by the caloric restriction that patients undergo before and acutely after the procedure. Altered DNA methylation occurs in metabolic diseases including obesity, as well as in skeletal, muscle eight months after RYGB. The objective of this study was to test whether promoter methylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1 A), pyruvate dehydrogenase kinase isozyme-4 (PDK4), transcription factor A (TFAM), interleukin-1 beta (IL1 B), interleukin-6 (IL6) and tumor necrosis factor-α (TNF) is altered in blood after a very low calorie diet (VLCD) or RYGB.


METHODS
Obese nondiabetic patients (n = 18, body mass index [BMI] 42.3 ± 4.9 kg/m(2)) underwent a 14-day VLCD followed by RYGB. Nonobese patients (n = 6, BMI 25.7 ± 2.1 kg/m(2)) undergoing elective cholecystectomy served as controls. DNA methylation of selected promoter regions was measured in whole blood before and after VLCD. A subgroup of seven patients was studied 1-2 days and 12 ± 3 months after RYGB. Promoter methylation was measured using methylated DNA capture and quantitative real-time polymerase chain reaction (PCR).


RESULTS
VLCD decreased promoter methylation of PPARGC1 A. Methylation of PPARGC1 A, TFAM, IL1 B, IL6, and TNF promoters was changed two days after RYGB. Similar changes were also seen on day one after cholecystectomy. Moreover, methylation increased in PDK4, IL1 B, IL6, and TNF promoters 12 months after RYGB.


CONCLUSIONS
RYGB induced more profound epigenetic changes than VLCD in promoters of the tested genes in whole blood. Changes in DNA methylation may contribute to the improved overall metabolic health after RYGB.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Henriette
H
Kirchner
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Carolina
C
Nylen
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Samantha
S
Laber
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Romain
R
Barrès
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Jie
J
Yan
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Anna
A
Krook
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Juleen R
JR
Zierath
Division of Surgery, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Sweden. Electronic address: Erik.Naslund@ki.se.
Erik
E
Näslund
D000328:Adult; D031204:Caloric Restriction; D016022:Case-Control Studies; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015390:Gastric Bypass; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009767:Obesity, Morbid / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D024101:Mitochondrial Proteins; C000631432:PDK4 protein, human; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C499631:TFAM protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases
Blood; DNA methylation; Gastric bypass; Very low calorie diet