title: Differential epigenetic and transcriptional response of the skeletal muscle carnitine palmitoyltransferase 1B (CPT1B) gene to lipid exposure with obesity.
abstract: The ability to increase fatty acid oxidation (FAO) in response to dietary lipid is impaired in the skeletal muscle of obese individuals, which is associated with a failure to coordinately upregulate genes involved with FAO. While the molecular mechanisms contributing to this metabolic inflexibility are not evident, a possible candidate is carnitine palmitoyltransferase-1B (CPT1B), which is a rate-limiting step in FAO. The present study was undertaken to determine if the differential response of skeletal muscle CPT1B gene transcription to lipid between lean and severely obese subjects is linked to epigenetic modifications (DNA methylation and histone acetylation) that impact transcriptional activation. In primary human skeletal muscle cultures the expression of CPT1B was blunted in severely obese women compared with their lean counterparts in response to lipid, which was accompanied by changes in CpG methylation, H3/H4 histone acetylation, and peroxisome proliferator-activated receptor-δ and hepatocyte nuclear factor 4α transcription factor occupancy at the CPT1B promoter. Methylation of specific CpG sites in the CPT1B promoter that correlated with CPT1B transcript level blocked the binding of the transcription factor upstream stimulatory factor, suggesting a potential causal mechanism. These findings indicate that epigenetic modifications may play important roles in the regulation of CPT1B in response to a physiologically relevant lipid mixture in human skeletal muscle, a major site of fatty acid catabolism, and that differential DNA methylation may underlie the depressed expression of CPT1B in response to lipid, contributing to the metabolic inflexibility associated with severe obesity.
authors.affiliation: Human Performance Laboratory, East Carolina University, Greenville, North Carolina; Department of Kinesiology, East Carolina University, Greenville, North Carolina; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina;
authors.forename: Jill M
authors.initials: JM
authors.lastname: Maples
authors.affiliation: Human Performance Laboratory, East Carolina University, Greenville, North Carolina; Department of Kinesiology, East Carolina University, Greenville, North Carolina; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina; Department of Biochemistry and Molecular Biology, East Carolina University, Greenville, North Carolina; Department of Physiology, East Carolina University, Greenville, North Carolina; and.
authors.forename: Jeffrey J
authors.identifier: http://orcid.org/0000-0003-3503-0528
authors.initials: JJ
authors.lastname: Brault
authors.affiliation: Human Performance Laboratory, East Carolina University, Greenville, North Carolina; Department of Kinesiology, East Carolina University, Greenville, North Carolina; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina; Department of Biochemistry and Molecular Biology, East Carolina University, Greenville, North Carolina; Department of Physiology, East Carolina University, Greenville, North Carolina; and.
authors.forename: Carol A
authors.identifier: http://orcid.org/0000-0003-4165-4740
authors.initials: CA
authors.lastname: Witczak
authors.affiliation: Human Performance Laboratory, East Carolina University, Greenville, North Carolina; Department of Kinesiology, East Carolina University, Greenville, North Carolina; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina;
authors.forename: Sanghee
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Integrative Systems Biology, Children's National Medical Center, Washington, DC.
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Hubal
authors.affiliation: Human Performance Laboratory, East Carolina University, Greenville, North Carolina; Department of Kinesiology, East Carolina University, Greenville, North Carolina; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina;
authors.forename: Todd M
authors.initials: TM
authors.lastname: Weber
authors.affiliation: Human Performance Laboratory, East Carolina University, Greenville, North Carolina; Department of Kinesiology, East Carolina University, Greenville, North Carolina; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina;
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Houmard
authors.affiliation: Department of Biochemistry and Molecular Biology, East Carolina University, Greenville, North Carolina; shewchukb@ecu.edu.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Shewchuk
mesh_terms: D000328:Adult; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects; D004041:Dietary Fats / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008055:Lipids / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009767:Obesity, Morbid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects; D055815:Young Adult
chemical_list: D004041:Dietary Fats; D008055:Lipids; C542591:CPT1B protein, human; D002334:Carnitine O-Palmitoyltransferase
keywords: DNA methylation; gene regulation; lipid metabolism; obesity; skeletal muscle