title: Lipid exposure elicits differential responses in gene expression and DNA methylation in primary human skeletal muscle cells from severely obese women.
abstract: The skeletal muscle of obese individuals exhibits an impaired ability to increase the expression of genes linked with fatty acid oxidation (FAO) upon lipid exposure. The present study determined if this response could be attributed to differential DNA methylation signatures. RNA and DNA were isolated from primary human skeletal muscle cells (HSkMC) from lean and severely obese women following lipid incubation. mRNA expression and DNA methylation were quantified for genes that globally regulate FAO [PPARγ coactivator (PGC-1α), peroxisome proliferator-activated receptors (PPARs), nuclear respiratory factors (NRFs)]. With lipid oversupply, increases in NRF-1, NRF-2, PPARα, and PPARδ expression were dampened in skeletal muscle from severely obese compared with lean women. The expression of genes downstream of the PPARs and NRFs also exhibited a pattern of not increasing as robustly upon lipid exposure with obesity. Increases in CpG methylation near the transcription start site with lipid oversupply were positively related to PPARδ expression; increases in methylation with lipid were depressed in HSkMC from severely obese women. With severe obesity, there is an impaired ability to upregulate global transcriptional regulators of FAO in response to lipid exposure. Transient changes in DNA methylation patterns and differences in the methylation signature with severe obesity may play a role in the transcriptional regulation of PPARδ in response to lipid. The persistence of differential responses to lipid in HSkMC derived from lean and obese subjects supports the possibility of stable epigenetic programming of skeletal muscle cells by the respective environments.
authors: School of Kinesiology, Recreation, and Sport, Western Kentucky University, Bowling Green, Kentucky; Biotechnology Center, Western Kentucky University, Bowling Green, Kentucky;
authors: Jill M
authors: JM
authors: Maples
authors: 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 & Molecular Biology, East Carolina University, Greenville, North Carolina; Department of Physiology, East Carolina University, Greenville, North Carolina; and.
authors: Jeffrey J
authors: http://orcid.org/0000-0003-3503-0528
authors: JJ
authors: Brault
authors: Department of Biochemistry & Molecular Biology, East Carolina University, Greenville, North Carolina;
authors: Brian M
authors: BM
authors: Shewchuk
authors: 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 & Molecular Biology, East Carolina University, Greenville, North Carolina; Department of Physiology, East Carolina University, Greenville, North Carolina; and.
authors: Carol A
authors: http://orcid.org/0000-0003-4165-4740
authors: CA
authors: Witczak
authors: 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: Kai
authors: K
authors: Zou
authors: Biotechnology Center, Western Kentucky University, Bowling Green, Kentucky;
authors: Naomi
authors: N
authors: Rowland
authors: Department of Integrative Systems Biology, Children's National Medical Center, Washington, District of Columbia.
authors: Monica J
authors: MJ
authors: Hubal
authors: 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: Todd M
authors: TM
authors: Weber
authors: 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; houmardj@ecu.edu.
authors: Joseph A
authors: JA
authors: Houmard
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008055:Lipids / Q000494:pharmacology*; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000473:pathology*; D051264:Nuclear Respiratory Factors / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics*; D010084:Oxidation-Reduction / Q000187:drug effects; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D005227:Fatty Acids; D008055:Lipids; D051264:Nuclear Respiratory Factors; D047492:Peroxisome Proliferator-Activated Receptors; D012333:RNA, Messenger
keywords: DNA methylation; obesity; skeletal muscle