title: Sodium butyrate epigenetically modulates high-fat diet-induced skeletal muscle mitochondrial adaptation, obesity and insulin resistance through nucleosome positioning.
abstract: OBJECTIVE
  Sodium butyrate (NaB), an epigenetic modifier, is effective in promoting insulin sensitivity. The specific genomic loci and mechanisms underlying epigenetically induced obesity and insulin resistance and the targets of NaB are not fully understood.
  
  
  METHODS
  The anti-diabetic and anti-obesity effects of NaB treatment were measured by comparing phenotypes and physiologies of C57BL/6J mice fed a low-fat diet (LF), high-fat diet (HF) or high-fat diet plus NaB (HF + NaB) for 10 weeks. We determined a possible mechanism of NaB action through induction of beneficial skeletal muscle mitochondrial adaptations and applied microccocal nuclease digestion with sequencing (MNase-seq) to assess whole genome differences in nucleosome occupancy or positioning and to identify associated epigenetic targets of NaB.
  
  
  RESULTS
  NaB prevented HF diet-induced increases in body weight and adiposity without altering food intake or energy expenditure, improved insulin sensitivity as measured by glucose and insulin tolerance tests, and decreased respiratory exchange ratio. In skeletal muscle, NaB increased the percentage of type 1 fibres, improved acylcarnitine profiles as measured by metabolomics and produced a chromatin structure, determined by MNase-seq, similar to that seen in LF. Targeted analysis of representative nuclear-encoded mitochondrial genes showed specific repositioning of the -1 nucleosome in association with altered gene expression.
  
  
  CONCLUSIONS
  NaB treatment may be an effective pharmacological approach for type 2 diabetes and obesity by inducing -1 nucleosome repositioning within nuclear-encoded mitochondrial genes, causing skeletal muscle mitochondrial adaptations that result in more complete β-oxidation and a lean, insulin sensitive phenotype.
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, IN, USA.
authors.forename: Tara M
authors.initials: TM
authors.lastname: Henagan
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, IN, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Stefanska
authors.affiliation: Biostatistics Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors.forename: Zhide
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Neurosignaling Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Navard
authors.affiliation: Antioxidant and Gene Regulation Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
authors.forename: Jianping
authors.initials: J
authors.lastname: Ye
authors.affiliation: Department of Sciences, Our Lady of the Lake College, Baton Rouge, LA, USA.
authors.forename: Natalie R
authors.initials: NR
authors.lastname: Lenard
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, IN, USA.
authors.forename: Prasad P
authors.initials: PP
authors.lastname: Devarshi
mesh_terms: D000222:Adaptation, Physiological; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D020148:Butyric Acid / Q000494:pharmacology*; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D059305:Diet, High-Fat; D004435:Eating; D004734:Energy Metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects*; D007333:Insulin Resistance / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009707:Nucleosomes / Q000187:drug effects* / Q000378:metabolism; D009765:Obesity / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D009707:Nucleosomes; C116917:acylcarnitine; D020148:Butyric Acid; D002331:Carnitine