The histone deacetylase inhibitor sodium butyrate improves insulin signalling in palmitate-induced insulin resistance in L6 rat muscle cells through epigenetically-mediated up-regulation of Irs1

Mol Cell Endocrinol. 2017 Jan 5;439:224-232. doi: 10.1016/j.mce.2016.09.006. Epub 2016 Sep 13.

Abstract

Dietary administration of the histone deacetylase (HDAC) inhibitor butyric acid - a short chain fatty acid present in milk products and also bacterially produced in the intestine - has been shown to increase energy expenditure and favour insulin sensitivity in mice through induction of PGC1α (peroxisome proliferator-activated receptor gamma co-activator 1α) and AMPK (AMP-activated protein kinase) in skeletal muscle, and a consequential increase of mitochondrial fatty acid oxidation. Here, we investigate whether such physiological improvements are associated to epigenetic effects dependent on increased histone acetylation and whether butyrate exerts a direct action on skeletal muscle insulin signalling. We show that sodium butyrate (NaBut) ameliorates the insulin-resistant phenotype, induced in L6 myotubes by prolonged exposure to palmitate, by i) increasing the insulin-induced phosphorylation of both PKB (protein kinase B) and MAPK (mitogen activated protein kinase), the two branches of insulin signalling and ii) increasing histone H3 acetylation - even in the presence of palmitate - on chromatin in proximity of the Irs1 (insulin receptor substrate 1) transcriptional start site. Consequently, NaBut induced Irs1 mRNA and protein overexpression, which in turn relayed higher insulin-stimulated IRS1 tyrosine phosphorylation and PI 3-kinase (phosphoinositide 3-kinase) association, suggesting that the increased IRS1 expression may mediate the insulin-sensitizing effects of NaBut. Furthermore, downstream of PKB, NaBut induced GSK3β gene upregulation. Our observations indicate that NaBut - through its action as HDAC inhibitor - can promote insulin responsiveness in L6 myotubes under conditions of lipid-induced insulin resistance.

Keywords: HDACi; Histone acetylation; Insulin signalling; L6 myotubes; Sodium butyrate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation / drug effects
  • Animals
  • Butyric Acid / pharmacology*
  • Cell Differentiation / drug effects
  • Epigenesis, Genetic / drug effects*
  • Glycogen Synthase Kinase 3 beta / genetics
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histones / metabolism
  • Insulin / metabolism*
  • Insulin Receptor Substrate Proteins / genetics*
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Resistance*
  • Models, Biological
  • Muscle Cells / drug effects
  • Muscle Cells / metabolism*
  • Palmitates / toxicity*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Signal Transduction / drug effects
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • Histone Deacetylase Inhibitors
  • Histones
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Palmitates
  • RNA, Messenger
  • Butyric Acid
  • Glycogen Synthase Kinase 3 beta