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.
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.
Carmen Laboratory, INSERM U1060, Lyon-1 University, South Lyon Medical Faculty, 69921 Oullins, France.
Sabrina
S
Chriett
Carmen Laboratory, INSERM U1060, Lyon-1 University, South Lyon Medical Faculty, 69921 Oullins, France.
Ouafa
O
Zerzaihi
Carmen Laboratory, INSERM U1060, Lyon-1 University, South Lyon Medical Faculty, 69921 Oullins, France.
Hubert
H
Vidal
Carmen Laboratory, INSERM U1060, Lyon-1 University, South Lyon Medical Faculty, 69921 Oullins, France. Electronic address: luciano.pirola@univ-lyon1.fr.
Luciano
L
Pirola
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D020148:Butyric Acid / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects*; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics* / Q000378:metabolism; D007333:Insulin Resistance; D008954:Models, Biological; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism*; D010168:Palmitates / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D010168:Palmitates; D012333:RNA, Messenger; D020148:Butyric Acid; D000071679:Glycogen Synthase Kinase 3 beta
HDACi; Histone acetylation; Insulin signalling; L6 myotubes; Sodium butyrate