Butyrate oxidation attenuates the butyrate-induced improvement of insulin sensitivity in myotubes

Melany Rios-Morales, Marcel A. Vieira-Lara, Esther Homan, Miriam Langelaar-Makkinje, Albert Gerding, Zhuang Li, Nicolette Huijkman, Patrick C.N. Rensen, Justina C. Wolters, Dirk Jan Reijngoud, Barbara M. Bakker*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Skeletal muscle insulin resistance is a key pathophysiological process that precedes the development of type 2 diabetes. Whereas an overload of long-chain fatty acids can induce muscle insulin resistance, butyrate, a short-chain fatty acid (SCFA) produced from dietary fibre fermentation, prevents it. This preventive role of butyrate has been attributed to histone deacetylase (HDAC)-mediated transcription regulation and activation of mitochondrial fatty-acid oxidation. Here we address the interplay between butyrate and the long-chain fatty acid palmitate and investigate how transcription, signalling and metabolism are integrated to result in the butyrate-induced skeletal muscle metabolism remodelling. Butyrate enhanced insulin sensitivity in palmitate-treated, insulin-resistant C2C12 cells, as shown by elevated insulin receptor 1 (IRS1) and pAKT protein levels and Slc2a4 (GLUT4) mRNA, which led to a higher glycolytic capacity. Long-chain fatty-acid oxidation capacity and other functional respiration parameters were not affected. Butyrate did upregulate mitochondrial proteins involved in its own oxidation, as well as concentrations of butyrylcarnitine and hydroyxybutyrylcarnitine. By knocking down the gene encoding medium-chain 3-ketoacyl-CoA thiolase (MCKAT, Acaa2), butyrate oxidation was inhibited, which amplified the effects of the SCFA on insulin sensitivity and glycolysis. This response was associated with enhanced HDAC inhibition, based on histone 3 acetylation levels. Butyrate enhances insulin sensitivity and induces glycolysis, without the requirement of upregulated long-chain fatty acid oxidation. Butyrate catabolism functions as an escape valve that attenuates HDAC inhibition. Thus, inhibition of butyrate oxidation indirectly prevents insulin resistance and stimulates glycolytic flux in myotubes treated with butyrate, most likely via an HDAC-dependent mechanism.

Original languageEnglish
Article number166476
Pages (from-to)1-13
Number of pages13
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1868
Issue number11
Early online date8 Jul 2022
DOIs
Publication statusPublished - 1 Nov 2022
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported by a UMCG-GSMS PhD fellowship, the De Cock-Hadders Foundation and the UMCG Hereditary Metabolic Diseases Fund .

Publisher Copyright:
© 2022 The Authors

Keywords

  • Butyrate
  • Fatty-acid oxidation
  • Glycolysis
  • Insulin resistance
  • Skeletal muscle

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