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

Autor: 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
Přispěvatelé: Molecular Cell Physiology, AIMMS, Center for Liver, Digestive and Metabolic Diseases (CLDM)
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Biochimica et Biophysica Acta-Molecular Basis of Disease, 1868(11):166476, 1-13. Elsevier
BBA-Molecular Basis of Disease, 1868(11). ELSEVIER
Biochimica et biophysica acta-Molecular basis of disease, 1868(11):166476. ELSEVIER SCIENCE BV
ISSN: 0925-4439
DOI: 10.1016/j.bbadis.2022.166476
Popis: 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 mito-chondrial 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.
Databáze: OpenAIRE
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