丁酸盐氧化减弱丁酸盐诱导的改善肌管中的胰岛素敏感性

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

 

 

 

Keywords：Butyrate, Fatty-acid oxidation, Glycolysis, Insulin resistance, Skeletal muscle 

关键词：丁酸盐、脂肪酸氧化、糖酵解、胰岛素抵抗、骨骼肌

哺乳动物：小鼠

组织：骨骼肌
作者：Rios-Morales Melany , Vieira-Lara Marcel A , Homan Esther , Langelaar-Makkinje Miriam , Gerding Albert , Li Zhuang , Huijkman Nicolette , Rensen Patrick CN , Wolters Justina C , Reijngoud Dirk-Jan , Bakker Barbara M
出版期刊：《Biochim Biophys Acta Mole Basic Dis》（2022）

 

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.

 

文章摘要：

骨骼肌胰岛素抵抗是 2 型糖尿病发展之前的关键病理生理过程。长链脂肪酸过多会导致肌肉胰岛素抵抗，而丁酸盐是一种由膳食纤维发酵产生的短链脂肪酸 (SCFA)，可以防止这种情况发生。丁酸盐的这种预防作用归因于组蛋白脱乙酰酶 (HDAC) 介导的转录调节和线粒体脂肪酸氧化的激活。在这里，我们解决了丁酸盐和长链脂肪酸棕榈酸盐之间的相互作用，并研究了转录、信号传导和代谢如何整合以导致丁酸盐诱导的骨骼肌代谢重塑。丁酸盐增强了棕榈酸盐处理的胰岛素抵抗 C2C12 细胞的胰岛素敏感性，如胰岛素受体 1 (IRS1) 和 pAKT 蛋白水平升高以及 Slc2a4 (GLUT4) mRNA 升高所示，这导致更高的糖酵解能力。长链脂肪酸氧化能力和其他功能性呼吸参数不受影响。丁酸盐确实上调了参与其自身氧化的线粒体蛋白，以及丁酰肉碱和羟基丁酰肉碱的浓度。通过敲除编码中链 3-酮脂酰辅酶 A 硫解酶 (MCKAT, Acaa2) 的基因，丁酸氧化被抑制，从而放大了 SCFA 对胰岛素敏感性和糖酵解的影响。基于组蛋白 3 乙酰化水平，这种反应与增强的 HDAC 抑制有关。丁酸盐增强胰岛素敏感性并诱导糖酵解，而不需要上调的长链脂肪酸氧化。丁酸盐分解代谢作为一个泄放阀，可减弱 HDAC 的抑制作用。因此，丁酸盐氧化的抑制间接地防止了胰岛素抵抗并刺激用丁酸盐处理的肌管中的糖酵解通量，最有可能通过HDAC依赖性机制。

 

点击链接即可查看和下载文章：https://linkinghub.elsevier.com/retrieve/pii/S0925-4439(22)00147-8

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