Butyrate stimulates adipose lipolysis and mitochondrial oxidative phosphorylation through histone hyperacetylation‐associated β₃‐adrenergic receptor activation in high‐fat diet‐induced obese mice

Abstract

What is the central question of this study? Butyrate can prevent diet-induced obesity through increasing energy expenditure. However, it is unclear whether β -adrenergic receptors (ARβ3) mediate butyrate-induced adipose lipolysis. What is the main finding and its importance? Short-term oral administration of sodium butyrate is effective in alleviating diet-induced obesity through activation of ARβ3-mediated lipolysis in white adipose tissue. Butyrate can prevent diet-induced obesity through increasing energy expenditure. However, it is unclear whether ARβ3 mediates butyrate-induced adipose lipolysis. In this study, weaned mice were were fed control (Con) or high-fat (HF) diet for 8 weeks to establish obesity. High-fat diet-induced obese mice maintained on the HF diet were divided into two subgroups; the HFB group was gavaged with 80 mg sodium butyrate (SB) per mouse every other day for 10 days, whereas the HF group received vehicle. Chromatin immunoprecipitation assay was performed to determine the status of histone H3 lysine 9 acetylation (H3K9Ac) on the promoter of the β -adrenergic receptor (ARβ3) gene in epididymal white adipose tissue. It was shown that five gavage doses of SB significantly alleviated HF diet-induced obesity and restored plasma leptin concentration to the control level. Protein contents of ARβ3 and PKA, as well as ATGL and p-HSL (Ser563), were significantly upregulated in the HFB group compared with the HF group. Mitochondrial oxidative phosphorylation was enhanced by SB treatment. Sodium butyrate significantly increased the expression of four out of 13 mitochondrial DNA-encoded genes and significantly upregulated the protein contents of peroxisome proliferator-activated receptor-γ coactivator 1α and COX4. Moreover, SB administration enhanced the expression of ARβ3 and its downstream signalling. The G protein-coupled receptor 43 and p-CREB (Ser133) were significantly stimulated by SB. In addition, an active transcription marker, H3K9Ac, was significantly enriched on the promoter of the ARβ3 gene. Our results indicate that short-term oral administration of SB is effective in alleviating diet-induced obesity through activation of the ARβ3-mediated lipolysis in the epididymal white adipose tissue.

Acetate and Butyrate Improve β-cell Metabolism and Mitochondrial Respiration under Oxidative Stress

“…Previous studies have shown that SCFAs may stimulate the antioxidant defense against e.g., ischemia-reperfusion injury in cell types other than β-cells such as in brain cells [27]. In addition, SCFAs have been shown to support mitochondrial function in mouse liver, skeletal muscle, and fat cells [12,13,28]. This was the main rational to test the impact of SCFAs on β-cells [29,30].…”

The Gut Microbiota and Inflammation: An Overview

“…In many animal studies, SCFA butyrate has been associated with a variety of roles that oppose the onset of metabolic disorders [ 40 ]. Through epigenetic interactions, butyrate promotes lipolysis and mitochondrial functioning in adipocytes, thus enabling a greater energy expenditure and preventing the onset or maintenance of obesity [ 77 , 78 ]. Butyrate is an anti-inflammatory metabolite that is known to inhibit the pathways that lead to the production of pro-inflammatory cytokines [ 79 , 80 ].…”

Adipokines and Adipose Tissue-Related Metabolites, Nuts and Cardiovascular Disease

“…In rats on a high-fat diet, butyrate supplementation induced the activation of AMP-activated 5 Protein Kinase (AMPK) and glucose transporter 4 (GLUT4) in the adipose tissue, attenuated diet-induced dysbiosis, promoted biosynthesis of resolvin E1 and lipoxin (anti-inflammatory lipid mediators) [175], attenuated weight gain, adiposity, adipocyte hypertrophy, inflammation, and leptin secretion [176]. In the same animal model, butyrate supplementation appears to induce lipolysis in WAT mediated by activation of β3-adrenergic receptors [177] and regulates gene expression related to intestinal cholesterol absorption resulting in attenuation of atherosclerosis [178].…”