Butyrate stimulates adipose lipolysis and mitochondrial OXPHOS through histone hyperacetylation-associated AR3β activation in high-fat diet-induced obese mice

Abstract

Butyrate can prevent diet-induced obesity through increasing energy expenditure. However, it is unclear whether AR3β 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. HF-induced obese mice maintained on the HF diet were divided into two sub-groups; HFB group was gavaged with 80 mg sodium butyrate (SB) per mouse every other day for 10 days, while 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 AR3β 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 AR3β and PKA, as well as ATGL and p-HSL (Ser 563), were significantly up-regulated in HFB group as compared with HF group. Mitochondrial oxidative phosphorylation was enhanced by SB treatment. SB significantly increased the expression of 4 out of 13 mtDNA-encoded genes, together with significantly up-regulated protein contents of PGC-1α and COX4. Moreover, SB administration enhanced the expression of AR3β and its downstream signaling. The G protein-coupled receptor 43 and p-CREB (Ser 133) were significantly stimulated by SB. In addition, an active transcription marker, H3K9Ac, was significantly enriched on the promoter of the AR3β gene. Our results indicate that short-term oral administration of SB is effective in alleviating diet-induced obesity through activation of the AR3β-mediated lipolysis in the epididymal white adipose tissue.

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