Distinct roles for REV-ERB alpha and REV-ERB beta in oxidative capacity and mitochondrial biogenesis in skeletal muscle

作者：Amador Ariadna; Campbell Sean; Kazantzis Melissa; Lan Gary; Burris Thomas P; Solt Laura A^*

来源：PLos One, 2018, 13(5): e0196787.

DOI：10.1371/journal.pone.0196787

The nuclear receptors REV-ERB alpha and REV-ERB beta have been demonstrated to be core members of the circadian clock and participate in the regulation of a diverse set of metabolic functions. Due to their overlapping tissue expression patterns and gene expression profiles, REV-ERB beta is thought to be redundant to REV-ERB alpha. Recent work has highlighted REV-ERB alpha's role in the regulation of skeletal muscle oxidative capacity and mitochondrial biogenesis. Considering the similarity between the REV-ERBs and the hypothesized overlap in function, we sought to determine whether REV-ERB beta-deficiency presented with a similar skeletal muscle phenotype as REV-ERB alpha-deficiency. Ectopic overexpression in C2C12 cells demonstrated that REV-ERB beta drives mitochondrial biogenesis and the expression of genes involved in fatty acid oxidation. Intriguingly, knock down of REV-ERB beta in C2C12 cultures also resulted in mitochondrial biogenesis and increased expression of genes involved in fatty acid beta-oxidation. To determine whether these effects occurred in vivo, we examined REV-ERB beta-deficient mice and observed a similar increase in expression of genes involved in mitochondrial biogenesis and fatty acid beta-oxidation. Consistent with these results, REV-ERB beta-deficient mice exhibited an altered metabolic phenotype compared to wild-type littermate controls when measured by indirect calorimetry. This likely compensated for the increased food consumption that occurred, possibly aiding in the maintenance of their weight over time. Since feeding behaviors are a direct circadian output, this study suggests that REV-ERB beta may have more subtle effects on circadian behaviors than originally identified. Furthermore, these data implicate REV-ERB beta in the control of skeletal muscle metabolism and energy expenditure and suggest that development of REV-ERB alpha versus REV-ERB beta selective ligands may have therapeutic utility in the treatment of metabolic syndrome.

• 出版日期2018-5-3