Journal Article

Distinct roles for REV-ERBα and REV-ERBβ in oxidative capacity and mitochondrial biogenesis in skeletal muscle

Amador, Ariadna, Campbell, Sean, Kazantzis, Melissa, Lan, Gary, Burris, Thomas P., Solt, Laura A.

2018

Overview

The nuclear receptors REV-ERBα and REV-ERBβ 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-ERBβ is thought to be redundant to REV-ERBα. Recent work has highlighted REV-ERBα'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-ERBβ-deficiency presented with a similar skeletal muscle phenotype as REV-ERBα-deficiency. Ectopic overexpression in C2C12 cells demonstrated that REV-ERBβ drives mitochondrial biogenesis and the expression of genes involved in fatty acid oxidation. Intriguingly, knock down of REV-ERBβ in C2C12 cultures also resulted in mitochondrial biogenesis and increased expression of genes involved in fatty acid β-oxidation. To determine whether these effects occurred in vivo, we examined REV-ERBβ-deficient mice and observed a similar increase in expression of genes involved in mitochondrial biogenesis and fatty acid β-oxidation. Consistent with these results, REV-ERBβ-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-ERBβ may have more subtle effects on circadian behaviors than originally identified. Furthermore, these data implicate REV-ERBβ in the control of skeletal muscle metabolism and energy expenditure and suggest that development of REV-ERBα versus REV-ERBβ selective ligands may have therapeutic utility in the treatment of metabolic syndrome.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Biology and Life Sciences / Biosynthesis / Body Weight / Calorimetry / Calorimetry, Indirect / Cell Line / Circadian rhythm / Circadian Rhythm - genetics / Circadian Rhythm - physiology / Circadian rhythms / Control / Endocrinology / Energy / Energy expenditure / Energy metabolism / Energy Metabolism - genetics / Energy Metabolism - physiology / Fatty acids / Fatty Acids - metabolism / Feeding behavior / Feeding Behavior - physiology / Female / Food consumption / Gene expression / Gene Expression Regulation / Genes / Homeostasis / Immunology / In vivo methods and tests / Ligands / Lipids / Male / Medicine / Medicine and Health Sciences / Metabolic disorders / Metabolic syndrome / Metabolism / Mice / Mice, Knockout / Mitochondria / Mitochondria, Muscle - physiology / Muscle, Skeletal - metabolism / Muscles / Musculoskeletal system / Nuclear Receptor Subfamily 1, Group D, Member 1 - antagonists & inhibitors / Nuclear Receptor Subfamily 1, Group D, Member 1 - deficiency / Nuclear Receptor Subfamily 1, Group D, Member 1 - genetics / Nuclear Receptor Subfamily 1, Group D, Member 1 - physiology / Nuclear receptors / Obesity / Organelle Biogenesis / Oxidation / Oxidation-Reduction / Oxidative Phosphorylation / Phenotypes / Physiology / Receptors / Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors / Receptors, Cytoplasmic and Nuclear - deficiency / Receptors, Cytoplasmic and Nuclear - genetics / Receptors, Cytoplasmic and Nuclear - physiology / Repressor Proteins - antagonists & inhibitors / Repressor Proteins - deficiency / Repressor Proteins - genetics / Repressor Proteins - physiology / Research and Analysis Methods / RNA Interference / RNA, Small Interfering - genetics / Rodents / Skeletal muscle