The role of Rev-erbalpha in adipose tissue physiology

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Abstract

In mammals, the circadian clock is critical to adapting behaviour and physiology to the recurrent fluctuations which dominate our external environment. In line with this, the clock is an important regulator of energy metabolism, and disruption of circadian timing in animals and humans is associated with an increased incidence of metabolic dysfunction, obesity and type 2 diabetes. The nuclear hormone receptor Rev-erb-alpha has been identified as an influential link which couples the molecular clockwork to energy state and orchestrates rhythms in lipid metabolism. Our lab and others have shown that mice lacking Rev-erb-alpha (Rev-erb-alpha-/-) exhibit a pronounced obese phenotype, yet retain insulin sensitivity, and reduced obesity-related inflammation in white adipose tissue (WAT). Here, we use novel global and tissue specific transgenic models and combine in vivo phenotyping with proteomic and transcriptional profiling under normal and obese conditions to define the role of Rev-erb-alpha in adipose tissue function. Our findings demonstrate that contrary to recent reports, the metabolic actions of Rev-erb-alpha cannot be segregated based on its ability to directly bind DNA. Specifically, mice lacking either the DNA binding domain of Rev-erb-alpha (Rev-erb-alphaDBD) or the complete protein are phenotypically similar and exhibit pronounced adiposity under normal chow feeding conditions which is exacerbated in response to high fat diet. Increased adiposity is associated with clear up-regulation of glycolytic and lipogenic processes in the WAT of Rev-erb-alpha-/- and Rev-erb-alphaDBD mice. However, in contrast to expectation, adipose selective deletion of Rev-erb-alpha did not lead to increased adiposity or deregulation of WAT metabolism on normal chow, suggesting that the phenotype of the global targeted mice may be driven by sites outside of WAT. Nevertheless, adipose-targeted mice did show exacerbated response to high fat diet. In addition to the circadian clock, we identify collagen dynamics as a direct target of REV-ERB-alpha in WAT, and suggest that altered extracellular matrix remodelling contributes to the enhanced lipid storage seen. In addition to metabolic consequences of Rev-erb-alpha disruption, we investigate the mechanism behind increased high molecular weight (HMW) adiponectin production in these mice. We identify a number of genes involved in lysyl and prolyl hydroxylation that are differentially regulated under diet-induced obesity (in which HMW adiponectin levels decrease) and in Rev-erb-alpha-/- mice. Specifically, our results implicate the lysyl hydroxylase, Plod2, as being a negative regulator of HMW adiponectin production, which is differentially regulated during obesity and in response to Rev-erb-alpha targeting. Overall, this work delineates the direct and indirect impacts of Rev-erb-alpha in governing WAT metabolism, adiponectin production, and obesity development. Rev-erb-alpha remains an important potential therapeutic target in obesity and metabolic dysfunction, although further research is required to fully define local tissue versus systemic actions.

Keyword(s)

Rev-erb; adiponectin; inflammation; metabolism; obesity

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