Tissue-autonomous regulation of adipose expansion by core clock protein REVERBα
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ABSTRACT:
PROVIDER: PRJEB37041 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR3971770_1.fastq.gz | Fastqsanger.gz | |||
| ERR3971770_2.fastq.gz | Fastqsanger.gz | |||
| ERR3971780_1.fastq.gz | Fastqsanger.gz | |||
| ERR3971780_2.fastq.gz | Fastqsanger.gz | |||
| ERR3971790_1.fastq.gz | Fastqsanger.gz |
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Project description:The circadian clock coordinates energy metabolism, with REVERBα considered a dominant regulator of lipid metabolism. REVERBα is a core clock protein, which demonstrates robust rhythmic expression across metabolic tissues. Here, we explore its role in white adipose metabolism, and propose that REVERBα plays a key part in the response of adipose to obesity. Mice globally lacking Reverbα (Reverbα-/-) display adiposity, increased susceptibility to diet-induced obesity, and up-regulation of the lipogenic proteome in white adipose depots. When Reverbα is deleted selectively in adipose (ReverbαFlox2-6AdipoCre), however, we observe only modest phenotypic and transcriptomic changes in the basal state, with altered regulation of clock and extracellular matrix (ECM) pathways. Thus the adipose-autonomous actions of REVERBα are shaped by context. On high-fat diet challenge, ReverbαFlox2-6AdipoCre mice accumulate more adipose mass than littermate controls, and are spared obesity-related inflammation. Gene expression analysis reveals pathways of lipid handling to be up-regulated. These findings therefore highlight a critical role for REVERBα in the regulation of adipose tissue expansion. Further, when transcriptomic data is integrated with the REVERBα cistrome, we detect strong associations of REVERBα binding sites, not only with the clock and ECM targets de-repressed under normal conditions, but with the broad range of metabolic genes unmasked as REVERBα targets by obesity. Thus our data favour a new interpretation of REVERBα function, not as conferring rhythmicity to lipogenesis, but as buffering against lipogenic cues asynchronous to the normal temporal routine.
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Project description:Tissue-autonomous regulation of adipose expansion by core clock protein REVERBα
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Project description:The diurnal variation in acetaminophen (APAP) hepatotoxicity (“chronotoxicity”) is thought to be due to oscillations in xenobiotic metabolism that are influenced by the circadian phases of feeding or fasting. Because of APAP’s relevance to human poisoning, we set out to determine the relative contributions of the central clock in the SCN and the autonomous clock in the hepatocyte in modulating the chronotoxicity of APAP. Using a conditional null allele of Mop3 (ArntL, Bmal1) we are able to delete the clock from hepatocytes while keeping the central and other peripheral clocks intact (eg, those controlling food intake). Our data from this hepatocyte-null mouse model suggests that, while the central circadian clock modulates some detoxification pathways indirectly by driving activity patterns and feeding rhythms, the autonomous hepatocyte circadian clock controls major aspects of APAP bioactivation independent of feeding rhythms, possibly through transcriptional regulation of cytochrome p450-oxidoreductase (Por). 10-20 week old Mop3fxfx mice positive or negative for Cre-recombinase driven by the albumin promoter, housed in 12 hour light:12 dark, ad lib feeding and drinking conditions were sacrificed every four hours over two separte days beginning at ZT0. A two color, reference design experiment in which kidney RNA from at least 3 mice per timepoint were pooled and labeled with Cy3 and hybridized according to Agilent protocols against a reference pool of RNA madeup from respective tissue taken from 10 week Mop3fxfx and Mop3fxfxCreAlb mice which was labeled with Cy5.
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