Adipocyte NR1D1 dictates adipose tissue expansion during obesity
- University of Manchester, United Kingdom
- University of Oxford, United Kingdom
- QIAGEN Bioinformatics, United States
Abstract
The circadian clock component NR1D1 (REVERBα) is considered a dominant regulator of lipid metabolism, with global Nr1d1 deletion driving dysregulation of white adipose tissue (WAT) lipogenesis and obesity. However, a similar phenotype is not observed under adipocyte-selective deletion (Nr1d1Flox2-6:AdipoqCre), and transcriptional pro1ling demonstrates that, under basal conditions, direct targets of NR1D1 regulation are limited, and include the circadian clock and collagen dynamics. Under high-fat diet (HFD) feeding, Nr1d1Flox2-6:AdipoqCre mice do manifest profound obesity, yet without the accompanying WAT in2ammation and 1brosis exhibited by controls. Integration of the WAT NR1D1 cistrome with differential gene expression reveals broad control of metabolic processes by NR1D1 which is unmasked in the obese state. Adipocyte NR1D1 does not drive an anticipatory daily rhythm in WAT lipogenesis, but rather modulates WAT activity in response to alterations in metabolic state. Importantly, NR1D1 action in adipocytes is critical to the development of obesity-related WAT pathology and insulin resistance.
Data availability
RNA-seq data generated in the course of this study has been uploaded to ArrayExpress and is available at http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-8840. For reviewer access, the following login details can be used: username "Reviewer_E-MTAB-8840", password "IGGB44Tx". ChIP-seq data generated in the course of this study has been uploaded to ArrayExpress and is available at http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-10573. For reviewer access, the follow690ing login details can be used: username "Reviewer_E-MTAB-10573", password "nncbrjdh". Access to these datasets will be opened to the public upon acceptance of themanuscript. Raw proteomics data has been uploaded to Mendeley Data . Output of 'omics analyses (proteomics, edgeR, stageR, ReactomePA outputs, peak calling) are provided in the Source Data Files.
Article and author information
Author details
Rebecca C Northeast
Funding
Biotechnology and Biological Sciences Research Council (BB/I018654/1)
- David A Bechtold
Medical Research Council (MR/N021479/1)
- Ann Louise Hunter
Medical Research Council (MR/P00279X/1)
- David A Bechtold
Medical Research Council (MR/P011853/1)
- David Ray
Medical Research Council (MR/P023576/1)
- David Ray
Wellcome Trust (107849/Z/15/Z)
- David Ray
Wellcome Trust (107851/Z/15/Z)
- David Ray
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments described here were conducted in accordance with local requirements and licenced under the UK Animals (Scientific Procedures) Act 1986, project licence number 70/8558 (licence holder Dr. David A Bechtold). Procedures were approved by the University of Manchester Animal Welfare and Ethical Review Body (AWERB).
Copyright
© 2021, Hunter et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Adipocyte NR1D1 dictates adipose tissue expansion during obesity
eLife 10:e63324.
https://doi.org/10.7554/eLife.63324
Further reading
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Single-nucleus RNA sequencing (snRNA-seq), an alternative to single-cell RNA sequencing (scRNA-seq), encounters technical challenges in obtaining high-quality nuclei and RNA, persistently hindering its applications. Here, we present a robust technique for isolating nuclei across various tissue types, remarkably enhancing snRNA-seq data quality. Employing this approach, we comprehensively characterize the depot-dependent cellular dynamics of various cell types underlying mouse adipose tissue remodeling during obesity. By integrating bulk nuclear RNA-seq from adipocyte nuclei of different sizes, we identify distinct adipocyte subpopulations categorized by size and functionality. These subpopulations follow two divergent trajectories, adaptive and pathological, with their prevalence varying by depot. Specifically, we identify a key molecular feature of dysfunctional hypertrophic adipocytes, a global shutdown in gene expression, along with elevated stress and inflammatory responses. Furthermore, our differential gene expression analysis reveals distinct contributions of adipocyte subpopulations to the overall pathophysiology of adipose tissue. Our study establishes a robust snRNA-seq method, providing novel insights into the biological processes involved in adipose tissue remodeling during obesity, with broader applicability across diverse biological systems.
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