Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
Thomas Cornfield
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, and NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, United Kingdom
Peter S Cunningham
Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
Jean-Noel Billaud
Digital Insights, Qiagen, Redwood City, United States
Leanne Hodson
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, and NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, United Kingdom
Andrew SI Loudon
Centre for Biological Timing, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
Richard D Unwin
Stoller Biomarker Discovery Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
Mudassar Iqbal
Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
David W Ray
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, and NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, United Kingdom
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 profiling 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 inflammation and fibrosis 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.
