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 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.
Highlights
The mammalian circadian clock directs rhythms in behaviour and physiology to coordinate our biology with predictable changes in food availability and daily alternations between fasted and fed states
In keeping with previous reports (Delezie et al, 2012; Hand et al, 2015), Nr1d1-/- mice are of similar body weight to littermate controls (Figure 1A), yet carry an increased proportion of fat mass (KO: 24.2 ± 3.0% of body weight; WT: 10.8 ± 1.4%; mean ± SEM, p
Consistent with the healthier metabolic phenotype observed in obese Nr1d1Flox2-6:AdipoqCre mice, we found that the large majority of the 863 NR1D1 gene targets unmasked by high-fat diet (HFD) feeding are normally repressed in obesity (Figure 6E), with 551 (63.8%) showing a significant down-regulation in obese control (Cre-ve) animals
Summary
The mammalian circadian clock directs rhythms in behaviour and physiology to coordinate our biology with predictable changes in food availability and daily alternations between fasted and fed states. In this way, profound cycles in nutrient availability and internal energy state can be managed across multiple organ systems. The rhythmic transcriptome that defines cells and tissues is shaped by both local tissue clock activity and input from the central clock and rhythmic systemic signals (Guo et al, 2005; Hughes et al, 2012; Kornmann et al, 2007; Koronowski et al, 2019; Lamia et al, 2008; Hunter et al, 2020).
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