Nuclear receptor REVERBα is a state-dependent regulator of liver energy metabolism

Hunter, Louise; Pelekanou, Charlotte E; Adamson, Antony; Downton, Polly; Barron, Nichola J; Cornfield, Thomas; Poolman, Toryn; Humphreys, Neil; Cunningham, Peter; Hodson, Leanne; Loudon, A. S. I.; Iqbal, Mudassar; Ray, David

doi:10.1073/pnas.2005330117

Cited by 42 publications

(50 citation statements)

References 79 publications

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“…Surprisingly, Reverbα expression in WAT appears to limits the energy buffering function of the tissue. This finding parallels our recent work in the liver (Hunter et al, 2020). Hepatic-selective loss of REVERBα carries no metabolic consequence, with REVERBα-dependent control over hepatic energy metabolism revealed only upon altered feeding conditions.…”

Section: Discussionsupporting

confidence: 92%

“…To define the role of REVERBα specifically within WAT, we generated a new mouse line with loxP sites flanking Reverbα exons 2-6 ( Reverbα Flox2-6 ), competent for Cre-mediated conditional deletion ( Figure 2A ; Hunter et al, 2020). We crossed this mouse with the well-established adiponectin Cre-driver line ( Adipo Cre ; Eguchi et al, 2011; Jeffery et al, 2014) to delete Reverbα selectively in adipocytes.…”

Section: Resultsmentioning

confidence: 99%

“…To define the cistrome, we used raw published gWAT ChIP-seq data (Zhang et al, 2015) to call 2,354 high-stringency REVERBα peaks. To infer which genes might be direct targets of REVERBα repression, we employed a custom Python script that calculates the enrichment of differentially expressed gene sets in spatial relation to identified transcription factor binding sites ( Figure 6 Supplemental A ) (Hunter et al, 2020; Yang et al, 2019), over all genes in the genome.…”

Section: Resultsmentioning

confidence: 99%

“…A CRISPR-Cas9 approach was used to generate a conditional knock allele for Nr1d1 ( Reverbα ), as described (Hunter et al, 2020). LoxP sites were integrated, in a two-step process, at intron 2 and intron 6, taking care to avoid any previously described transcriptional regulatory sites (Yamamoto et al, 2004).…”

Section: Methodsmentioning

confidence: 99%

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Adipocyte REVERBα dictates adipose tissue expansion during obesity

Hunter

Pelekanou

Barron

et al. 2020

Preprint

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The circadian clock component REVERBα is considered a dominant regulator of lipid metabolism, with global Reverbα deletion driving dysregulation of white adipose tissue (WAT) lipogenesis and obesity. However, a similar phenotype is not observed under adipocyte-selective deletion (ReverbαFlox2-6AdipoCre), and transcriptional profiling demonstrates that, under basal conditions, direct targets of REVERBα regulation are limited, and include the circadian clock and collagen dynamics. Under high-fat diet (HFD) feeding, ReverbαFlox2-6AdipoCre mice do manifest profound obesity, yet without the accompanying WAT inflammation and fibrosis exhibited by controls. Integration of the WAT REVERBα cistrome with differential gene expression reveals broad control of metabolic processes by REVERBα which is unmasked in the obese state. Adipocyte REVERBα does not drive an anticipatory daily rhythm in WAT lipogenesis, but rather modulates WAT activity in response to alterations in metabolic state. Importantly, REVERBα action in adipocytes is critical to the development of obesity-related WAT pathology and insulin resistance.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Adipocyte REVERBα dictates adipose tissue expansion during obesity

Hunter

Pelekanou

Barron

et al. 2020

Preprint

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“…In a similar fashion, major perturbations of the regulatory environment that likely induce chromatin remodelling (e.g. fasting (15), chronic high fat diet (17)), have been shown to alter the observed actions of GR, and we suggest that, operating through a similar mechanism, this phenomenon extends to other nuclear receptors whose activity is state-sensitive (40,41). Indeed, 'cistromic plasticity' of the oestrogen receptor is proposed to be of clinical importance in breast cancer (42).…”

Section: Discussionsupporting

confidence: 55%

HNF4A is required to specify glucocorticoid action in the liver

Hunter

Poolman²,

Kim³

et al. 2021

Preprint

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The glucocorticoid receptor (GR) is a nuclear hormone receptor critical to the regulation of energy metabolism and the inflammatory response. The actions of GR are highly dependent on cell type and environmental context. Here, we demonstrate the necessity for liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining liver-specificity of GR action. In normal mouse liver, the HNF4 motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites found within regions of open chromatin. In the absence of HNF4A, the liver GR cistrome is remodelled, with both loss and gain of GR recruitment evident. Lost sites are characterised by HNF4 motifs and weak GRE motifs. Gained sites are characterised by strong GRE motifs, and typically show GR recruitment in non-liver tissues. The functional importance of these HNF4A-regulated GR sites is further demonstrated by evidence of an altered transcriptional response to glucocorticoid treatment in the Hnf4a-null liver.

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Effect of dietary factors and time of day on iron absorption from oral iron supplements in iron deficient women

et al. 2023

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Guidelines generally recommend taking iron supplements in the morning away from meals and with ascorbic acid (AA) to increase iron absorption. However, there is little direct evidence on the effects of dietary factors and time of day on absorption from iron supplements. In iron‐depleted women (n = 34; median serum ferritin 19.4 μg/L), we administered 100 mg iron doses labeled with 54Fe, 57Fe, or 58Fe in each of six different conditions with: (1) water (reference) in the morning; (2) 80 mg AA; (3) 500 mg AA; (4) coffee; (5) breakfast including coffee and orange juice (containing ~90 mg AA); and (6) water in the afternoon. Fractional iron absorption (FIA) from these n = 204 doses was calculated based on erythrocyte incorporation of multiple isotopic labels. Compared to the reference: 80 mg AA increased FIA by 30% (p < .001) but 500 mg AA did not further increase FIA (p = .226); coffee decreased FIA by 54% (p = .004); coffee with breakfast decreased FIA by 66% (p < .001) despite the presence of ~90 mg of AA. Serum hepcidin was higher (p < .001) and FIA was 37% lower (p = .059) in the afternoon compared to the morning. Our data suggest that to maximize efficacy, ferrous iron supplements should be consumed in the morning, away from meals or coffee, and with an AA‐rich food or beverage. Compared to consuming a 100 mg iron dose in the morning with coffee or breakfast, consuming it with orange juice alone results in a ~ 4‐fold increase in iron absorption, and provides ~20 more mg of absorbed iron per dose. The trial was registered at http://clinicaltrials.gov(NCT04074707).

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Nuclear receptor REVERBα is a state-dependent regulator of liver energy metabolism

Cited by 42 publications

References 79 publications

Adipocyte REVERBα dictates adipose tissue expansion during obesity

Adipocyte REVERBα dictates adipose tissue expansion during obesity

HNF4A is required to specify glucocorticoid action in the liver

Effect of dietary factors and time of day on iron absorption from oral iron supplements in iron deficient women

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