Targeting nuclear receptor NR4A1–dependent adipocyte progenitor quiescence promotes metabolic adaptation to obesity

Zhang, Yang; Federation, Alexander; Kim, Soomin; O’Keefe, John; Lun, Mingyue; Xiang, Dongxi; Brown, J.; Steinhauser, Matthew L.

doi:10.1172/jci98353

Cited by 25 publications

(18 citation statements)

References 92 publications

(98 reference statements)

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“…An additional question is the underlying degree of macrophage heterogeneity and whether AT macrophages converge on a common phenotype with fasting. While each induced transcription factor (for example, SPIC and SPI1 ) could control distinct macrophage phenotypes, it is perhaps more likely that they represent a circuit of collaborating transcription factors that are increasingly recognized to establish specialized cell states [ 24 , 25 ]. However, our study cannot definitively answer this question, in part due to the challenge of deciphering the relative degrees to which transcriptional changes in AT arise from transcriptional reprogramming vs changes in cellularity.…”

Section: Discussionmentioning

confidence: 99%

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Prolonged fasting drives a program of metabolic inflammation in human adipose tissue

Fazeli

Zhang

O’Keefe

et al. 2020

Molecular Metabolism

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Objective The human adaptive fasting response enables survival during periods of caloric deprivation. A crucial component of the fasting response is the shift from glucose metabolism to utilization of lipids, underscoring the importance of adipose tissue as the central lipid-storing organ. The objective of this study was to investigate the response of adipose tissue to a prolonged fast in humans. Methods We performed RNA sequencing of subcutaneous adipose tissue samples longitudinally collected during a 10-day, 0-calorie fast in humans. We further investigated observed transcriptional signatures utilizing cultured human monocytes and Thp1 cells. We examined the cellularity of adipose tissue biopsies with transmission electron microscopy and tested for associated changes in relevant inflammatory mediators in the systemic circulation by ELISA assays of longitudinally collected blood samples. Results Coincident with the expected shift away from glucose utilization and lipid storage, we demonstrated downregulation of pathways related to glycolysis, oxidative phosphorylation, and lipogenesis. The canonical lipolysis pathway was also downregulated, whereas fasting drove alternative lysosomal paths to lipid digestion. Unexpectedly, the dominant induced pathways were associated with immunity and inflammation, although this only became evident at the 10-day time point. Among the most augmented transcripts were those associated with macrophage identity and function, such as members of the erythroblast transformation-specific (ETS) transcription factor family. Key components of the macrophage transcriptional signal in fasting adipose tissue were recapitulated with induced expression of two of the ETS transcription factors via cultured macrophages, SPIC and SPI1 . The inflammatory signal was further reflected by an increase in systemic inflammatory mediators. Conclusions Collectively, this study demonstrates an unexpected role of metabolic inflammation in the human adaptive fasting response.

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Section: Discussionmentioning

confidence: 99%

“…RNA extraction, cDNA preparation, and qPCR were performed as previously described [ 25 ]. Briefly, cells were placed in TRIzol (Life Technologies) and RNA extracted according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

Prolonged fasting drives a program of metabolic inflammation in human adipose tissue

Fazeli

Zhang

O’Keefe

et al. 2020

Molecular Metabolism

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“…Their data demonstrated muscular insulin resistance, decreased Glut4 expression, decreased insulin receptor phosphorylation and decreased expression of glycolytic genes such as Eno3, Bpgm and Pgk1. Further findings demonstrated that loss of Nr4a1 in muscle significantly impairs myofiber size and regeneration [166,167]. Nr4a1 overexpression or induction with metformin or the Nr4a1 pharmaceutical ligand DIM-C-pPhOH and its derivatives in C2C12 muscle cells increased expression of metabolic genes associated with glucose uptake, glycolysis and glycogenolysis, such as Glut4, PHKG1, PGAM2, Eno3, Aldo1 and Pygm [172].…”

Section: Fuel Utilizationmentioning

confidence: 99%

“…Nr4a1 overexpression in C2C12 cells resulted in increased mitochondria number [167]. The increased expression of TCA and ETC components corresponds with enhanced glucose tolerance.…”

Section: Fuel Utilizationmentioning

confidence: 99%

Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues

Herring

Elison

Tessem

2019

Cells

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The Nr4a family of nuclear hormone receptors is composed of three members—Nr4a1/Nur77, Nr4a2/Nurr1 and Nr4a3/Nor1. While currently defined as ligandless, these transcription factors have been shown to regulate varied processes across a host of tissues. Of particular interest, the Nr4a family impinge, in a tissue dependent fashion, on cellular proliferation, apoptosis and fuel utilization. The regulation of these processes occurs through both nuclear and non-genomic pathways. The purpose of this review is to provide a balanced perspective of the tissue specific and Nr4a family member specific, effects on cellular proliferation, apoptosis and fuel utilization.

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“…MTFs are thought to form core transcriptional regulatory circuitries by co-occupying genomic sites, particularly at SEs, and co-regulating the expression of MTF genes and others genes critical for cellular identity (Chen et al, 2019a;Durbin et al, 2018;Sanda et al, 2012). Presently, the main approaches to identifying MTFs in cancer cells attempts to model these features by identifying TFs predicted to exhibit evidence of interconnected autoregulation Saint-André et al, 2016;Zhang et al, 2018). This involves performing ChIP-seq experiments to map enhancers and identifying SE associated TFs whose predicted binding motifs are enriched at SEs, both upstream and regulating other MTFs .…”

Section: Introductionmentioning

confidence: 99%

Predicting master transcription factors from pan-cancer expression data

Reddy

Fonseca

Fuente

et al. 2019

Preprint

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The function of critical developmental regulators can be subverted by cancer cells to control expression of oncogenic transcriptional programs. These "master transcription factors" (MTFs) are often essential for cancer cell survival and represent vulnerabilities that can be exploited therapeutically. The current approaches to identify candidate MTFs examine super-enhancer associated transcription factor-encoding genes with high connectivity in network models. This relies on chromatin immunoprecipitation-sequencing (ChIP-seq) data, which is technically challenging to obtain from primary tumors, and is currently unavailable for many cancer types and clinically relevant subtypes. In contrast, gene expression data are more widely available, especially for rare tumors and subtypes where MTFs have yet to be discovered. We have developed a predictive algorithm called CaCTS (Cancer Core Transcription factor Specificity) to identify candidate MTFs using pancancer RNA-sequencing data from The Cancer Genome Atlas. The algorithm identified 273 candidate MTFs across 34 tumor types and recovered known tumor MTFs. We also made novel predictions, including for cancer types and subtypes for which MTFs have not yet been characterized. Clustering based on MTF predictions reproduced anatomic groupings of tumors that share 1-2 lineage-specific candidates, but also dictated functional groupings, such as a squamous group that comprised five tumor subtypes sharing 3 common MTFs. PAX8, SOX17, and MECOM were candidate factors in high-grade serous ovarian cancer (HGSOC), an aggressive tumor type where the core regulatory circuit is currently uncharacterized. PAX8, SOX17, and MECOM are required for cell viability and lie proximal to super-enhancers in HGSOC cells. ChIPseq revealed that these factors co-occupy HGSOC regulatory elements globally and co-bind at critical gene loci including MUC16 (CA-125). Addiction to these factors was confirmed in studies using THZ1 to inhibit transcription in HGSOC cells, suggesting early down-regulation of these genes may be responsible for cytotoxic effects of THZ1 on HGSOC models. Identification of MTFs across 34 tumor types and 140 subtypes, especially for those with limited understanding of transcriptional drivers paves the way to therapeutic targeting of MTFs in a broad spectrum of cancers.

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Targeting nuclear receptor NR4A1–dependent adipocyte progenitor quiescence promotes metabolic adaptation to obesity

Cited by 25 publications

References 92 publications

Prolonged fasting drives a program of metabolic inflammation in human adipose tissue

Prolonged fasting drives a program of metabolic inflammation in human adipose tissue

Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues

Predicting master transcription factors from pan-cancer expression data

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