Dataset Information

Nr4a1 is required for fasting-induced down-regulation of Ppar?2 in white adipose tissue.

ABSTRACT: Expression of the nuclear receptor gene, Nur77 (Nr4a1), is induced in white adipose tissue (WAT) in response to ?-adrenergic stimulation and fasting. Recently, Nur77 has been shown to play a gene regulatory role in the fasting response of several other major metabolic tissues. Here we investigated the effects of Nur77 on the WAT transcriptome after fasting. For this purpose, we performed gene expression profiling of WAT from wild-type and Nur77(-/-) mice submitted to prolonged fasting. Results revealed Nur77-dependent changes in expression profiles of 135 transcripts, many involved in insulin signaling, lipid and fatty acid metabolism, and glucose metabolism. Network analysis identified the deregulated genes Ppar?2 and Nur77 as central hubs and closely connected in the network, indicating overlapping biological function. We further assayed the expression level of Ppar?2 in a bigger cohort of fasted mice and found a significant Nur77-dependent down-regulation of Ppar?2 in the wild-type mice (P = 0.021, n = 10). Consistently, the expression of several known Ppar?2 targets, found among the Nur77-regulated genes (i.e. G0s2, Grp81, Fabp4, and Adipoq), were up-regulated in WAT of fasted Nur77(-/-) mice. Finally, we show with chromatin immunoprecipitation and luciferase assays that the Ppar?2 promoter is a direct target of Nurr-related 77-kDa protein (Nur77)-dependent repressive regulation and that the N-terminal domain of Nur77 is required for this regulation. In conclusion, we present data implicating Nur77 as a mediator of fasting-induced Ppar?2 regulation in WAT.

SUBMITTER: Duszka K

PROVIDER: S-EPMC5416946 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Nr4a1 is required for fasting-induced down-regulation of Pparγ2 in white adipose tissue.

Duszka Kalina K Bogner-Strauss Juliane G JG Hackl Hubert H Rieder Dietmar D Neuhold Claudia C Prokesch Andreas A Trajanoski Zlatko Z Krogsdam Anne-M AM

Molecular endocrinology (Baltimore, Md.) 20121218 1

Expression of the nuclear receptor gene, Nur77 (Nr4a1), is induced in white adipose tissue (WAT) in response to β-adrenergic stimulation and fasting. Recently, Nur77 has been shown to play a gene regulatory role in the fasting response of several other major metabolic tissues. Here we investigated the effects of Nur77 on the WAT transcriptome after fasting. For this purpose, we performed gene expression profiling of WAT from wild-type and Nur77(-/-) mice submitted to prolonged fasting. Results r ...[more]

PMID: 23250487

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Project description:BackgroundA hypothesis exists whereby an exercise- or dietary-induced negative energy balance reduces human subcutaneous white adipose tissue (scWAT) mass through the formation of brown-like adipocyte (brite) cells. However, the validity of biomarkers of brite formation has not been robustly evaluated in humans, and clinical data that link brite formation and weight loss are sparse.ObjectivesWe used rosiglitazone and primary adipocytes to stringently evaluate a set of biomarkers for brite formation and determined whether the expression of biomarker genes in scWAT could explain the change in body composition in response to exercise training combined with calorie restriction in obese and overweight women (n = 79).DesignGene expression was derived from exon DNA microarrays and preadipocytes from obesity-resistant and -sensitive mice treated with rosiglitazone to generate candidate brite biomarkers from a microarray. These biomarkers were evaluated against data derived from scWAT RNA from obese and overweight women before and after supervised exercise 5 d/wk for 16 wk combined with modest calorie restriction (∼0.84 MJ/d).ResultsForty percent of commonly used brite gene biomarkers exhibited an exon or strain-specific regulation. No biomarkers were positively related to weight loss in human scWAT. Greater weight loss was significantly associated with less uncoupling protein 1 expression (P = 0.006, R(2) = 0.09). In a follow-up global analysis, there were 161 genes that covaried with weight loss that were linked to greater CCAAT/enhancer binding protein α activity (z = 2.0, P = 6.6 × 10(-7)), liver X receptor α/β agonism (z = 2.1, P = 2.8 × 10(-7)), and inhibition of leptin-like signaling (z = -2.6, P = 3.9 × 10(-5)).ConclusionWe identify a subset of robust RNA biomarkers for brite formation and show that calorie-restriction-mediated weight loss in women dynamically remodels scWAT to take on a more-white rather than a more-brown adipocyte phenotype.

Dataset Information

Nr4a1 is required for fasting-induced down-regulation of Ppar?2 in white adipose tissue.

Publications

Nr4a1 is required for fasting-induced down-regulation of Pparγ2 in white adipose tissue.

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