The NR4A family of orphan nuclear receptors are not required for adipogenesis

Ws, Au; Va, Payne; O’Rahilly, Stephen; Rochford, Justin J.

doi:10.1038/sj.ijo.0803763

Cited by 25 publications

(19 citation statements)

References 21 publications

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“…As an additional control, we also tested the effect of Nur77-898, an N-terminally truncated dominant-negative receptor (deletion of the first 897 nucleotides of Nur77). Deletion of the N-terminal transactivation domain has previously been shown to antagonize the activity of all three NR4A isotypes (12, 17, 28). Following puromycin selection of large mixed pool of cells (not single clones), each cell line was differentiated in standard differentiation cocktail for 7 days (DMI for 2 days, followed by insulin alone for 5 days).…”

Section: Resultsmentioning

confidence: 99%

“…Others have reported, however, that induction of NR4A receptors occurs some 24 to 48 hours after the addition of the PPARγ ligands troglitazone or pioglitazone to fully differentiated adipocytes (16). On the other hand, Au et al have suggested that NR4A receptors are not required for adipogenesis (17). Collectively, these studies raise the possibility the NR4As may be involved in the regulation of adipocyte gene expression during differentiation.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Adipocyte Differentiation by Nur77, Nurr1, and Nor1

Chao

Bensinger

Villanueva

et al. 2008

Molecular Endocrinology

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Members of the NR4A subgroup of nuclear receptors have been implicated in the regulation of glucose and lipid metabolism in insulin-sensitive tissues such as liver and skeletal muscle. However, their function in adipocytes is not well defined. Previous studies have reported that these receptors are rapidly upregulated following treatment of 3T3-L1 preadipocytes with an adipogenic cocktail. We show here that although Nur77 expression is acutely induced by cAMP agonists in 3T3-L1 cells, it is not induced by other adipogenic stimuli, such as PPARγ ligands, nor is it induced during the differentiation of 3T3-F442A preadipocytes, suggesting that Nur77 induction is not an obligatory feature of preadipocyte differentiation. We further demonstrate that inflammatory signals that antagonize differentiation, such as TNFα and lipopolysaccharide, acutely induce Nur77 expression both in vitro and in vivo. We also show that NR4A expression in adipose tissue is responsive to fasting/refeeding. Retroviral transduction of each of the NR4A receptors (Nur77, Nurr1 and NOR1) into either 3T3-L1 or 3T3-F442A preadipocytes potently inhibits adipogenesis. Interestingly, NR4A-mediated inhibition of adipogenesis cannot not be rescued by PPARγ overexpression or activation. Transcriptional profiling of Nur77-expressing preadipocytes led to the identification of gap-junction protein alpha 1 (Gja1) and tolloid-like 1 (Tll1) as Nur77-responsive genes. Remarkably, retroviral expression of either Gja1 or Tll1 in 3T3-L1 preadipocytes also inhibited adipocyte differentiation, implicating these genes as potential mediators of Nur77’s effects on adipogenesis. Finally, we show that Nur77 expression inhibits mitotic clonal expansion of preadipocytes, providing an additional mechanism by which Nur77 may inhibit adipogenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of Adipocyte Differentiation by Nur77, Nurr1, and Nor1

Chao

Bensinger

Villanueva

et al. 2008

Molecular Endocrinology

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“…Initial studies using siRNA approaches and overexpression of a Nur77 mutant lacking the N-terminal AF-1 transactivation domain indicated that Nur77 is not required for adipocyte differentiation 55. However, a functional role for NR4A receptors in adipogenesis was suggested by two recent in vitro studies, which have demonstrated that constitutive NR4A receptor expression in 3T3-L1 preadipocytes inhibits adipocyte differentiation 56, 57.…”

Section: Nr4a Receptors In Metabolism and Energy Balancementioning

confidence: 99%

NR4A Orphan Nuclear Receptors

Zhao

Bruemmer

2010

ATVB

201

122

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Abstract-Members of the nuclear hormone receptor superfamily, including the peroxisome proliferator-activated receptor and the liver X receptor subfamilies, orchestrate transcriptional networks involved in the control of metabolism and the development of vascular disease. In addition to these well-characterized ligand-activated transcription factors, the nuclear receptor (NR) superfamily comprises many orphan receptors, whose ligands and physiological functions remain unknown. Among this group of orphan receptors is the NR4A subfamily, including Nur77 (NR4A1), Nurr1 (NR4A2), and NOR1 (NR4A3). These orphan NRs constitute an evolutionary ancient and highly conserved group of transcription factors. In contrast to other members of the superfamily, NR4A receptors function as ligand-independent transcription factors and immediate-or early-response genes, which are rapidly induced by a pleiotropy of environmental cues. Early functional studies have pointed to a critical role of NR4A receptors in regulating differentiation, proliferation, and apoptosis. More recent research has characterized NR4A receptors as key transcriptional regulators of glucose and lipid homeostasis, adipogenesis, inflammation, and vascular remodeling. In this review, we will summarize recent advances in understanding the molecular biology and physiological functions of NR4A receptors and discuss their role in the transcriptional control of metabolism and vascular remodeling.

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“…Satu dari tahap pertama STAT3 maupun RNAi CREB; 2) kelompok perlakuan A: adipogenesis adalah peningkatan ekspresi dan akumulasi kultur sel preadiposit yang diinduksi diferensiasinya faktor transkripsi CCAAT/enhancer-binding proteins ditambah rapamycin dengan dosis 10 nM; 3) kelompok C/EBPβ dan C/EBPδ. Selanjutnya secara bertahap terjadi perlakuan B: kultur sel preadiposit yang diinduksi pengaktifan transkripsi C/EBPα dan PPARγ2 yang diferensiasinya ditambah dengan inhibitor STAT3 100 µM merupakan regulator dari proses adipogenesis (8,9). tanpa rapamycin; 4) kelompok perlakuan C: kultur sel preadiposit yang diinduksi diferensiasinya ditambah Peningkatan ekspresi C/EBPβ dan C/EBPδ diregulasi oleh dengan inhibitor STAT3 100 µM ditambah rapamycin 10 faktor transkripsi di atasnya yaitu cAMP respon element nM.…”

Section: Pendahuluanunclassified

Regulasi Adipogenesis oleh mTORC1 melalui Jalur ST A T3

Triawanti

Indra

Tjokroprawiro

et al. 2013

JKB

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ABSTRAKObesitas merupakan suatu penyakit kelebihan massa lemak tubuh yang mempunyai efek merugikan bagi kesehatan. Pada saat ini proses adipogenesis menjadi salah satu target terapi obesitas. Salah satu jalur yang diduga teraktivasi pada proses adipogenesis adalah melalui aktivasi STAT3 yang salah satu jalur hulunya melalui protein mammalian target of rapamycin complex 1 (mTOR). Penelitian ini bertujuan untuk membuktikan proses adipogenesis melalui jalur STAT3 yang diaktivasi oleh mTORC1. Penelitian ini merupakan penelitian eksperimental dengan rancangan post test only control. Untuk penghambatan mTORC1 digunakan rapamycin dan penghambatan STAT3 digunakan inhibitor STAT3 peptide. Subjek penelitian adalah kultur primer sel preadiposit yang diambil dari lemak viseral tikus putih Rattus norvegicus. Setelah kultur sel preadiposit dinilai konfluen minimal 70-80% dilakukan induksi diferensiasi dan dibagi menjadi 4 kelompok yakni (K) kontrol (A): diberi rapamycin 10 nM, (B): diberi inhibitor STAT3 100 µM (C): diberi inhibitor STAT3 100 µM dan rapamycin 10 nM. Parameter yang diukur adalah aktivasi p70S6K1, STAT3, ekspresi C/EBPδ, aktivitas enzim Glyserol-3-fosfodehidrogenase (GPDH) pada hari ke-2, ke-4 dan ke-6 serta gambaran morfologis sel adiposit. Analisis statistik menggunakan uji ANOVA, Duncan dan korelasi Pearson dengan tingkat kepercayaan 95%. Hasil penelitian membuktikan terjadi penghambatan proses adipogenesis karena penghambatan aktivasi p70S6K1, dan STAT3 oleh rapamycin dan inhibitor STAT3. Penghambatan akan lebih kuat pada pemberian kombinasi rapamycin dengan inhibitor STAT3. Secara statistik terdapat hubungan antara p70S6K1 dengan STAT3 serta antara STAT3 dengan enzim GPDH. Dapat disimpulkan bahwa proses adipogenesis dapat diregulasi oleh mTORC1 melalui aktivasi p70S6K1 dan STAT3.Kata Kunci: Adiposit, obesitas, mTORC1, p70S6K1, STAT3 ABSTRACT Recently, the processes of adipogenesis become a treatment target for obesity. One of the pathways that allegedly participated in the process of adipogenesis is activated via STAT3. The upstream line of is protein of mammalian targets of rapamycin complex 1 (mTOR). This study aimed to determine the role of STAT3 in adipogenesis through activation of p70S6K1 by mTORC1. This was an experimental study with a post test only with control group design. Subjects were primary cultured preadipocytes taken from visceral fat white rat (Rattus norvegicus). As cell cultured were at least 70-80% confluent, the induction of differentiation of preadipocytes were initiated. Cell cultures were divided into 4 groups: (K) Control of adipogenesis (

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The NR4A family of orphan nuclear receptors are not required for adipogenesis

Cited by 25 publications

References 21 publications

Inhibition of Adipocyte Differentiation by Nur77, Nurr1, and Nor1

Inhibition of Adipocyte Differentiation by Nur77, Nurr1, and Nor1

NR4A Orphan Nuclear Receptors

Regulasi Adipogenesis oleh mTORC1 melalui Jalur ST A T3

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