Adipocyte conversion of cultured 3T3-Ll preadipocytes by bezafibrate

Brandes, Ruth; Hertz, Rachel; Arad, Rivka; Naishtat, S.; Weil, Shulamit; Bar‐Tana, Jacob

doi:10.1016/0024-3205(87)90312-2

Cited by 26 publications

(12 citation statements)

References 12 publications

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“…If fatty acids or other lipids derived from the diet can serve to activate mPPAR~/2, this may stimulate adipogenic gene expression or even fat cell differentiation per se. Although this paper presents no data that directly implicate mPPAR~/2 in the regulation of the differentiation process, PPAR activators such as the fibrate hypolidipemic drugs have been reported previously to induce and/or potentiate the differentiation of certain preadipocyte cell lines (Brandes et al 1987;Gharbi-Chihi et al 1993). It is reasonable to hypothesize that this effect may be mediated by an adi-pocyte-specific family member such as mPPAR~/2.…”

Section: Discussionmentioning

confidence: 80%

mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer.

Tontonoz¹,

Hu²,

Graves³

et al. 1994

Genes Dev.

2,063

1,531

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Previously, we have isolated and characterized an enhancer from the 5'-flanking region of the adipocyte P2 (aP2) gene that directs high-level adipocyte-specific gene expression in both cultured cells and transgenic mice. The key regulator of this enhancer is a cell type-restricted nuclear factor termed ARF6. Target sequences for ARF6 in the aP2 enhancer exhibit homology to a direct repeat of hormone response elements (HREs) spaced by one nucleotide; this motif (DR-l) has been demonstrated previously to be the preferred binding site for heterodimers of the retinoid X receptor (RXR) and the peroxisome proliferator-activated receptor (PPAR). We have cloned a novel member of the peroxisome proliferator-activated receptor family designated mPPART2, and we demonstrate that a heterodimeric complex of mPPAR~/2 and RXR~ constitute a functional ARF6 complex. Expression of mPPAR,/2 is induced very early during the differentiation of several cultured adipocyte cell lines and is strikingly adipose-specific in vivo. mPPAR-/2 and RXRc~ form heterodimers on ARF6-binding sites in vitro, and antiserum to RXRc~ specifically inhibits ARF6 activity in adipocyte nuclear extracts. Moreover, forced expression of mPPAR~/2 and RXR~ activates the adipocyte-specific aP2 enhancer in cultured fibroblasts, and this activation is potentiated by peroxisome proliferators, fatty acids, and 9-cis retinoic acid. These results identify mPPAR~/2 as the first adipocyte-specific transcription factor and suggest mechanisms whereby fatty acids, peroxisome proliferators, 9-cis retinoic acid, and other lipids may regulate adipocyte gene expression and differentiation.

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Section: Discussionmentioning

confidence: 80%

mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer.

Tontonoz¹,

Hu²,

Graves³

et al. 1994

Genes Dev.

2,063

1,531

View full text Add to dashboard Cite

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“…PPAR␣ is most abundant in liver, while the tissue distribution of PPAR␦ is more widespread. In contrast, expression of PPAR␥ is limited to adipose tissue (15,16) and, indeed, activators of PPAR can suffice to induce adipose conversion of preadipocyte cell lines (17,18). Moreover, ectopic expression of PPAR␥ causes fibroblast cell lines to differentiate into adipocytes in the presence of PPAR activators (19).…”

mentioning

confidence: 99%

Differential Activation of Peroxisome Proliferator-activated Receptors by Eicosanoids

Yu¹,

Bayona²,

Kallen

et al. 1995

Journal of Biological Chemistry

637

408

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Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate gene transcription in response to peroxisome proliferators and fatty acids. PPARs also play an important role in the regulation of adipocyte differentiation. It is unclear, however, what naturally occurring compounds activate each of the PPAR subtypes. To address this issue, a screening assay was established using heterologous fusions of the bacterial tetracycline repressor to several members of the peroxisome proliferator-activated receptor (PPAR) family. This assay was employed to compare the activation of PPAR family members by known PPAR activators including peroxisome proliferators and fatty acids. Interestingly, the activation of PPARs by fatty acids was partially inhibited by the cyclooxygenase inhibitor indomethacin, which prevents prostaglandin synthesis. Indeed, prostaglandins PGA1 and 2, PGD1 and 2, and PGJ2-activated PPARs, while a number of other prostaglandins had no effect. We also screened a variety of hydroxyeicosatetraenoic acids (HETEs) for the ability to activate PPARs. 8(S)-HETE, but not other (S)-HETEs, was a strong activator of PPAR␣. Remarkably, PPAR activation by 8(S)-HETE was stereoselective. In addition, 8(S)-HETE was able to induce differentiation of 3T3-L1 preadipocytes. These results indicate that PPARs are differentially activated by naturally occurring eicosanoids and related molecules.The cloning and characterization of nuclear receptors has greatly enhanced our understanding of gene regulation by lipophilic hormones such as steroids, vitamin D, thyroxine, and retinoids. These receptors comprise a superfamily of transcription factors containing highly related DNA-binding domains (1, 2). This family includes multiple subtypes of receptors for thyroxine and retinoids, encoded by distinct genes which are regulated quite differently during development and in the adult.

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“…Inhibition of differentiation is an unusual effect of RA, which more commonly promotes differentiation (19). In contrast to the effects of RA, peroxisome proliferators such as clofibrate have been shown to potentiate adipose conversion of 3T3-L1 cells in the presence of Dex, FCS, and insulin (20).…”

mentioning

confidence: 99%

Peroxisome proliferator and retinoid signalingpathways co-regulate preadipocyte phenotype and survival.

Chawla

Lazar

1994

Proc. Natl. Acad. Sci. U.S.A.

213

148

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Culture of mouse 3T3-L1 preadipocytes in medium containing delipidated bovine calf serum caused the cells to elongate and divide after reaching confluency. The continued proliferation correlated with sustained expression of the c-myc gene, which was repressed in control cells. Exposure of the cells to activators of peroxisome proliferator-activated receptor (PPAR), including clofibrate, WY-14,643, and 5,8,11,14-eicosatetraynoic acid, reversed and prevented the effects of culturing preadipocytes in delipidated serum. Continued exposure to PPAR activators led to adipose conversion, during which PPAR and its heterodimerization partner (retinoid X receptor) were induced. Retinoic acid (RA) had no effect on the growth or survival of preadipocytes grown in the presence of normal bovine serum. However, treatment of cells cultured in delipidated serum with RA caused death of the cells by apoptosis. Thus, preadipocyte phenotype and survival are regulated by activators of nuclear hormone receptors.

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Adipocyte conversion of cultured 3T3-Ll preadipocytes by bezafibrate

Cited by 26 publications

References 12 publications

mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer.

mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer.

Differential Activation of Peroxisome Proliferator-activated Receptors by Eicosanoids

Peroxisome proliferator and retinoid signalingpathways co-regulate preadipocyte phenotype and survival.

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