PPARs and adipocyte function

Christodoulides, Constantinos; Vidal-Puig, António

doi:10.1016/j.mce.2009.09.014

Cited by 115 publications

(85 citation statements)

References 100 publications

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“…PPARs belong to a large superfamily of nuclear hormone receptors, which play an important role in the regulation of lipid homoeostasis and glucose metabolism (Stienstra et al, 2007;Christodoulides and Vidal-Puig, 2010). So far, three Fig.…”

Section: Discussionmentioning

confidence: 99%

Methyl 2-Cyano-3,11-dioxo-18-olean-1,12-dien-30-oate (CDODA-Me), a Derivative of Glycyrrhetinic Acid, Functions as a Potent Angiogenesis Inhibitor

Pang¹,

Zhang²,

Wu³

et al. 2010

J Pharmacol Exp Ther

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Methyl 2-cyano-3,11-dioxo-18-olean-1,12-dien-30-oate (CDODA-Me), a triterpenoid acid derived synthetically from glycyrrhetinic acid, has been characterized as a peroxisome proliferator-activated receptor ␥ agonist with a broad range of receptor-dependent and -independent anticancer activities. Although CDODA-Me decreases the expression of some angiogenic genes in cancer cells, the direct effects of this compound on angiogenesis have not been defined. In this study, we have extensively investigated the activities of CDODA-Me in multiple angiogenesis assays. Our results showed that this agent inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration, invasion, and lamellipodium and capillary-like structure formation of human umbilical endothelial cells (HUVECs) in a concentrationdependent manner. Moreover, CDODA-Me abrogated VEGFinduced sprouting of microvessels from rat aortic rings ex vivo and inhibited the generation of new vasculature in the Matrigel plugs in vivo, where CDODA-Me significantly decreased the number of infiltrating von Willebrand factor-positive endothelial cells. To understand the molecular basis of this antiangiogenic activity, we examined the signaling pathways in CDODA-Me-treated HUVECs. Our results showed that CDODA-Me significantly suppressed the activation of VEGF receptor 2 (VEGFR2) and interfered with the mammalian target of rapamycin (mTOR) signaling, including mTOR kinase and its downstream ribosomal S6 kinase (S6K), but had little effect on the activities of extracellular signalregulated protein kinase and AKT. Taken together, CDODA-Me blocks several key steps of angiogenesis by inhibiting VEGF/ VEGFR2 and mTOR/S6K signaling pathways, making the compound a promising agent for the treatment of cancer and angiogenesis-related pathologies.

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Section: Discussionmentioning

confidence: 99%

Methyl 2-Cyano-3,11-dioxo-18-olean-1,12-dien-30-oate (CDODA-Me), a Derivative of Glycyrrhetinic Acid, Functions as a Potent Angiogenesis Inhibitor

Pang¹,

Zhang²,

Wu³

et al. 2010

J Pharmacol Exp Ther

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“…3,4 PPARg belongs to the RXR-heterodimeric group 1 of the nuclear receptor superfamily (NR1C3). Of its two major isoforms, PPARg1 is expressed in a variety of tissues, including the liver, skeletal muscle, macrophages, adipose tissue and bone.…”

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confidence: 99%

“…PPARg2 possesses a 30-amino-acid extension at its extreme N-terminus, and exclusively occurs in adipogenic cells. 4 General and adipose-specific deletion of PPARg in mice [5][6][7] and dominant-negative PPARg mutations in humans 8 lead to lipodystrophy and severe insulin resistance. PPARg activation by the antidiabetic thiazolidinediones as well as by adipocytetargeted transgene expression of PPARg2 improves insulin sensitivity, adipokine and inflammatory profiles.…”

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confidence: 99%

Hsp90 chaperones PPARγ and regulates differentiation and survival of 3T3-L1 adipocytes

2013

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Adipose tissue dysregulation has a major role in various human diseases. The peroxisome proliferator-activated receptor-c (PPARc) is a key regulator of adipocyte differentiation and function, as well as a target of insulin-sensitizing drugs. The Hsp90 chaperone stabilizes a diverse set of signaling 'client' proteins, thereby regulates various biological processes. Here we report a novel role for Hsp90 in controlling PPARc stability and cellular differentiation. Specifically, we show that the Hsp90 inhibitors geldanamycin and novobiocin efficiently impede the differentiation of murine 3T3-L1 preadipocytes. Geldanamycin at higher concentrations also inhibits the survival of both developing and mature adipocytes, respectively. Further, Hsp90 inhibition disrupts an Hsp90-PPARc complex, leads to the destabilization and proteasomal degradation of PPARc, and inhibits the expression of PPARc target genes, identifying PPARc as an Hsp90 client. A similar destabilization of PPARc and a halt of adipogenesis also occur in response to protein denaturing stresses caused by a single transient heat-shock or proteasome inhibition. Recovery from stress restores PPARc stability and adipocyte differentiation. Thus, our findings reveal Hsp90 as a critical stress-responsive regulator of adipocyte biology and offer a potential therapeutic target in obesity and the metabolic syndrome.

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“…Among a number of transcription factors involved in the regulation of adipogenesis, peroxisome proliferator-activated receptor (PPAR)␥ and CCAAT/enhancer-binding proteins (C/EBPs) are master regulators that control many adipogenic and lipogenic genes (18,29,44). PPAR␥ belongs to the nuclear receptor superfamily of transcription factors, which are activated in a ligandmediated fashion (3,31,33,35). The activity of PPAR␥ is exploited by synthetic PPAR␥ ligands, notably the thiazolidinediones such as pioglitazone and rosiglitazone, to improve insulin sensitivity (10).…”

mentioning

confidence: 99%

Very long-chain-fatty acids enhance adipogenesis through coregulation of Elovl3 and PPARγ in 3T3-L1 cells

Kobayashi

Fujimori

2012

American Journal of Physiology-Endocrinology and Metabolism

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PPARs and adipocyte function

Cited by 115 publications

References 100 publications

Methyl 2-Cyano-3,11-dioxo-18-olean-1,12-dien-30-oate (CDODA-Me), a Derivative of Glycyrrhetinic Acid, Functions as a Potent Angiogenesis Inhibitor

Methyl 2-Cyano-3,11-dioxo-18-olean-1,12-dien-30-oate (CDODA-Me), a Derivative of Glycyrrhetinic Acid, Functions as a Potent Angiogenesis Inhibitor

Hsp90 chaperones PPARγ and regulates differentiation and survival of 3T3-L1 adipocytes

Very long-chain-fatty acids enhance adipogenesis through coregulation of Elovl3 and PPARγ in 3T3-L1 cells

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