Hsp90 Blockers Inhibit Adipocyte Differentiation and Fat Mass Accumulation

Desarzens, Sébastien; Liao, Wan-Hui; Mammi, Caterina; Caprio, Massimiliano; Faresse, Nourdine

doi:10.1371/journal.pone.0094127

Cited by 32 publications

(21 citation statements)

References 38 publications

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“…Modulation of MR activity can occur through posttranslational modification by protein kinases and enzymes involved in adipogenic pathways (Faresse 2014). Among the transcription factors involved in adipogenesis, a relevant role for CREB has been demonstrated.…”

Section: Modulation Of Mr Activity By Adipogenic Signaling Pathways Amentioning

confidence: 99%

“…However, phosphorylation of MR has been detected in renal cells, cardiomyocytes and adipocytes (Galigniana 1998, Desarzens et al 2014. Aldosterone itself is able to induce phosphorylation of MR on serine residues located in the N-terminal domain with subsequent proteosomal degradation of the receptor (Faresse et al 2012).…”

Section: Modulation Of Mr Activity By Adipogenic Signaling Pathways Amentioning

confidence: 99%

See 1 more Smart Citation

Cellular mechanisms of MR regulation of adipose tissue physiology and pathophysiology

Armani¹,

Marzolla²,

Fabbri³

et al. 2015

Journal of Molecular Endocrinology

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In addition to the well-documented expression and activity of the mineralocorticoid receptor (MR) in the kidney, in the last decade research on MR has also revealed its important role in regulating functions of extrarenal tissues, including adipose tissue, where MR is involved in adipocyte fundamental processes such as differentiation, autophagy and adipokine secretion. MR expression is increased in adipose tissue of murine models of obesity and in obese human subjects, suggesting that over-activation of the mineralocorticoid signaling leads to dysfunctional adipocyte and associated metabolic disorders. Notably, pharmacological blockade of MR prevents metabolic dysfunctions observed in obese mice and suggests a potential therapeutic use of MR antagonists in the treatment of obesity and metabolic syndrome. However, the molecular pathways affected by MR blockade have been poorly investigated. This review summarizes the functions of MR in the adipocyte, discusses potential signaling pathways mediating MR action, and describes post-translational modifications regulating its activity.

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Section: Modulation Of Mr Activity By Adipogenic Signaling Pathways Amentioning

confidence: 99%

Section: Modulation Of Mr Activity By Adipogenic Signaling Pathways Amentioning

confidence: 99%

Cellular mechanisms of MR regulation of adipose tissue physiology and pathophysiology

Armani¹,

Marzolla²,

Fabbri³

et al. 2015

Journal of Molecular Endocrinology

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“…Nguyen et al ( 25 ) have shown that Hsp90 chaperones Ppar ␥ , while Desarzens et al ( 32 ) have shown that Hsp90 inhibition blocks adipocyte lipid accumulation in vivo. Indeed, Hsp90 interacts with and chaperones many different transcription factors ( 33 ), most notably the nuclear hormone receptors, providing precedent for this observation ( 34 ).…”

Section: Y344h/y344hmentioning

confidence: 99%

Hsp90 modulates PPARγ activity in a mouse model of nonalcoholic fatty liver disease

Wheeler

Gekakis²

2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org the molecular and cellular levels can have a signifi cant effect on treatment of this disease and its comorbidities.Different cellular and molecular mechanisms are hypothesized to play a role in the development of steatosis. The liver plays a key role in lipid metabolism. It must balance secretion of VLDL, which requires uptake of dietary lipids or de novo synthesis, with oxidation of fatty acids to fuel its own anabolic programs, such as gluconeogenesis ( 1 ). A disturbance in this balance can lead to a deleterious accumulation of excess lipids. Increases in synthesis, via constitutively active sterol-regulatory element binding protein (SREBP) 1c, for example, or increases in uptake, via overexpression of the fatty acid transporter CD36, are suffi cient to induce steatosis ( 4, 5 ). On the other hand, reductions in fatty acid oxidation or VLDL secretion increase fatty acid accumulation ( 6, 7 ). Furthermore, insulin resistance is thought to exacerbate steatosis, as higher levels of insulin can drive increased lipogenesis in the liver ( 8 ).With respect to rodent models, both dietary manipulations (e.g., high-fat or methionine-and-choline-defi cient diet) and genetic obesity (e.g., the ob/ob mouse) model aspects of NAFLD ( 9 ). These models suggest many possible mechanisms for steatosis, such as infl ammation, endoplasmic reticulum (ER) stress, and lipotoxic stress. Investigation in mouse models that are independent of dietary manipulation, obesity, or insulin resistance can therefore be helpful in describing primary etiological factors involved in the pathogenesis of NAFLD.Previously, we have shown that mice homozygous for an ethylnitrosourea-induced point mutation in the Sec61a1 gene ( Sec61a1 Y344H/Y344H) develop diabetes due to ␤ -cell apoptosis ( 10 ). Sec61a1 encodes Sec61 ␣ , a 10-pass transmembrane Abstract Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent complication of obesity, yet cellular mechanisms that lead to its development are not well defi ned. Previously, we have documented hepatic steatosis in mice carrying a mutation in the Sec61a1 gene. Here we examined the mechanism behind NAFLD in Sec61a1 mutant mice. Livers of mutant mice exhibited upregulation of Pparg and its target genes Cd36 , Cidec , and Lpl , correlating with increased uptake of fatty acid. Interestingly, these mice also displayed activation of the heat shock response (HSR), with elevated levels of heat shock protein (

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“…We previously found that pharmacological inhibition of both MR and GR abolished the adipogenesis and prevented adipose tissue expansion and adipocyte hypertrophy during a chronic high fat diet (Desarzens et al 2014). Other studies evidenced that GR has a more prevalent role, compared with MR, in promoting the maturation of preadipocytes (Lee & Fried 2014a).…”

Section: Introductionmentioning

confidence: 97%

Adipocyte glucocorticoid receptor has a minor contribution in adipose tissue growth

Desarzens

Faresse

2016

Journal of Endocrinology

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The glucocorticoids bind and activate both the glucocorticoid receptor (GR) as well as the mineralocorticoid receptor in adipocytes. Despite several studies to determine the function of these two receptors in mediating glucocorticoids effects, their relative contribution in adipose tissue expansion and obesity is unclear. To investigate the effect of GR in adipose tissue function, we generated an adipocyte-specific Gr-knockout mouse model (Gr ad-ko ). These mice were submitted either to a standard diet or a high-fat high sucrose diet. We found that adipocyte-specific deletion of Gr did not affect body weight gain or adipose tissue formation and distribution. However, the lack of Gr in adipocyte promotes a diet-induced inflammation determined by higher pro-inflammatory genes expression and macrophage infiltration in the fat pads. Surprisingly, the adipose tissue inflammation in Gr ad-ko mice was not correlated with insulin resistance or dyslipidemia, but with disturbed glucose tolerance. Our data demonstrate that adipocyte-specific ablation of Gr in vivo may affect the adipose tissue function but not its expansion during a high calorie diet.

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Hsp90 Blockers Inhibit Adipocyte Differentiation and Fat Mass Accumulation

Cited by 32 publications

References 38 publications

Cellular mechanisms of MR regulation of adipose tissue physiology and pathophysiology

Cellular mechanisms of MR regulation of adipose tissue physiology and pathophysiology

Hsp90 modulates PPARγ activity in a mouse model of nonalcoholic fatty liver disease

Adipocyte glucocorticoid receptor has a minor contribution in adipose tissue growth

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