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Vitiello L.,Laboratory of Molecular and Cellular Immunology | Spoletini I.,Center for Clinical and Basic Research | Gorini S.,Laboratory of Molecular and Cellular Immunology | Pontecorvo L.,Laboratory of Molecular and Cellular Immunology | And 5 more authors.
IJC Metabolic and Endocrine | Year: 2014

Atherogenesis is the pathogenetic process leading to formation of the atheroma lesion. It is associated to a chronic inflammatory state initially stimulated by an aberrant accumulation of lipid molecules beyond the endothelial barrier. This event triggers a cascade of deleterious events mainly through immune cell stimulation with the consequent liberation of potent pro-inflammatory and tissue damaging mediators. The atherogenetic process implies marked modifications of endothelial cell functions and a radical change in the endothelial-leukocyte interaction pattern. Moreover, accumulating evidence shows an important link between microvascular and inflammatory responses and major cardiovascular risk factors. This review illustrates the current knowledge on the effects of obesity, hypercholesterolemia and diabetes on microcirculation; their pathophysiological implications will be discussed. © 2014 The Authors.


Background:We have previously shown that antagonism of the mineralocorticoid receptor (MR) results in a potent antiadipogenic activity, in vitro and in vivo. Excessive glucocorticoid exposure is associated with obesity and related disorders in humans and mice.Methods:In this study, responses to a novel combined glucocorticoid receptor (GR)/MR antagonist were investigated in a model of diet-induced obesity. Female 10-week-old C57BL/6J mice were fed with normal chow or a high-fat diet (HFD) for 9 weeks. Mice fed a HFD were concomitantly treated for 9 weeks with the GR antagonist mifepristone (80 mg kg-1 per day) or the novel combined GR/MR antagonist CORT118335 (80 mg kg-1 per day). Male, juvenile 6-week-old C57BL/6J mice fed HFD were treated with CORT118335 for 4 weeks.Results:Mice fed a HFD showed a significant increase in total body weight and white fat mass, with impaired glucose tolerance and increased fat infiltration in livers. Interestingly, only CORT118335 completely prevented the HFD-induced weight gain and white fat deposition, whereas mifepristone showed no effect on body weight and modestly increased subcutaneous fat mass. Importantly, food intake was not affected by either treatment, and CORT118335 dramatically increased PGC-1α protein expression in adipose tissue, without any effect on UCP1. Both CORT118335 and mifepristone produced metabolic benefit, improving glucose tolerance, increasing adiponectin plasma levels, decreasing leptin and reducing mean adipocyte size. When tested in vitro, CORT118335 markedly reduced 3T3-L1 differentiation and reversed MR-mediated pro-adipogenic effects of aldosterone; differently, GR-mediated effects of dexamethasone were not antagonized by CORT118335, suggesting that it mostly acts as an antagonist of MR in cultured preadipocytes.Conclusions:Combined GR/MR pharmacological antagonism markedly reduced HFD-driven weight gain and fat mass expansion in mice through the increase in adipose PGC-1α, suggesting that both receptors represent strategic therapeutic targets to fight obesity. The effects of CORT118335 in adipocytes seem predominantly mediated by MR antagonism.International Journal of Obesity advance online publication, 22 March 2016; doi:10.1038/ijo.2016.13. © 2016 Macmillan Publishers Limited


Urbanet R.,University of Paris Descartes | Urbanet R.,University of Padua | Cat A.N.D.,University of Glasgow | Feraco A.,University of Paris Descartes | And 13 more authors.
Hypertension | Year: 2015

Metabolic syndrome is a major risk factor for the development of diabetes mellitus and cardiovascular diseases. Pharmacological antagonism of the mineralocorticoid receptor (MR), a ligand-activated transcription factor, limits metabolic syndrome in preclinical models, but mechanistic studies are lacking to delineate the role of MR activation in adipose tissue. In this study, we report that MR expression is increased in visceral adipose tissue in a preclinical mouse model of metabolic syndrome and in obese patients. In vivo conditional upregulation of MR in mouse adipocytes led to increased weight and fat mass, insulin resistance, and metabolic syndrome features without affecting blood pressure. We identified prostaglandin D2 synthase as a novel MR target gene in adipocytes and AT56, a specific inhibitor of prostaglandin D2 synthase enzymatic activity, blunted adipogenic aldosterone effects. Moreover, translational studies showed that expression of MR and prostaglandin D2 synthase is strongly correlated in adipose tissues from obese patients. © 2015 American Heart Association, Inc.


Mammi C.,Laboratory of Cardiovascular Endocrinology | Marzolla V.,Laboratory of Cardiovascular Endocrinology | Armani A.,Laboratory of Cardiovascular Endocrinology | Feraco A.,Laboratory of Cardiovascular Endocrinology | And 9 more authors.
International Journal of Obesity | Year: 2016

Background:We have previously shown that antagonism of the mineralocorticoid receptor (MR) results in a potent antiadipogenic activity, in vitro and in vivo. Excessive glucocorticoid exposure is associated with obesity and related disorders in humans and mice.Methods:In this study, responses to a novel combined glucocorticoid receptor (GR)/MR antagonist were investigated in a model of diet-induced obesity. Female 10-week-old C57BL/6J mice were fed with normal chow or a high-fat diet (HFD) for 9 weeks. Mice fed a HFD were concomitantly treated for 9 weeks with the GR antagonist mifepristone (80 mg kg -1 per day) or the novel combined GR/MR antagonist CORT118335 (80 mg kg -1 per day). Male, juvenile 6-week-old C57BL/6J mice fed HFD were treated with CORT118335 for 4 weeks.Results:Mice fed a HFD showed a significant increase in total body weight and white fat mass, with impaired glucose tolerance and increased fat infiltration in livers. Interestingly, only CORT118335 completely prevented the HFD-induced weight gain and white fat deposition, whereas mifepristone showed no effect on body weight and modestly increased subcutaneous fat mass. Importantly, food intake was not affected by either treatment, and CORT118335 dramatically increased PGC-1α protein expression in adipose tissue, without any effect on UCP1. Both CORT118335 and mifepristone produced metabolic benefit, improving glucose tolerance, increasing adiponectin plasma levels, decreasing leptin and reducing mean adipocyte size. When tested in vitro, CORT118335 markedly reduced 3T3-L1 differentiation and reversed MR-mediated pro-adipogenic effects of aldosterone; differently, GR-mediated effects of dexamethasone were not antagonized by CORT118335, suggesting that it mostly acts as an antagonist of MR in cultured preadipocytes.Conclusions:Combined GR/MR pharmacological antagonism markedly reduced HFD-driven weight gain and fat mass expansion in mice through the increase in adipose PGC-1α, suggesting that both receptors represent strategic therapeutic targets to fight obesity. The effects of CORT118335 in adipocytes seem predominantly mediated by MR antagonism.


Armani A.,Laboratory of Cardiovascular Endocrinology | Marzolla V.,Laboratory of Cardiovascular Endocrinology | Fabbri A.,University of Rome Tor Vergata | Caprio M.,Laboratory of Cardiovascular Endocrinology | Caprio M.,University San Raffaele
Journal of Molecular Endocrinology | Year: 2015

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. © 2015 Society for Endocrinology.

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