Adipocyte Mineralocorticoid Receptor Activation Leads to Metabolic Syndrome and Induction of Prostaglandin D2 Synthase

Riccardo Urbanet; Aurelie Nguyen Dinh Cat; Alessandra Feraco; Nicolas Venteclef; Soumaya El Mogrhabi; Catalina Sierra-Ramos; Diego Alvarez de la Rosa; Gail K Adler; Didier Quilliot; Patrick Rossignol; Francesco Fallo; Rhian M Touyz; Frédéric Jaisser

doi:10.1161/HYPERTENSIONAHA.114.04981

Adipocyte Mineralocorticoid Receptor Activation Leads to Metabolic Syndrome and Induction of Prostaglandin D2 Synthase

Hypertension. 2015 Jul;66(1):149-57. doi: 10.1161/HYPERTENSIONAHA.114.04981. Epub 2015 May 11.

Affiliations

¹ From the INSERM, UMR_S 1138, Teams 1 (R.U., A.F., S.E.M., F.J.) and 8 (N.V.), Centre de Recherche des Cordeliers, UPMC Univ Paris 06, Université Paris Descartes, Paris, France; Department of Medicine (DIMED), University of Padova, Padova, Italy (R.U., F.F.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (A.N.D.C., R.M.T.); Laboratory of Cardiovascular Endocrinology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy (A.F.); Department of Physiology and Institute of Biomedical Technologies, University of La Laguna, Tenerife, Spain (D.A.D.l.R.); Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (G.K.A.); Department of Nutrition, Nancy University Hospital, INSERM U954, Medical Faculty and CHU of Nancy, Vandoeuvre-les-Nancy, France (D.Q.); and INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, CHU de Nancy, and Université de Lorraine, and Investigation Network Initiative Cardiovascular and Renal Clinical Trialists (INI-CRCT) French Clinical Research Infrastructure Network (F-CRIN), Nancy, France (P.R., F.J.).
² From the INSERM, UMR_S 1138, Teams 1 (R.U., A.F., S.E.M., F.J.) and 8 (N.V.), Centre de Recherche des Cordeliers, UPMC Univ Paris 06, Université Paris Descartes, Paris, France; Department of Medicine (DIMED), University of Padova, Padova, Italy (R.U., F.F.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (A.N.D.C., R.M.T.); Laboratory of Cardiovascular Endocrinology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy (A.F.); Department of Physiology and Institute of Biomedical Technologies, University of La Laguna, Tenerife, Spain (D.A.D.l.R.); Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (G.K.A.); Department of Nutrition, Nancy University Hospital, INSERM U954, Medical Faculty and CHU of Nancy, Vandoeuvre-les-Nancy, France (D.Q.); and INSERM, Centre d'Investigations Cliniques-Plurithématique 1433, CHU de Nancy, and Université de Lorraine, and Investigation Network Initiative Cardiovascular and Renal Clinical Trialists (INI-CRCT) French Clinical Research Infrastructure Network (F-CRIN), Nancy, France (P.R., F.J.). frederic.jaisser@inserm.fr.

PMID: 25966493
DOI: 10.1161/HYPERTENSIONAHA.114.04981

Abstract

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.

Keywords: aldosterone; obesity; prostaglandin D2 synthase 21kDa, brain; spironolactone.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3T3-L1 Cells
Adipocytes, White
Aldosterone / pharmacology
Animals
Cell Line, Tumor
Dibenzocycloheptenes / pharmacology
Enzyme Induction / drug effects
Humans
Insulin Resistance
Intra-Abdominal Fat / metabolism
Intra-Abdominal Fat / pathology
Intra-Abdominal Fat / physiopathology*
Intramolecular Oxidoreductases / biosynthesis*
Intramolecular Oxidoreductases / genetics
Lipocalins / biosynthesis*
Lipocalins / genetics
Male
Metabolic Syndrome / drug therapy
Metabolic Syndrome / etiology*
Metabolic Syndrome / physiopathology
Mice
Mice, Obese
Mice, Transgenic
Mineralocorticoid Receptor Antagonists / pharmacology
Mineralocorticoid Receptor Antagonists / therapeutic use
Obesity / genetics
Obesity / physiopathology*
Piperidines / pharmacology
RNA, Messenger / biosynthesis
RNA, Messenger / genetics
Receptors, Leptin / deficiency
Receptors, Mineralocorticoid / biosynthesis
Receptors, Mineralocorticoid / genetics
Receptors, Mineralocorticoid / physiology*
Spironolactone / pharmacology
Spironolactone / therapeutic use
Subcutaneous Fat / metabolism
Up-Regulation

Substances

4-(5H-dibenzo(a,d)cyclohepten-5-ylidene)-1-(4-(2H-tetrazol-5-yl)butyl)piperidine
Dibenzocycloheptenes
Lipocalins
Mineralocorticoid Receptor Antagonists
Piperidines
RNA, Messenger
Receptors, Leptin
Receptors, Mineralocorticoid
leptin receptor, mouse
Spironolactone
Aldosterone
Intramolecular Oxidoreductases
prostaglandin R2 D-isomerase