title: Adipocyte Mineralocorticoid Receptor Activation Leads to Metabolic Syndrome and Induction of Prostaglandin D2 Synthase.
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.
authors.affiliation: 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.).
authors.forename: Riccardo
authors.initials: R
authors.lastname: Urbanet
authors.affiliation: 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.).
authors.forename: Aurelie
authors.initials: A
authors.lastname: Nguyen Dinh Cat
authors.affiliation: 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.).
authors.forename: Alessandra
authors.initials: A
authors.lastname: Feraco
authors.affiliation: 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.).
authors.forename: Nicolas
authors.initials: N
authors.lastname: Venteclef
authors.affiliation: 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.).
authors.forename: Soumaya
authors.initials: S
authors.lastname: El Mogrhabi
authors.affiliation: 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.).
authors.forename: Catalina
authors.initials: C
authors.lastname: Sierra-Ramos
authors.affiliation: 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.).
authors.forename: Diego
authors.initials: D
authors.lastname: Alvarez de la Rosa
authors.affiliation: 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.).
authors.forename: Gail K
authors.initials: GK
authors.lastname: Adler
authors.affiliation: 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.).
authors.forename: Didier
authors.initials: D
authors.lastname: Quilliot
authors.affiliation: 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.).
authors.forename: Patrick
authors.initials: P
authors.lastname: Rossignol
authors.affiliation: 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.).
authors.forename: Francesco
authors.initials: F
authors.lastname: Fallo
authors.affiliation: 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.).
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
authors.affiliation: 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.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Jaisser
mesh_terms: D041721:3T3-L1 Cells; D052438:Adipocytes, White; D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D054834:Lipocalins / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D009765:Obesity / Q000235:genetics / Q000503:physiopathology*; D010880:Piperidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D054411:Receptors, Leptin / Q000172:deficiency; D018161:Receptors, Mineralocorticoid / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013148:Spironolactone / Q000494:pharmacology / Q000627:therapeutic use; D050151:Subcutaneous Fat / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C569292:4-(5H-dibenzo(a,d)cyclohepten-5-ylidene)-1-(4-(2H-tetrazol-5-yl)butyl)piperidine; D003986:Dibenzocycloheptenes; D054834:Lipocalins; D000451:Mineralocorticoid Receptor Antagonists; D010880:Piperidines; D012333:RNA, Messenger; D054411:Receptors, Leptin; D018161:Receptors, Mineralocorticoid; C515447:leptin receptor, mouse; D013148:Spironolactone; D000450:Aldosterone; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase
keywords: aldosterone; obesity; prostaglandin D2 synthase 21kDa, brain; spironolactone