title: Mineralocorticoid receptor antagonism induces browning of white adipose tissue through impairment of autophagy and prevents adipocyte dysfunction in high-fat-diet-fed mice.
abstract: The mineralocorticoid receptor (MR) controls adipocyte function, but its role in the conversion of white adipose tissue (WAT) into thermogenic fat has not been elucidated. We investigated responses to the MR antagonists spironolactone (spiro; 20 mg/kg/d) and drospirenone (DRSP; 6 mg/kg/d) in C57BL/6 mice fed a high-fat (HF) diet for 90 d. DRSP and spiro curbed HF diet-induced impairment in glucose tolerance, and prevented body weight gain and white fat expansion. Notably, either MR antagonist induced up-regulation of brown adipocyte-specific transcripts and markedly increased protein levels of uncoupling protein 1 (UCP1) in visceral and inguinal fat depots when compared with the HF diet group. Positron emission tomography and magnetic resonance spectroscopy confirmed acquisition of brown fat features in WAT. Interestingly, MR antagonists markedly reduced the autophagic rate both in murine preadipocytes in vitro (10(-5) M) and in WAT depots in vivo, with a concomitant increase in UCP1 protein expression. Moreover, the autophagy repressor bafilomycin A1 (10(-8) M) mimicked the effect of MR antagonists, increasing UCP1 protein expression in primary preadipocytes. Hence, we showed that adipocyte MR regulates brown remodeling of WAT through a modulation of autophagy. These results provide a rationale for the use of MR antagonists to prevent the adverse metabolic consequences of adipocyte dysfunction.
authors.affiliation: Laboratory of Cardiovascular Endocrinology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: Armani
authors.affiliation: Laboratory of Cardiovascular Endocrinology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy; Department of Experimental and Clinical Medicine, Center for the Study of Obesity, United Hospitals University of Ancona, Ancona, Italy;
authors.forename: Francesca
authors.initials: F
authors.lastname: Cinti
authors.affiliation: Laboratory of Cardiovascular Endocrinology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy;
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Marzolla
authors.affiliation: Monash Institute of Medical Research-Prince Henry's Institute (MIMR-PHI) Medical Research Institute, Clayton, Victoria, Australia;
authors.forename: James
authors.initials: J
authors.lastname: Morgan
authors.affiliation: Monash Institute of Medical Research-Prince Henry's Institute (MIMR-PHI) Medical Research Institute, Clayton, Victoria, Australia;
authors.forename: Greg A
authors.initials: GA
authors.lastname: Cranston
authors.affiliation: Laboratory of Cardiovascular Endocrinology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy;
authors.forename: Antonella
authors.initials: A
authors.lastname: Antelmi
authors.affiliation: Department of Cell Biology and Neurosciences and.
authors.forename: Giulia
authors.initials: G
authors.lastname: Carpinelli
authors.affiliation: Department of Cell Biology and Neurosciences and.
authors.forename: Rossella
authors.initials: R
authors.lastname: Canese
authors.affiliation: Endocrinology Unit and Center for Applied Biomedical Research, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater University of Bologna, Bologna, Italy;
authors.forename: Uberto
authors.initials: U
authors.lastname: Pagotto
authors.affiliation: Endocrinology Unit and Center for Applied Biomedical Research, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, Alma Mater University of Bologna, Bologna, Italy;
authors.forename: Carmelo
authors.initials: C
authors.lastname: Quarta
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Rome, Italy; San Raffaele Institute Sulmona, L'Aquila, Italy;
authors.forename: Walter
authors.initials: W
authors.lastname: Malorni
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Rome, Italy; Center of Integrated Metabolomics, Rome, Italy; and.
authors.forename: Paola
authors.initials: P
authors.lastname: Matarrese
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, Rome, Italy;
authors.forename: Matteo
authors.initials: M
authors.lastname: Marconi
authors.affiliation: Department of Medicina dei Sistemi, Endocrinology Unit, S. Eugenio and CTO A. Alesini Hospitals, University Tor Vergata, Rome, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: Fabbri
authors.affiliation: Laboratory of Cardiovascular Endocrinology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy;
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rosano
authors.affiliation: Department of Experimental and Clinical Medicine, Center for the Study of Obesity, United Hospitals University of Ancona, Ancona, Italy;
authors.forename: Saverio
authors.initials: S
authors.lastname: Cinti
authors.affiliation: Department of Physiology and Department of Medicine, Monash University, Clayton, Victoria, Australia.
authors.forename: Morag J
authors.initials: MJ
authors.lastname: Young
authors.affiliation: Laboratory of Cardiovascular Endocrinology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy; massimiliano.caprio@sanraffaele.it.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Caprio
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D050156:Adipogenesis / Q000187:drug effects / Q000502:physiology; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000187:drug effects*; D000450:Aldosterone / Q000494:pharmacology; D000736:Androstenes / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001823:Body Composition / Q000187:drug effects; D054338:Cell Transdifferentiation / Q000187:drug effects*; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D020869:Gene Expression Profiling; D018149:Glucose Intolerance / Q000209:etiology / Q000517:prevention & control*; D007264:Inguinal Canal; D050152:Intra-Abdominal Fat / Q000187:drug effects; D007473:Ion Channels / Q000096:biosynthesis / Q000235:genetics; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D009765:Obesity / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000502:physiology*; D013148:Spironolactone / Q000494:pharmacology* / Q000627:therapeutic use; D000071256:Uncoupling Protein 1; D015854:Up-Regulation / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000736:Androstenes; D007473:Ion Channels; D018942:Macrolides; D000451:Mineralocorticoid Receptor Antagonists; D024101:Mitochondrial Proteins; D018161:Receptors, Mineralocorticoid; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C057620:bafilomycin A; D013148:Spironolactone; D000450:Aldosterone; C035144:drospirenone
keywords: UCP1; adipogenesis; aldosterone; metabolic syndrome; obesity; uncoupling protein 1