Mineralocorticoid receptor antagonism induces browning of white adipose tissue through impairment of autophagy and prevents adipocyte dysfunction in high-fat-diet-fed mice.

Andrea Armani, Francesca Cinti, Vincenzo Marzolla, James Morgan, Greg A. Cranston, Antonella Antelmi, Giulia Carpinelli, Rossella Canese, Uberto Pagotto, Carmelo Quarta, Walter Malorni, Paola Matarrese, Matteo Marconi, Andrea Fabbri, Giuseppe Rosano, Saverio Cinti, Morag J. Young, Massimiliano Caprio
FASEB j.. 2014-05-07; 28(8): 3745-3757
DOI: 10.1096/fj.13-245415

PubMed

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Armani A(1), Cinti F(2), Marzolla V(1), Morgan J(3), Cranston GA(3), Antelmi
A(1), Carpinelli G(4), Canese R(4), Pagotto U(5), Quarta C(5), Malorni W(6),
Matarrese P(7), Marconi M(8), Fabbri A(9), Rosano G(1), Cinti S(10), Young
MJ(11), Caprio M(12).

Author information:
(1)Laboratory of Cardiovascular Endocrinology, Istituto di Ricovero e Cura a
Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy;
(2)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;
(3)Monash Institute of Medical Research-Prince Henry’s Institute (MIMR-PHI)
Medical Research Institute, Clayton, Victoria, Australia;
(4)Department of Cell Biology and Neurosciences and.
(5)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;
(6)Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore
di Sanità, Rome, Italy; San Raffaele Institute Sulmona, L’Aquila, Italy;
(7)Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore
di Sanità, Rome, Italy; Center of Integrated Metabolomics, Rome, Italy; and.
(8)Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore
di Sanità, Rome, Italy;
(9)Department of Medicina dei Sistemi, Endocrinology Unit, S. Eugenio and CTO A.
Alesini Hospitals, University Tor Vergata, Rome, Italy;
(10)Department of Experimental and Clinical Medicine, Center for the Study of
Obesity, United Hospitals University of Ancona, Ancona, Italy;
(11)Department of Physiology and Department of Medicine, Monash University,
Clayton, Victoria, Australia.
(12)Laboratory of Cardiovascular Endocrinology, Istituto di Ricovero e Cura a
Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy;
.

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.