Journal of Steroid Biochemistry & Molecular Biology 137 (2013) 99–106 Contents lists available at ScienceDirect Journal of Steroid Biochemistry and Molecular Biology jo ur nal home page: www.elsevier.com/locate/jsbmb Review Role of mineralocorticoid receptor and renin–angiotensin–aldosterone system in adipocyte dysfunction and obesity Alessandra Feraco b , Andrea Armani a , Caterina Mammi a , Andrea Fabbri c , Giuseppe M.C. Rosano a , Massimiliano Caprio a,* a Centre for Clinical and Basic Research, IRCCS San Raffaele Pisana, Rome, Italy b San Raffaele Sulmona, Sulmona (AQ), Italy c Department of Medicina dei Sistemi, Endocrinology Unit, S. Eugenio & CTO A. Alesini Hospitals, University Tor Vergata, Rome, Italy a r t i c l e i n f o Article history: Received 13 December 2012 Received in revised form 7 February 2013 Accepted 20 February 2013 Keywords: Mineralocorticoid receptor Adipocyte Adipose tissue Renin–angiotensin–aldosterone system a b s t r a c t The mineralocorticoid receptor (MR) classically mediates aldosterone effects on salt homeostasis and blood pressure regulation in epithelial target tissues. In recent years, functional MRs have been identified in non classical targets of aldosterone actions, in particular in adipose tissue, where they mediate the effects of aldosterone and glucocorticoids in the control of adipogenesis, adipose expansion and its pro- inflammatory capacity. In this context, inappropriate MR activation has been demonstrated to be a causal factor in several pathologic conditions such as vascular inflammation, endothelial dysfunction, insulin resistance and obesity. The aim of this review is to summarize the latest developments in this rapidly developing field, and will focus on the role of MR and renin–angiotensin–aldosterone system (RAAS) as potential leading characters in the early steps of adipocyte dysfunction and obesity. Indeed modulation of MR activity in adipose tissue has promise as a novel therapeutic approach to treat obesity and its related metabolic complications. This article is part of a Special Issue entitled ‘CSR 2013’. © 2013 Elsevier Ltd. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 1.1. Mineralocorticoid receptor signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 1.2. MR function in the adipose tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 1.3. Brown and “brown-like” adipocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 2. From adipogenesis to the development of metabolic dysfunctions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 2.1. The “adipose” RAAS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 2.2. Glucocorticoid and mineralocorticoid receptor contribution to obesity-related adipocyte dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 3. Potential role of MR in skeletal muscle and pancreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 4. Potential applications of MR antagonism in the treatment of obesity and insulin resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 * Corresponding author at: Laboratory of Cardiovascular Endocrinology, Adipose Organ Unit, IRCCS San Raffaele Pisana, Via di Val Cannuta, 247 Rome, Italy. Tel.: +39 06 5225 3419; fax: +39 06 5225 5668. E-mail address: massimiliano.caprio@sanraffaele.it (M. Caprio). 1. Introduction 1.1. Mineralocorticoid receptor signaling Corticosteroid hormones, including glucocorticoids and min- eralocorticoids, are crucial for the regulation of a large number of physiological processes through their receptors, namely the glucocorticoid (GR) and mineralocorticoid receptor (MR). These receptors are members of the superfamily of nuclear hormone 0960-0760/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jsbmb.2013.02.012