Mineralocorticoid receptor in adipocytes and macrophages: A promising target to fight metabolic...

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Steroids xxx (2014) xxx–xxx

STE 7562 No. of Pages 8, Model 5G

14 May 2014

Contents lists available at ScienceDirect

Steroids

journal homepage: www.elsevier .com/locate /s teroids

Mineralocorticoid receptor in adipocytes and macrophages: A promisingtarget to fight metabolic syndrome

http://dx.doi.org/10.1016/j.steroids.2014.05.0010039-128X/� 2014 Published by Elsevier Inc.

⇑ Corresponding author. Address: Laboratory of Cardiovascular Endocrinology,IRCCS San Raffaele Pisana, Via di Val Cannuta 247, Rome, Italy. Tel.: +39 06 52253419; fax: +39 06 5225 5668.

E-mail address: [email protected] (M. Caprio).

Please cite this article in press as: Marzolla V et al. Mineralocorticoid receptor in adipocytes and macrophages: A promising target to fight metabodrome. Steroids (2014), http://dx.doi.org/10.1016/j.steroids.2014.05.001

Vincenzo Marzolla a, Andrea Armani a, Alessandra Feraco a, Massimo U. De Martino b, Andrea Fabbri c,Giuseppe M.C. Rosano a, Massimiliano Caprio a,⇑a Centre for Clinical and Basic Research, IRCCS San Raffaele Pisana, Rome, Italyb Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italyc Department of Internal Medicine, Endocrinology Unit, S. Eugenio & CTO A. Alesini Hospitals, University Tor Vergata, Rome, Italy

a r t i c l e i n f o

293031323334353637383940

Article history:Received 1 February 2014Received in revised form 29 April 2014Accepted 2 May 2014Available online xxxx

Keywords:Mineralocorticoid receptorAdipocyteAdipose tissueMacrophageInsulin resistance

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a b s t r a c t

Aldosterone is the primary ligand for the mineralocorticoid receptor (MR) and has been considered longtime a ‘‘renal’’ hormone, acting at this site as a key regulator of plasma volume, electrolyte homeostasisand blood pressure. A new exciting era of MR biology began with the identification of MR in differentnon-epithelial tissues such as brain, heart, vessels, macrophages/monocytes, and adipose tissue. The dis-tribution of MR in such a wide range of tissues has suggested novel and unexpected roles for MR, forexample in energy metabolism and inflammation. An increasing body of evidence suggests a detrimentaleffect of aldosterone excess on the development of metabolic alterations. Disturbances in glucose metab-olism due to inappropriate activation of MR are frequently observed in patients with primary aldosteron-ism as well as in obese subjects. MR antagonists have beneficial effects on glucose tolerance andmetabolic parameters in experimental animals, whereas their role in humans remains unclear. Theaim of this review is to discuss the pathophysiology of MR activation in experimental models, particularlyat the level of adipocytes and macrophages, to discuss novel and sometimes contrasting insights fromemerging studies, and to highlight deficiencies in the field.

� 2014 Published by Elsevier Inc.

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1. Introduction

Modern societies are plagued by obesity with its metaboliccomplications. Together with autoimmunity and allergy disorders,anxiety, insomnia, and depression, these diseases represent multi-factorial polygenic disorders that are complex and influenced bymultiple mechanisms. Among them, it is not surprising that gluco-corticoids (GCs), the main effectors of the stress system, have beenproposed to play a key role [1]. Glucocorticoid hormones aresecreted by the adrenal cortex under the strict control of the hypo-thalamic–pituitary–adrenal (HPA) axis [1]. They exert their func-tion in different target tissues by binding two intracellularreceptors: the glucocorticoid receptor (GR) and the mineralocorti-coid receptor (MR) [2], and are able to regulate multiple metabolicpathways, including glycolysis/gluconeogenesis, fatty acids andcholesterol metabolism [3]. GC is potent inducers of hepatic gluco-neogenesis [4] and through this activity they increase circulating

glucose and insulin, which results in insulin resistance, a hallmarkof metabolic syndrome [5].

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2. MR and GR: from a single corticosteroid receptor to theacquisition of distinct functions

It is hypothesized that MR and GR descend from a single ances-tral corticosteroid receptor, which gave rise to two distinct recep-tors with different signaling functions [6]. This hypothesis mayexplain the similar affinity of MR for aldosterone, its natural ligand,and physiological glucocorticoids. While in most vertebrates GR isspecifically activated by the stress hormone cortisol to in turn reg-ulate metabolism, inflammation, and immunity [7], the MR is acti-vated by aldosterone to control electrolyte homeostasis and otherprocesses [8]. MR activation by cortisol is limited in epithelial tis-sues by the presence of the cortisol-inactivating enzyme 11bHSD2to allow selective aldosterone binding [8]. Interestingly, the capac-ity to synthesize aldosterone has evolved relatively recently, andthe sensitivity of corticoid receptors to aldosterone is thereforemore ancient than the hormone itself. The evolution of an MR thatcould be independently regulated by aldosterone enabled more

lic syn-

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specific endocrine responses, developing new functions for cortisolthat could be controlled separately to the GR-mediated responses[6]. In such context, it is possible that the mineralocorticoid systemmay have later developed important functions also in extra-renalsites, involving the regulation of energy homeostasis, tissueinflammation and fibrosis, and creating several overlaps withactions classically defined as GR-mediated.

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3. Mineralocorticoids and glucocorticoids: two convergingsystems controlling glucose metabolism

MR and GR activation, despite major differences in the regula-tion of tissue inflammation [9], exerts converging effects in thecontrol of glucose homeostasis and insulin resistance. Importantly,chronic exposure to glucocorticoid excess in humans, as seen inCushing syndrome, leads to a clinical phenotype harboring all com-ponents of the metabolic syndrome, including hypertension, vis-ceral obesity and hyperglycemia (extensively reviewed by DiDalmazi et al.). Differently, chronic exposure to mineralocorticoids,as seen in primary aldosteronism, may also be associated with dia-betes mellitus and glucose intolerance [10], but displays a moresubtle and still controversial effect on glucose metabolism. Theexact mechanism that links glucose intolerance and aldosteroneexcess is still unclear. However, hypokalemia may be at least partlyresponsible and aldosterone may directly inhibit insulin secretionby the pancreas [11]. A study by Fallo et al. describes a higher prev-alence of metabolic syndrome in patients with primary aldosteron-ism compared to patients with essential hypertension [12], withrelevant differences in glucose metabolism between patientgroups. The association between hyperaldosteronism, insulin resis-tance and insulin deficiency has been recently reviewed [13], withclear evidence for a strict relationship between aldosterone and theincreased risk in metabolic syndrome [14]. Importantly, excessaldosterone has been shown also in obesity as an epiphenomenonof an increased fat mass, and weight loss after gastric banding hasbeen demonstrated to reduce aldosterone levels along with areduction in blood pressure and insulin resistance [15]. Such a rela-tionship has been confirmed in an experimental model of life-longobesity in rodents, where exposure to HF diet from weaning leadsto hypertension and hyperaldosteronism [16]. In summary, popu-lation-based observational studies suggest a clear correlationbetween obesity and aldosterone levels, while experimental stud-ies have shown that adipocyte-related factors are possible atypical‘‘triggers’’ for aldosterone release from adrenal cells [17,18], whichmight explain the hyperaldosteronism often observed in obesesubjects. Finally, recent reports seem to support the hypothesisthat adipocytes are able to produce and secrete per se modestamounts of aldosterone, which may contribute to enhance totalcirculating aldosterone levels [19] and the higher degree of MRactivation in obesity.

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4. Are MR blockers protective in insulin resistance and obesity?

Beneficial effects of MR antagonists have been demonstrated inseveral animal models of genetic and diet-induced obesity, but stillremain to be proven in human insulin resistance states. Interest-ingly, Guo et al. reported that systemic MR antagonism witheplerenone reversed the adverse metabolic consequences ofgenetic obesity in db/db mice, improving glucose tolerance, insulinresistance and adipokine expression in adipose tissue [20]. Similareffects were obtained in a model of diet-induced obesity, whereMR blockade induced a marked reduction of hypertrophicadipocytes and macrophage infiltration with a concomitantdecrease of pro-inflammatory adipokine levels in adipose tissue[21]. Importantly, our group recently showed that pharmacological

Please cite this article in press as: Marzolla V et al. Mineralocorticoid receptor idrome. Steroids (2014), http://dx.doi.org/10.1016/j.steroids.2014.05.001

MR antagonism with either spironolactone (Spiro, 7a-acetiltio-3-osso-17a-pregn-4-ene-21,17-carbolattone) or drospirenone (DRSP,6b,7b,15b,16b-dimethylene-3-foxo-17a-pregn-4-ene-21,17-carbo-lactone, a potent synthetic antimineralocorticoid with progesto-genic and moderate antiandrogenic properties) was able tocounter metabolic dysfunctions in a model of high-fat diet inducedobesity in female mice, and that beneficial effects on body fat com-position and glucose tolerance were associated to ‘‘browning’’ ofadipose tissue [22]. It is worthy to remark that different MR block-ers display distinct pharmacokinetic profiles. Therefore, the effectof MR blockade on metabolic parameters may vary by the MRantagonist applied. In fact, Homma et al. demonstrated that Spiro,but not eplerenone, negatively affected parameters of glucosemetabolism in a rat model of metabolic syndrome. These dataare in contrast with most of the current literature, and were likelyexplained by the increased aldosterone levels induced by Spiro, aswell as by possible species differences between rat and mice [23].

Clinical studies addressing the potential impact of MR blockadeon metabolic parameters are limited, since the largest clinical trialswith MR blockers have been conducted in the clinical setting ofheart failure [24–27]. Particular attention has been raised by clin-ical trials of oral contraceptives containing estrogens conjugated toDRSP. The relative binding affinity of DRSP for the human MR wasdemonstrated to be two to five times higher than that of aldoste-rone [28]. Given these pharmacological properties, DRSP has beenshown to display favorable effects on blood pressure [29–31] andbody weight [32–34]. In addition to its effects on salt and waterretention, a study conducted in healthy postmenopausal womenshowed that DRSP, in combination with estradiol, caused a signif-icant decrease in central fat mass and central fat mass/peripheralfat mass, as measured by dual-energy X-ray absorptiometry [35].We recently demonstrated that DRSP strongly inhibits adipose dif-ferentiation in murine and in human primary preadipocytes,through specific antagonism on the MR [36], providing new mech-anistic insights that may explain its aforementioned favorablemetabolic effects in clinical settings.

However, major concerns for the use of DRSP were raised aftercareful evaluation of the risk of non-fatal idiopathic venous throm-boembolism in women using oral contraceptives containing DRSP:use of the DRSP contraceptive was associated with a threefoldhigher risk of non-fatal idiopathic venous thromboembolism com-pared with levonorgestrel, in a study based on data from the UKGeneral Practice Research Database [37]. Similar results emergedfrom a study based on United States claims data [38], and discour-aged any further attempt to investigate the potential beneficialeffects of DRSP in clinical trials.

Divergent conclusions were suggested by the CHARM study, inwhich spironolactone therapy showed significant positive associa-tions with the development of diabetes in a population affected bychronic heart failure [39]. However, interventional studies specifi-cally designed to test the effects of MR antagonists on glucose andlipid metabolism are limited.

A recent work [40] conducted in healthy adult males did notshow any significant effect of a low, non-blood pressure-modifyingdose of eplerenone, on basal and postprandial glucose and lipidlevels. This study suggests that it may be necessary to study pop-ulations where the MR is inappropriately activated, in order toevaluate the potential favorable effects of MR antagonists on met-abolic function. However, recent work from the same group con-firmed the lack of beneficial effects of spironolactone on insulinsensitivity and endothelial function in a small population of nor-motensive obese patients with no other comorbidities [41], sug-gesting that excess MR activation does not significantlycontribute to changes in insulin resistance or endothelial dysfunc-tion induced by early obesity. Finally, a nicely designed study byDerosa et al. evaluated the effects of canrenoate on metabolic

n adipocytes and macrophages: A promising target to fight metabolic syn-


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parameters of patients affected by metabolic syndrome, but with-out overt diabetes or cardiovascular diseases. In this work, treat-ment with MR antagonist did not affect body mass index orwaist circumference, but significantly reduced insulin resistance,as measured by fasting plasma insulin and HOMA index, and sys-temic inflammation (C-reactive protein; CRP and tumor necrosisfactor-a; TNF-a) [42]. To date, evidence from available studies inhumans are divergent, due to the heterogeneity of the populationsexamined and the different treatment protocols. There is indeed anurgent need for interventional studies conducted on carefullyselected populations, in order to understand the real potential ofMR antagonists for the prevention or amelioration of insulin resis-tance and other metabolic disturbances in different clinicalconditions.

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5. Pathophysiological role of MR in the adipose

5.1. MR in white adipose tissue (WAT) metabolism and plasticity

Since the discovery of MR expression in murine and human adi-pose tissue, significant progress has been made in the understand-ing of the role of MR in adipocyte biology. Several reports indicatethat MR affects adipocyte function. In vitro studies showed thataldosterone as well as glucocorticoids promote murine and humanwhite preadipocyte differentiation through MR [36,43–45]. In par-ticular, we recently demonstrated that pharmacological blockadeof MR strongly inhibits 3T3-L1 adipocyte clonal expansion anddifferentiation by reducing the expression of peroxisome prolifer-ator-activated receptor gamma (PPARc), the master regulator ofadipogenesis [36]. Moreover, knock-down of MR by specific siRNAin primary human preadipocyte markedly inhibited adipocyte dif-ferentiation in vitro [46].

Obese individuals develop insulin resistance, characterized by areduced ability of insulin to inhibit the production of glucose fromthe liver and to promote glucose uptake in adipose tissue andskeletal muscle [47,48]. In obesity, impaired insulin sensitivity is

Hypertrophic White Adipocyte Functional White Adip

Brown-like Adipo

MR BLOCKA

White Adipocyte

Fig. 1. Schematic representation of the effects of MR blockade on adipocyte and macropreduce hypertrophic white adipocytes and increase small white and brown-like adipoadipokines and adipogenesis-related genes resulting in reduction of adipocyte size. (B) Ibrown adipocyte transcriptional profile, favoring a phenotypic change into a brown-likgenetic deletion and pharmacological antagonism in vitro are able to induce a switchinterpretation of the references to color in this figure legend, the reader is referred to th


associated with adipocyte hypertrophy [49]. Hypertrophic adipo-cytes are characterized by increased expression of adipokines withpro-inflammatory activity such as leptin, interleukin-6 (IL-6), plas-minogen activator inhibitor-1 (PAI-1), TNF-a and monocyte che-moattractant protein 1 (MCP-1). On the other hand, theexpression of anti-inflammatory adipokines i.e. adiponectin andinterleukin-10 (IL-10) is reduced in enlarged adipocytes [50–52].It is well known that adiponectin is an insulin-sensitizing factorwith major role in controlling glucose and lipid homeostasis[53,54]. Interestingly, Guo et al. reported that aldosteroneincreases mRNA levels of TNF-a, MCP-1, and IL-6 and decreasesmRNA and protein levels of adiponectin in 3T3-L1 preadipocytes[20]. Local increase in pro-inflammatory adipokines, in particularMCP-1, contributes to macrophage infiltration within adipose tis-sue. Accordingly, in mouse models of genetic or diet-induced obes-ity, MR blockade induced a marked reduction of hypertrophicadipocytes and macrophage infiltration with a concomitantdecrease of pro-inflammatory adipokine levels in white adiposetissue (WAT) [20,21] (Figs. 1 and 2). Such effects suggest that spe-cific MR blockade in adipocytes could explain, at least in part,improvements in glucose homeostasis observed in mice treatedwith MR antagonists.

In contrast to the above-mentioned literature, Kuhn et al. haverecently described a paradoxical response to high fat diet in trans-genic mice globally over-expressing human MR. Global overexpression of human MR had beneficial metabolic effects in termsof decreased fat mass and concomitant improved glucose tolerancecompared to wild type mice. White preadipocytes derived frommice over-expressing human MR did not display impairedadipogenesis in vitro, suggesting that reduced adipocyte size thatwas observed in vivo did not depend on intrinsic defects in thecapability to differentiate of MR over-expressing adipocytes. Theauthors showed that although adipose tissue macrophage numberdid not differ between genotypes, transgenic mice displayed adistinct macrophage polarization phenotype, and demonstratedthat transgenic mice macrophage-conditioned media impairedpreadipocyte differentiation. This suggests that diffusible signaling

ocyte

cyte

Macrophage M2

Macrophage M1

DE

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hage phenotypic transition. (A) In murine models of obesity, MR blockade is able tocytes abundance in fat depots. Adipocyte MR blockade modulates expression ofn white adipocytes, MR antagonism promotes gene expression transition toward ae adipocyte. (C) MR modulates macrophage polarization: macrophage-specific MR

from a pro-inflammatory (M1) into an anti-inflammatory (M2) phenotype. (Fore web version of this article.)



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MCP-1IL-6TNF-αIL-10

MCP-1IL-6TNF-αPAILEPTINADIPONECTIN

INSULIN RESISTANCEINFLAMMATION

MR ACTIVATION

MONOCYTES

MR BLOCKADE

MCP-1IL-6TNF-αPAILEPTINADIPONECTIN

INSULIN SENSITIVITYINFLAMMATION

MCP-1IL-6TNF-αIL-10

ICAM-1VCAM-1

ICAM-1VCAM-1

A B

Fig. 2. Schematic overview summarizing the role of MR in the adipose organ. (A) In obesity, adipocyte MR activation causes an increase of hypertrophic adipocytes and amarked infiltration of macrophages (M1, red cells). Adipose tissue macrophages and hypertrophic adipocytes produce an increased release of pro-inflammatory cytokines(TNF-a, IL-6, and MCP-1) leading to insulin resistance. The increase in leptin accompanied by a reduction in anti-inflammatory mediators (IL-10 and adiponectin) contributesto a state of chronic low-grade inflammation in the adipose organ. The increase in macrophage infiltration is also due to the increased expression of adhesion molecules(ICAM-1, VCAM-1 and E-SELECTIN) of the blood vessels supplying the adipose organ due to the activation of the MR. (B) In mouse models of genetic or diet-induced obesity,MR blockade counteracts the development of hypertrophic adipocytes and increases the presence of brown-like adipocytes (gray cells) in WAT. Moreover, MR antagonisminduces a switch in the polarization of resident tissue macrophages from M1 (red cells) to M2 (cyan cells), resulting in reduced release of pro-inflammatory molecules andincreased production of anti-inflammatory molecules (adiponectin, IL-10) by macrophages and adipocytes. (For interpretation of the references to color in this figure legend,the reader is referred to the web version of this article.)



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molecules derived from macrophages may control adipocyte dif-ferentiation in vivo, although no information is provided aboutthe precise nature of the interactions between macrophages andadipocytes resulting in these unexpected effects on adipose tissue[55]. Such paradoxical effects on adipose tissue and metabolichomeostasis are indeed difficult to interpret, and probably relyon non-specific effects due to global human MR over-expression,which may lead to altered metabolism in these mice under basalcondition [56]. Increased expression of MR in the central nervoussystem might also affect responses to metabolic stress.

It is well established that obesity and insulin resistance areassociated to the hyperactivity of the renin-angiotensin-aldoste-rone system (RAAS), resulting in elevated plasma aldosterone lev-els [57] that could activate adipocyte MR and promote adiposedifferentiation and expansion [58]. Adipose tissue itself has beenshown to stimulate aldosterone production from adrenal glandsby releasing soluble bioactive factors [18,59–61]. Moreover, ithas been suggested that the hypertrophied adipocyte producesaldosterone which can stimulate adipose differentiation throughan autocrine loop [19]. Notably, increased aldosterone levels areable to activate endothelial MR promoting expression of adhesionmolecules such as intracellular adhesion molecule 1 (ICAM1) [62]and vascular cell adhesion molecule 1 (VCAM1) [63], resulting inincreased endothelial adhesion of monocytes that leave the bloodstream and migrate into adipose depots, hence contributing toinflammation and dysfunction of adipose tissue (Fig. 2).


In summary, the major lines of evidences suggest that hyper-activation of MR due to glucocorticoids or aldosterone results indeleterious effects on adipose tissue function and glucose homeo-stasis. Further studies with mice lacking adipocyte MR expressionare deemed necessary to elucidate the role of adipocyte MR inmodulating metabolism of adipose cells and other types of cellspresent in adipose tissue (macrophages, endothelial cells, etc.) aswell as glucose and lipid metabolism.

6. MR antagonism in adipocytes and browning of WAT

Despite many studies on MR function in WAT, there are onlyfew reports focusing on the role of MR in brown adipose tissue(BAT) physiology. In mammals, WAT and BAT display different his-tological structure as well as distinct physiological roles. WAT hasnot only the capacity to store energy but it is capable of influencingmetabolic activity of the whole body secreting a large number ofadipokines [64]. Conversely, BAT evolved in mammals to dissipatechemical energy in the form of heat, a process termed not-shiver-ing thermogenesis which is required to maintain stable body tem-perature in a cold environment [65].

Cold exposure is the main stimulus for BAT activity. Such effectsare mediated by activation of the sympathetic nervous system,resulting in the stimulation of b-adrenergic receptors present inbrown adipocytes with increase in uncoupling protein 1 (UCP1)



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activity [66,67]. Apart from classic brown adipocytes found ininterscapular adipose tissue, thermogenic adipocytes (calledbrown-like or beige or brite adipocytes) [68,69] are also presentin WAT depots and their abundance in mice is strain- and loca-tion-dependent and increases in response to cold or b3-adrenergicstimuli [70]. Increase of thermogenic adipocytes under specificstimuli in WAT is known as ‘‘browning’’. Stanford and collaboratorshave shown that BAT transplantation, in mice fed either a high fatdiet or a normal chow, results in improved glucose metabolism andreduction in body weight and fat mass [71]. Importantly, recentreports indicate that functional BAT is present in adult humansand that its activity positively correlates with body mass index,suggesting a protective role against obesity [72–75].

Brilliant studies using transgenic mice have shown that MRgene is expressed and active in BAT [76]. Subsequent investigationsdemonstrated that MR activation in T37i cells, derived from ahibernoma expressing the SV40 large T antigen under the controlof the P1 promoter of the human MR, up-regulates general markersof adipocyte differentiation [(PPAR-c and adipocyte-specific fattyacid binding protein 2 (aP2)], but represses expression of UCP1,the hallmark of brown adipocytes [77,78].

Notably, recent data from our laboratory [22] have shown thatpharmacological MR antagonism, in female mice fed a high fat diet,induces browning of WAT through a direct control of autophagicrate in adipose tissue, hence promoting an increase in metabolicactivity of WAT depots and interscapular BAT; such effects couldaccount for the improvement in glucose homeostasis alreadyobserved in other studies [20,21,79]. Additional in vivo studiesusing adipocyte MR null-mice are mandatory to better understandthe role of MR in the context of adipocyte metabolism and brown-ing of WAT.

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7. Role of MR in macrophages

7.1. Inflammation and macrophage polarization

It is well established that macrophage-mediated inflammationin adipose tissue contributes to the development of insulin resis-tance [80]. The number of macrophages in adipose tissue of obesemice is markedly higher compared to lean animals, with a preva-lent pro-inflammatory (M1) polarization. M1 polarized macro-phages release pro-inflammatory cytokines [TNF-a, interleukin 1beta (IL-1b), etc.] that inhibit insulin signaling through phosphory-lation of insulin receptor substrate (IRS) proteins [81]. In contrast,anti-inflammatory (M2) polarized macrophages are predominantin fat tissue of lean mice and release interleukin 10 (IL-10), whichprevents the detrimental effects of TNF-a on insulin signaling [82].Notably, under metabolic stress, the presence of pro-inflammatorymacrophages has also been detected in skeletal muscle and liverwhere M1 polarization leads to insulin resistance [83,84]. In suchcontext, a deeper knowledge of pathways affecting polarizationof the macrophage could help to design pharmacological strategiesaimed at preventing M1 activation and subsequent impairment ofinsulin sensitivity.

Interestingly, mice with macrophage-specific deletion of theMR gene displayed protection against cardiac fibrosis induced bypharmacological treatment [85–87], with reduction in M1 macro-phage markers [87] and parallel increase in M2 macrophage mark-ers in cardiac tissue [86]. These data confirmed a role for MR inregulating macrophage polarization and, in turn, inflammatoryresponse and cardiac remodeling [85–87]. In vitro treatment ofhuman and murine macrophages with MR antagonists confirmedthat MR blockade represses expression of M1 markers andpromotes M2 polarization [86,88] (Fig. 1). Accordingly, stimulationof MR function with aldosterone has been shown to increase


lipopolysaccharide (LPS)-induced TNF-a expression, while co-treatment with eplerenone prevented LPS-induced expression ofTNF-a [89] in primary cultures of rat hepatic macrophages (knownas Kupffer cells) and mouse bone-marrow-derived macrophages.Inhibition of Kupffer cell and macrophage MR with eplerenonewas suggested to prevent the development of non-alcoholic steato-hepatitis in a mouse model of metabolic syndrome [89].

Interestingly, the effects of macrophage-specific deletion of MRhave not been explored in animal models of obesity. In obesity andmetabolic syndrome, increased levels of aldosterone and glucocor-ticoids are able to stimulate MR activity of resident macrophages inadipose tissue, hence inducing M1 activation and, in turn, insulinresistance. Considering that MR antagonists find wide applicationin clinical practice in patients with heart failure [90], it could bechallenging to investigate the metabolic effects of MR antagonistson macrophage polarization and glucose metabolism also in obesesubjects.

Surprisingly, the recent data by Kuhn et al. [55] show that adi-pose tissue macrophages derived from mice overexpressing thehuman MR display reduced M1 pro-inflammatory polarization,without any significant changes in M2 markers, and propose thatsuch effect, although of modest entity, could be responsible forthe protection against high fat-induced obesity. Elegant co-cultureexperiments in this study indicated that macrophages derivedfrom MR over-expressing mice are able to repress adipocyte differ-entiation in preadipocytes extracted from wild-type mice, througha modest reduction of the adipogenic factor PPAR-c and the lipo-genic enzyme fatty acid synthase (FAS).

Again in contrast with this work, most available studies indicatethat MR blockade in macrophages suppresses the pro-inflamma-tory M1 phenotype with beneficial effects in terms of attenuatedfibrotic responses and protection from high blood pressure. Furtherstudies will be required to better elucidate the complex role playedby macrophage MR in modulating adipocyte metabolism, plasticityand proinflammatory profile. Considering that macrophage polari-zation affects inflammation of adipose tissue which, in turn, repre-sents a hallmark of obesity, the design of new antagonists specificfor macrophage MR may represents a potentially valid tool to fightadipocyte dysfunction (Fig. 2).

8. Macrophage polarization and ‘‘browning’’ of WAT

Elegant data by Nguyen et al. have showed that macrophagepolarization affects metabolic changes occurring in fat depots dur-ing adaptive thermogenesis in mice [91]. In mice exposed to cold,increased expression of alternative/M2 polarization markers (Arg1,Mrc1and Clec10a) was detected in BAT and WAT, whereas classi-cal/M1 polarization markers were not modulated. Notably, coldexposure did not induce alternative macrophage polarization inskeletal muscle and liver [91].

Interleukin-4 (IL-4) and interleukin-13 (IL-13) are known toinduce M2 polarization [92–95]. whereas Signal Transducer andActivator of Transcription 6 (STAT6) mediates interleukin 4 and13 (IL-4 and IL-13) effects on macrophage polarization [96]. Ngu-yen et al. observed that cold exposure was not able to induce alter-native macrophage polarization in IL-4/IL-13–/– as well as inSTAT6–/– mice [91]. Importantly, both mouse models exposed tocold displayed a reduced capacity to induce thermogenic genesin BAT and reduced mobilization of fatty acids in WAT. Moreover,the authors showed that alternative activation of macrophagespresent in BAT and WAT leads to release of catecholamines bymacrophages themselves, which in turn activates a thermogenicgene program and lipolysis in fat depots [91]. These data demon-strate for the first time that macrophages play a major role in theregulation of thermogenic adaptation. Modulation of macrophage



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MR may then regulate such complex phenomenon, given its abilityto affect M1/M2 polarization, and in particular to control theiralternative activation.

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9. Conclusions

In humans, modest or contradictory effects of pharmacologicalMR antagonism have been observed on adipose metabolic param-eters. In contrast, MR antagonists clearly improve glucose toler-ance and lipid parameters in different mouse models of obesity.The reasons for these differences remain obscure and difficult tointerpret. Appropriate and properly designed metabolic studiesfocused on insulin resistance and weight gain in obese humans,using different type, dose and duration of treatment with MRantagonists, will be necessary to better characterize the effects ofMR antagonists and explain the discrepancies between humanand murine models. The specific contribution of MR in adipocytesand macrophages in the regulation of adipose tissue adaptation tometabolic distress, represents a central issue that needs furtherinvestigation. Comparative studies with macrophage- or adipo-cyte-specific MR null mice may provide precious information forbetter understanding the role of MR in the development of dys-functional adipocytes.

Indeed, MR modulates the inflammatory status of the macro-phage, which in turn markedly affects adipose tissue metabolism(Fig. 2). For this reason, a better understanding of the mechanismsby which adipocyte-macrophage MR inhibition improves meta-bolic function, could identify new molecular targets to treat adipo-cyte dysfunction, obesity and its metabolic complications.

Acknowledgments

This work was supported by a grant from Ministero della Salute(Bando Giovani Ricercatori 2009, to MC) and by institutional fun-dings from University Tor Vergata (Progetti Ricerca Interesse Naz-ionale Ministero dell’Università e della Ricerca 2009, to AF).

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