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Metabolic syndrome (Mets) is a cluster of insulin resistance, hypertension, dyslipidemia, pro inflammatory and pro coagulatory condition.1 It is grown to be major problem around the world, especially in developed countries. It is estimated that 20-25% of adult population has the metabolic syndrome around the world and still growing over time.2 The prevalence of Mets is also high in countries in south east Asia, about 14 - 28% of total population. In addition, its trends seems to increase over time, parallel with increasing prevalence in obesity and development of the countries.3
Because of the complexity of the abnormalities that present in Mets, person who are suffered from Mets have high risk of Type 2 Diabetes Mellitus (T2DM) and Cardiovascular Disease (CVD). People with Mets are twice as likely to die from and three times as likely to have heart attack or strokes compared to normal person. Additionally, they also have fivefold greater risk of developing T2DM.2 Considering high prevalence of metabolic syndrome, it most likely that metabolic syndrome has great contribution to the world health burden in the future.
Currently, adipose tissue dysfunction is proposed to be the central part in pathogenesis of mets.4 But the exact mechanisms of adipose tissue dysfunction are still on debate. Recent evidences reveal that aldosterone has many important roles in mets. By its complex signaling pathway, aldosterone contributes to all abnormality of the mets (insulin resistance, dyslipidemia, proinflammatory state, procoagulatory state, and hypertension). In addition, aldosterone also involve in the progression of mets toward CVD and T2DM either independently or by amplifying abnormality in mets. Aldosterone also shows to amplify the adverse effect of angiotensin II.5,6,7,8
The vast roles of aldosterone in mets render it as new target in the management of mets. Today, aldosterone antagonist (spironolactone and eplerenone) still limited in heart failure and resistant.9 But many researches show that these regiments are effective in reversing adipose tissue dysfunction in mouse model. Those evidences indicate the possibility to apply these regiments in mets. However, their adverse effect should be taken into consideration.
This review will focused toward the cause of excess aldosterone secretion in obesity and metabolic syndrome and its role in pathogenesis of metabolic syndrome and progression of cardiovascular disease and type 2 diabetes mellitus in metabolic syndrome. In addition, the supporting evidences that promote the usage of aldosterone antagonist in metabolic syndrome will be described in last session.
Aldosterone Excess in Obese and Metabolic Syndrome
Growing body of evidences show that aldosterone has direct correlation with obesity and metabolic syndrome. Recent evidence shows that plasma aldosterone level is positively correlates with BMI.9 Plasma aldosterone level also increase in greater extent after angiotensin II infusion in overweight persons compare to normal ones. Consistently, aldosterone also positively correlated with obesity-induced hypertension in black.10 Moreover, waist circumference also positively correlates with plasma aldosterone level.11 Another study also reveal that aldosterone:plasma renin activity (PRA) ratio also increased in obese-induced hypertension.12 These results suggest that obesity, especially abdominal obesity, can increase aldosterone expression. Since abdominal obesity is one component of metabolic syndrome, these result explain why plasma aldosterone level is shift to higher level in subject with metabolic syndrome (20% higher than normal), whether not as high as patients with primary aldosteronism.13
Figure 1. Proposed general mechanism of obesity inducing aldosterone secretion and its role in metabolic syndrome
Some factors play a role in aldosterone excess in metabolic syndrome. Hyperreactivity of RAS has been implicated as one of them since dysfunctional adipocyte also secretes angiotensinogen into the blood stream.14 This substance will convert into angiotensin I which will cleaved by ACE to produce angiotensin II. This will results in increase plasma angiotensin II level that eventually can stimulate aldosterone secretion by adrenal glands. Other stimuli like K+ and adrenocorticotropin hormon also has been implicated whether not as potent as angiotensin II.15
Recent finding shows that dysfunctional adipocytes also play significant role in stimulating aldosterone secretion. Free fatty acid that release by adipocyte is also potential stimuli for aldosterone secretion. One of the most is 12,13-epoxy-9-keto-10[trans]-octadecanoic acid.16 Despite the fact that non-esterified fatty acid can inhibit aldosterone secretion, after oxydation in the liver they become potential stimuli.
Dysfuctinal adipocyte also secretes mineralocorticoid releasing factor that induces aldosterone secretion independent to RAS.17,18 The active form of this factor is the heat sensitive fraction (molecular mass > 50 kDa) which account for 60% of total activity. This factor can increase steroid acute regulatory peptide about 10 times than normal in microscopic study. On the other hand, adipocytes also indirectly increase aldosterone secretion by sensitizing adrenal glands to angiotensin II via mitogen activated protein kinase pathway.19 All of these mechanisms explain why increased aldosterone level in metabolic syndrome often accompanied by decreased renin activity and might be play a role, in part, in pathogenesis of obesity-induced hypertension.
Role of Aldosterone in Metabolic Syndrome
Growing body of evidences show that aldosterone has contribution to adipocyte dysfunction. Aldosterone treatment to murine brown preadipocytes inhibits uncoupling protein-1 (UCP-1), inducing insulin resistance, and stimulates proinflammatory adipokines.20 In another study, eplerenone treatment to ob/ob mice adipocytes ameliorates this effect.21 This study also report increase expression of PPARγ and adiponectine in adipocytes and cardiomyocytes. The exact mechanism and supporting evidences will be described in more detail in this section.
Inflammation has significant role in metabolic syndrome since it contributes to the occurrence of the other components of metabolic syndrome. For example, TNF-α and IL-6 have been known as causes of insulin resistance.22 Oxidative stress that is produced by TNF-α also contributes to adipose tissue dysfunction.23 In some extent, TNF-α and IL-6 cause endothelial cell dysfunction and decrease production of NO, contribute to pro coagulation state.24
Growing clinical evidences have elucidated the role of aldosteron in inflammatory process. Aldosterone is known as one factor that cause and interstitial fibrosis in the heart, aortic fibrosis and remodeling and renal injury, the process that require inflammation.25,26,27 The mechanism involve increase expression of osteopontin, MCP-1, IL-6, IL-1β, IL-12, PAI-1, and leptin. Interestingly, the major source of these cytokines is adipose tissue, suggesting that aldosterone can cause dysfunctional adipose tissue. In addition, there are also increase expression of intercellular adhesion molecule and cyclooxygenase-2. All of these evidence prove the inflammatory properties of aldosterone.
Aldosterone induces inflammation principally by generating ROS. Aldosterone, like Ang II, induces activation of NADPH oxidase in rats vascular smooth muscle cell (VSMC).28 The same effect also appears in human with activation of NADPH oxidase subunit p22phox and NOX2.29 This enzyme induces the oxidation of NADPH and produce ROS. Increase oxidative stress then activates NF-kB that will act as transcription factor for several pro inflammatoric cytokines. The importance of oxidative stress in aldosterone mediated inflammation is obvious since administration of superoxide dismutase Tempol, NADPH oxidase inhibitor apocynin, or N-acetylcysteine decrease inflammation and renal injury in aldosterone treated mice.30 Increased expression of endothelin may also contribute to inflammatoric process.31
Aldosterone also can induce inflammation via MR-independent pathway or nongenomic pathway especially in VSMC.32 Although the precise mechanism is not fully understood, it seems that extracellular signal-regulated kinase (ERK) 1 and 2 play an important role in this process. Aldosterone enhances rapid and delay activation of ERK1/2 by Ang II. Treatment by spironolactone and inhibitor of transcription or protein synthesis blocker delayed activation of ERK1/2, suggesting that this effect occur through MR-dependent mechanism. In contrast, treatment with spironolactone did not inhibit rapid activation of ERK1/2. Non genomic pathway of aldosterone is likely mediated by EGFR phosphorilation. As reported by Mazak et.al33, treatment with spironolactone inhibited ERK1/2 activation and EGFR phosphorilation at 10 minutes but not at 2 minutes. This result indicated that the non genomic pathway did not exclude MR-dependent mechanism since aldosterone is also reported to increase expression of EGFR in aortic smooth muscle cells.
Insulin resistance is the abnormality that becomes the hallmark of metabolic syndrome. Insulin resistance plays important role in metabolic syndrome since it gives great contribution to the progression of T2DM and CVD. That's why insulin resistance, manifest in hyperglycemia, becomes the central target therapy in the metabolic syndrome in the present day.
There are increasing evidences that show the important role of aldosterone in insulin resistance. Aldosterone level positively correlates with plasma insulin, C-peptide, and HOMA but inversely correlated with insulin induced glucose disposal.34 Aldosterone decrease insulin stimulated glucose uptake by 50% in vascular smooth muscle cells and adopose tissue by reducing level of IRS-1.35 This effect is relieved by treatment with eplerenone. Finally, Sindelka et.al36 demonstrated increased insulin sensitivity in patients with PA after adrenalectomy, supporting the evidences that show important role of aldosterone in insulin resistance
There are several other possible mechanisms of aldosterone induced insulin resistance. As describe previously, aldosterone can induce systemic inflammation and increases expression of TNF-α and IL-6.37 TNF-α and IL-6 have been proven to cause insulin resistance as reported by several study.22 Proposed mechanism of TNF-α and IL-6 to cause insulin resistance is SOCS activation that will inhibit activation of IRS-1 and IRS-2 as well as activate SREBP-1c that decrease IRS-2 gene expression.38 Futhermore, SOCS is also involved in leptin resistance that increases appetite and energy intake.39 Hyperleptinemia that occur as compensation for leptin resistance further increases production of IL-6 and TNF-α because of inflammatoric properties of the leptin. In addition, aldosterone also increases expression of MCP-1 by adipocytes, VSMC, and endothelial cells that act as chemoatractant for macrophage and initiate inflammation, finally increases the production of TNF-α and IL-6 even more and hence insulin resistance.37 Decrease production of insulin sensitizing adipokine adiponectin also play a role in occurrence of insulin resistance as well as inflammatory state.40
As Angiotensin-II, aldosteron also causes insulin resistance by activating NADPH oxydase.28 The result is increased production of ROS and subsequent activation of serine kinase. Serine kinase will phosphorilate serine residue of IRS-1 that lessens its engagement with phosphatidylinositol 3-kinase and decrease activation of AKT/protein kinase - B. In addition, serine phosphorilation also makes IRS-1 protein vulnerable to be degraded by proteasomes that decrease the number of plasmic IRS-1.41 This will lead to decreased metabolic effect of insulin and cause effects such as impaired glucose transport and glucose utilization.
Excess amount of aldosterone causes electrolyte imbalance that is marked by sodium retention and decrease concentration of plasma potassium. Excess amount of sodium has been known to have deleterious effect, since it enhances the effect of aldosterone. Some studies have reported the correlation of excess sodium with insulin resistance, possibly by generating oxidative stress.42 In contrast, potassium has inverse correlation with insulin resistance. Its depletion is supposed to correlate with insulin resistance in hypertensive and Mets patient.43
Aldosteron also exerts positive feedback mechanism in RAAS. By its genomic effect, aldosterone can increase expression of angiotensin II receptor class 1 (AT1R) and angiotensin converting enzyme (ACE).44,45 As a result, there will be local increase of angiotensin II concentration and also enhancement of its effect. Increase amount of angiotensin II will stimulate adrenal glands to produce aldosteron, increasing its concentration, and the cycle will begin again. This positive feedback mechanism describes the important role of interaction between aldosteron and angiotensin II because this interaction will exacerbate the insulin resistance, infalammatory state, and also hypertension that experience by patients with metabolic syndrome as described latter.
Like previously described, normal function of aldosterone is to maintain blood volume by retaining sodium and reducing water excretion.46 So it is not surprising that excess amount of aldosterone in metabolic syndrome will cause hypertension. For decades, attention is directed toward angiotensin II in order to effectively manage the hypertension. However, emerging clinical evidence showed that aldosterone also plays important role in hypertension in metabolic syndrome whether the level of aldosteron in metabolic syndrome just shifts to a higher value.
Recent evidences show that aldosterone and activation of its cognate receptor also play significant role in hypertension. Kidambi et.al11 show that plasma aldosterone is significantly higher in hypertensive patient. Plasma aldosterone is also positively correlates with waist circumference and metabolic syndrome. Consistently, Ramachandran et.al47 reports that there is positive correlation between risk of hypertension and increase plasma aldosterone per quartile. The highest serum aldosterone quartile, relative to the lowest, was associated with a 1.60-fold risk of an elevation in blood pressure (95 percent confidence interval, 1.19 to 2.14) and a 1.61-fold risk of hypertension (95 percent confidence interval, 1.05 to 2.46). Finally, aldosterone blocker effectively inhibits the development of obese-induced hypertension in dog48, suggesting the important role of aldosterone in pathogenesis of hypertension in metabolic syndrome.
Laboratory study reveals that genomic effect of aldosterone plays more important role in pathogenesis of hypertension than its non-genomic effect. Aldosterone increases expression of sgk1, kirsten ras GTP-binding-protein-2A (Ki-RasA), and corticosteroid hormone-induced factor (CHIF).49 These molecules will activate epithelial Na channel (eNaC) and Na+/K+ ATPase in epithelial cells of transition tubule.50 The result is sodium reabsorption from renal tubule and subsequent volume expansion and hypertension.
Local increase of angiotensin II and its effect caused by aldosterone also plays significant role in hypertension.44 Like previously described, aldosterone induces positive feedback mechanism in RAAS. Because angiotensin II is a potent vasoconstrictor, its excess production and amplification of its effect will cause global vasoconstriction of blood vessels that increase blood pressure in the end. Aldosterone, in conjuction with angiotensin II also suppress the production of nitric oxide (NO) by endothelial cell that will impair the ability of blood vessels to compensate the increased blood pressure.45
Procoagulation State and Dyslipidemia
Aside from other disorder previously described, aldosterone also contributes to the hemodinamic disorder in metabolic syndrome, shifting it towards procoagulatory state. As described by Yuan et.al51, administration of aldosterone significantly increase PAI-1 expression by messengial cells. Co-administration of angiotensin II increased either mRNA and PAI-1 protein even further, describing synergistic effect of PAI-1 and angiotensin II to cause hemodynamic disorder. Consistently, treatment by eplerenone to db/db rat decreased PAI-1 mRNA expression significantly, strengthen the possibility that aldosterone was the inductor of PAI-1 expression.21,52
In some extent, aldosterone also contributes to the dyslipidemia in the metabolic syndrome. Although still controversial and not well establish yet, some study reported significant negative correlation between aldosterone and HDL concentration and positive correlation with plasma triglyceride level.53,54 But there is no correlation between plasma HDL level with plasma aldosterone in the result of Framingham Heart Study.55 In conclusion, aldosterone seems to negatively affect HDL concentration, but this hypothesis still need further studies in order to confirm the exact relationship between aldosterone and HDL.
Aldosterone as Target Therapy in Metabolic Syndrome
Aldosteron has shown its effect on human health and its action attracts many researchers to put their focus on this. According to the explanation previously mentioned and many data collected until present, we would like to introduce some of aldosteron antagonist to prove aldosteron impact. There are two kinds of aldosteron antagonist or blocker, which are divided according to their action.56 First, the non selective aldosteron blocker that nonselectively inhibit the mineralocorticoid receptor and glucocorticoid receptor. And then the selective aldosteron blocker that act selectively on mineralocorticoid receptor. The regimen that are widely used are spironolactone as the non selective blocker and eplerenone as the selective one. Their effect on aldosteron will be explained on the next section, primarily on to the mechanism of action oppose to aldosteron on the metabolic syndrome and its progression to another diseases.
Aldosterone antagonist is proven to be able to cure metabolic syndrome components. Although much of these studies still limited in animal trials, most of them show promising results.
Aldosterone antagonist has positive effect toward insulin sensitivity. Recent animal study showed that spironolactone, even in low dose, could effectively increase IRS-1 and Akt level and also reduced activity of NADPH oxidase back to normal level in skeletal muscle of TG(mRen2)27 rats.57 This study also reported an increase in GLUT-4 expression, reduction in ROS formation and improvement of insulin mediated glucose transport. Consistently, Hirata et.al also reported improvement of insulin sensitivity in adipocyte of ob/ob and db/db mice. This improvement might be caused by reduction of ROS production, inflammation, and cytokines production in adipose tissues.
Aldosterone antagonist also has anti inflammatoric properties. Recent study reports that it can block NF-κB activation and downregulate the expression of several proinflammatoric cytokines. Miura et.al58 reported that spironolactone had direct anti-inflammatory effect on peripheral blood mononuclear cells induced by exogenous angiotensin II by blocking the expression of MCP-1 and TNF-α. Apparently, the anti-inflammatory property of aldosterone antagonist is due to decrease activation of NADPH oxydase that will decrease ROS production. Decrease in ROS production will result in decrease activity of NF-κB and hence downregulation of several inflammatoric cytokines. Since pro inflammatory cytokines is the cause, in part, of another disorders found on metabolic syndrome, it is not surprising that aldosterone antagonist has same underlying mechanism in relieving other disorder of metabolic syndrome. It also has significant effect to inhibit atherosclerosis development.
Effect of aldosterone antagonist on hypertension has been established long before its effect on other component of metabolic syndrome was found. The anti hypertensive properties of aldosterone antagonist is largely due to blood volume reduction by blocking sodium and water retention in distal convoluted tubules.46 But recently, it has been proven that aldosterone antagonist spironolactone can improve the bioavailability of NO possibly by attenuating chronic overexpression RAAS overstimulation of NADPH oxidase.59 Reduction of sympathetic neuronal activity also has been reported since administration of eplerenone to heart failure rat model could reduce prostaglandin E2 level in nucleus paraventricular thus attenuating chronic sympathetic stimulation by cytokines.60 Reduction in plasma norepinephrine is also reported in this study. Both increase NO bioavailability and reduction of sympathetic stimulation will increase blood vessels capability of vasodilatin and hence accommodate blood pressure. This is consistent with current clinical trial that reports the effect spironolactone compare with simvastatine and L-arginine.61 Reduction of blood pressure by spironolactone is comparable to simvastatine but L-arginine is failed to reduce blood pressure.
The effect of aldosterone antagonist to other components of metabolic syndrome is not well established. But recent evidences show that aldosterone can relieve procoagulatory condition and also dyslipidemia. Spironolactone has been shown to attenuate aldosterone-induced expression of PAI-1 in nine male hypertensive subjects.52 This would result in improvement of fibrinolisis system since PAI-1 inhibits tPA in nature as previously stated. Consistently, Schafer et.al62 reported that eplerenone reduces platelet activation in diabetic rats by reducing fibrinogen binding on activated GPIIb/IIIa. Effect of aldosterone antagonist on dyslipidemia is still poorly recorded. But some reports that it might offer some protection against dylipidemia. Guo et.al21 showed that treatment db/db rats with eplerenone reduced serum triglyceride level to the level almost the same like normal db/+ rats. Consistently, administration of eplerenone to polycystic ovarian syndrome patient eventually reduces triglyceride level in overweight subject and increase plasma HDL-cholesterol level in lean subject.63 Despite the presence of clinical data, the effect of aldosterone antagonist to dyslipidemia and procoagulation state should undergo further investigation.
Figure 2. Comparison of expression of TNF-α (A), macrophage marker CD68 (B), MCP-1 (C), and PAI-1 (D) in retroperitoneal adipose tissue of 25-week old
lean db/+ mice, obese db/db mice, and obese db/db mice treated with the MR antagonist eplerenone (100mg/kg/day).21
Finally, in relation to metabolic syndrome, some laboratoric data has shown promising result. Aldosterone antagonist has been shown to have capabilities to relieve adipocyte dysfunction. Guo et.al21 showed that administration of eplerenone to db/db mice markedly reduce expression of TNF-α, CD-68 (marker of macrophage), leptin, MCP-1, and PAI-1. At the same time, adiponectine expression was elevated together with PPAR-γ expression in both adipose tissues and heart tissues, approaching normal level. The same study also observes the effect of eplerenone on cultured 3T3-L1 preadipocyte cells. Consistent with animal study, administration of eplerenone markedly reduced expression of proinflammatory adipokines (TNF-α, IL-6, and MCP-1) and restored their expression to normal level. There are also normalization expression of adiponectine and increase expression of PPARγ. This data suggest that aldosterone antagonist is able to relieve adipocyte dysfunction, the central pathogenesis of metabolic syndrome, and so will provide causal therapy for patient with metabolic syndrome.
Figure 3. Attenuation of vascular cell apoptosis by MR blocker spironolactone. (A) Photomicrograph showed apoptotic endothelial and smooth muscle cells. (B) Confirmation by TUNEL staining photomicrograph. (C) Bar graph ratio of TUNEL-positive/total cells. (D) Immunoblot and quantitative densitometri analisis of activated caspase-3.64
Aldosterone antagonist also provides protection against CVD and T2DM development in metabolic syndrome. Its cardioprotective properties are largely caused by prevention of endothelial dysfunction. Several studies confirm the ability of aldosterone antagonist to protect endothelium. Recent study reports that spironolactone markedly attenuates vascular apoptosis and injury in Ren2 rats.64 This effect is mediated by increased activation of protein kinase B which results in increase expression of anti apoptotic gene Bcl-2 and Bcl-xL, reduce expression of pro apoptotic protein BAD and caspase-3, and decrease cytochrome c release which overall promote vascular cell survival. Spironolactone also reduces elevated activation of NADPH oxidase, lipid peroxidation, expression of angiotensin II, AT1R expression, and MR itself in vascular tissue, indicating the ability of spironolactone to inhibit atherosclerosis development. Consistent with this study, Takai et.al65 also reported that eplerenone inhibited atherosclerosis development in non human primates. Eplerenone also increase vascular relaxation and suppress the expression of ACE in vasculature.
In addition, aldosterone antagonist eplerenone also decreases vascular stiffness in hypertensive patient.66 Eplerenone decrease vascular collagen/elastin ratio and circulating inflammatory mediator. This effect might be accomplished through reduction in inflammatoric process and fibroblast activation. Another possible mechanism of eplerenone in decreasing vascular stiffness is by increasing NO bioavailability by reducing NO conversion into peroxynitrite, possibly by inhibiting NADPH oxidase activity and hence superoxide formation.59 Potassium retention that is induced by aldosterone antagonist together with decrease in plasma sodium level may also have contribution since potassium is known to soften vascular endothelium and increase NO release, opposite the effect of sodium.67,68
Aldosterone antagonist also attenuates cardiac hypertrophy and remodeling as described by several studies. Simko et.al69 showed that spironolactone significantly inhibited left ventricular hypertrophy (LVH) development and partially decreased blood pressure. This effect was mediated, in part, by attenuation of NO-synthase inhibition. However, spironolactone did not effect aortic remodelling, suggesting that different mechanism worked on aortic remodelling process. The same author also reported same result in L-NAME treated Wistar rats. The most prominent LVH reduction was observe in spironolactone group. In addition, Aldosterone antagonist also attenuates fibrotic process that is induced by aldosterone and there is also evidence of increasing coronary circulatory function in diabetic patient treated by eplerenone whether there are no significant differences in blood pressure, serum potassium and glycemia compare to hydrochlorothiazyde treated patients.70,71
RALES trial72 confirmed the cardioprotective effect of aldosterone antagonist. In this study, mortality reduction by 30 % in patients with severe heart failure was revealed when a small dose of aldosterone receptor antagonist spironolactone was added to the standard treatment with ACE-inhibitors. The protective effect of spironolactone against the left ventricular remodeling was considered to be the most important mechanism participating on the reduction of morbidity and mortality in the RALES trial. This benefit may be explained partly by the inhibition of the deleterious effects of aldosterone on cardiovascular system structure and function.
Aldosterone antagonist also has potential role on preventing T2DM. This is largely based on anti hyperglycemic effect of aldosterone because hyperglycemia has been proven to have negative correlation with pancreatic β-cells function.73 The other possibility is by anti inflammatory effect of aldosterone antagonist and reduction of ROS formation. This is based on the fact that aldosterone, via inflammatoris process and ROS formation, induce islet fibrosis and promote amyloid deposition.74 Potential downregulation of local pancreatic RAAS and enhancement of insulin release by pancreatic β-cell may also contribute to the anti-diabetic properties of aldosterone antagonist.57
All of the evidences described above show that aldosterone antagonist might be useful modalities in treating patient with metabolic syndrome. Based on the evidences aldosterone antagonist could serve some advantage and are able to work synergistically with other modalities of metabolic syndrome such as anti hyperglycemic agent (metformin, thiazolidinediones), lipid reducing agent (statin, fibrates), and antihypertensive agent such as hydrochlorothiazid. But it may also serves adverse effect like gynecomastia (in case of spironolactone) and hyperkalemia (especially if combine with ACE inhibitor or angiotensin receptor blockade (ARB)).71 So administration of aldosterone antagonist should be carefully adjusted and require patient monitoring to maximize its beneficial effect while reducing the possibilities of adverse effect occurence.
Based on recent studies it is clear that aldosterone often present in excessive amount in obesity and metabolic syndrome. Several factors work to induce aldosterone secretion in obesity and metabolic syndrome include hyperinsulinemia, hypereactivity of RAS, free fatty acid, and newly found mineralocorticaid releasing factor. This high level of aldosterone eventually plays important role, at least in part, in the occurrence of each component of metabolic syndrome, although its contribution in dyslipidemia is still unclear. Aldosterone, both by its contribution in metabolic syndrome or independent with metabolic syndrome may lead to development of cardiovascular disease and type 2 diabetes mellitus. Present data provide the possibilities of aldosterone antagonist usage in metabolic syndrome because its ability to relieve most of the component of metabolic syndrome and importantly, it relieves adipocytes dysfunction, the central pathogenesis of metabolic syndrome. In addition, aldosterone antagonist offers some protection from cardiovascular disease and type 2 diabetes mellitus. However, further investigation is needed in order to confirm the exact role of aldosterone in metabolic syndrome, the beneficial effect and efficacy of aldosterone antagonist in metabolic syndrome.