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Role of mineralocorticoid receptor and renin-angiotensin-aldosterone system in adipocyte dysfunction and obesity
... Many cardiovascular complications are caused by one or more components of the renin-angiotensin-aldosterone system (RAAS) [89,[156][157][158]. Excessive activity of the RAAS may also affect lipid metabolism [89,[156][157][158]. ...
... Many cardiovascular complications are caused by one or more components of the renin-angiotensin-aldosterone system (RAAS) [89,[156][157][158]. Excessive activity of the RAAS may also affect lipid metabolism [89,[156][157][158]. Many studies suggest that the adipose tissue has a local RAAS system [89,[156][157][158]. ...
... Excessive activity of the RAAS may also affect lipid metabolism [89,[156][157][158]. Many studies suggest that the adipose tissue has a local RAAS system [89,[156][157][158]. Accordingly, it was shown that an increase in visceral adiposity was associated with high levels of angiotensinogen, angiotensin-II [159][160][161][162]. Furthermore, it was reported that angiotensinogen is constitutively expressed by mature adipocytes [159][160][161][162], and these cells may also synthesize aldosterone [161,162]. ...
The growing incidence of obesity and related complications such as cardiomyopathy and nephropathy remains a global health challenge. Many pathophysiological factors including inflammation, oxidative stress and endothelial dysfunction are implicated in obesity-induced abnormalities in the heart and kidney. Moreover, obesity and nutrient-overload are associated with the activation of different inflammatory/oxidative signaling pathways such as endoplasmic reticulum stress, nuclear factor-kappaB (NF-B), toll-like-receptor-4 (TLR4) and the renin-angiotensin-aldosterone system (RAAS). The pathophysiological role of RAAS, TLR4 and NF-B in perturbing physiological milieu is well acknowledged. Several pharmacological agents have been formulated to target one or more of these pathways. Although significant strides have been made in elucidating mechanisms implicated in obesity-related cardio-renal diseases, much still has to be done. The pathophysiology of cardiomyopathy and nephropathy is complex and multifaceted. Besides NF-B, TLR4, RAAS and inflammatory mediators such as cytokines and chemokines, a wide spectrum of different factors including, the environment, diets, lifestyles, genetics and epigenetics are also involved. With such multifactorial etiology, it remains a daunting challenge to identify the factor(s) that initiate the activation and propagation of adverse stimuli that eventually lead to cardiomyopathy and/or nephropathy in obese individuals. Similarly, the mechanisms of such activation and propagation should be clearly elucidated. Should these hurdles be overcome, there would be a greater likelihood for the development of more-effective therapeutic strategies for the prevention, treatment and management of obesity-induced cardiomyopathy and nephropathy. The present review examines the current state of knowledge and future directions of research in the area of obesity-related cardiomyopathy and nephropathy.
... Further studies have shown that under normal conditions, perivascular adipose tissue releases vasodilator mediators, such as adiponectin and adipocyte-derived relaxing factors. However, upon obesity, enhanced MR signaling in perivascular adipose tissue activates NADPH oxidase and promotes the release of inflammatory mediators, which impair vascular function and relaxation (Feraco et al., 2013;Gil-Ortega et al., 2015;Omar et al., 2014). Indeed, MR over-activation in adipose tissue may lead to the malfunctioning of adipocyte autophagy, oxidative stress, and the release of pro-inflammatory mediators (Armani et al., 2014;Feraco et al., 2013). ...
... However, upon obesity, enhanced MR signaling in perivascular adipose tissue activates NADPH oxidase and promotes the release of inflammatory mediators, which impair vascular function and relaxation (Feraco et al., 2013;Gil-Ortega et al., 2015;Omar et al., 2014). Indeed, MR over-activation in adipose tissue may lead to the malfunctioning of adipocyte autophagy, oxidative stress, and the release of pro-inflammatory mediators (Armani et al., 2014;Feraco et al., 2013). Moreover, during obesity, the renin angiotensin aldosterone system is activated and adipose tissue releases aldosterone and contributes to hypertension, coronary heart disease, heart failure, and cardiovascular disease (Jia et al., 2017). ...
Mineralocorticoid receptor activation in endothelial and smooth muscle cells can promote vascular disease by increasing oxidative stress, promoting inflammation, accelerating vascular stiffness, remodeling, and calcification, altering vessel responsiveness to various vasoactive factors, thus altering vascular tone and blood pressure, and by altering angiogenesis. Here, we review the recent evidence highlighting the impact of vascular mineralocorticoid receptor activation in pathological situations, including kidney injury, vascular injury associated with metabolic diseases, atherosclerosis, cerebral vascular injury during hypertension, vascular stiffening and aging, pulmonary hypertension, vascular calcification, cardiac remodeling, wound healing, inflammation, thrombosis, and disorders related to angiogenic defects in the eye. The possible mechanisms implicating mineralocorticoid receptor activation in various vascular disorders are discussed. Altogether, recent evidence points towards pharmacological mineralocorticoid receptor inhibition as a strategy to treat diseases in which overactivation of the mineralocorticoid receptor in endothelial and/or smooth muscle cells may play a pivotal role.
... Under normal physiological conditions, PVAT releases vasodilator substances such as adiponectin and adipocyte-derived relaxing factors that contribute to the maintenance of normal vascular tone (5,6). In pathological conditions such as obesity, however, enhanced MR signaling in PVAT and VAT activates NADPH oxidase-derived reactive oxygen species and releases proinflammatory adipokines such as visfatin, resistin, tumor necrosis factor-a, and interleukin-6, contributing to impaired vascular insulin metabolic signaling and vascular relaxation (3,7). Indeed, in the Framingham Heart Study (FHS), increased PVAT was an independent risk factor for CVD (8). ...
... Overall, these new and interesting data emphasize the functional importance of adipocyte MR in CVD complications associated with obesity. Indeed, adipose MR overexpression resulted in increased adiposity owing to the known adipogenic actions of MR signaling (7). Therefore, this model presents a unique phenotype of MR-dependent adipose expansion resulting in a unique hypocontractile vascular phenotype that contrasts that typically seen in obesity models such as diet-induced obesity. ...
Obesity, insulin resistance, and type 2 diabetes mellitus (T2DM) are associated with increased levels of aldosterone and activation of cardiovascular mineralocorticoid receptors (MRs) contributing to hypertension and associated cardiovascular disease (CVD) (1). Large randomized controlled trials such as the Randomized Aldactone Evaluation Study (RALES), the Epleronone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), and the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) have demonstrated the CVD-related mortality and morbidity benefits of MR antagonists, further implicating MR signaling as a key mediator of CVD (2). The actions of kidney MR signaling to increase cardiovascular and renal fibrosis and blood pressure is well known; however, recent research suggests that inappropriate activation of extrarenal MR signaling in vascular endothelial cells (ECs), vascular smooth muscle cells (VSMCs), immune cells, and adipocytes promotes insulin resistance, T2DM, and associated CVD (1,3,4). For example, in association with obesity and insulin resistance, perivascular and visceral adipose tissue (PVAT and VAT) is dysfunctional, in part, because of adipose MR activation (3). Furthermore, PVAT and VAT secrete aldosterone, the ligand for MRs in endothelial and smooth muscle cells, and this is increased in obesity (3, …
... RAAS has a pivotal role in the regulation of blood pressure, fluid and electrolyte balance and is strictly linked to the pathophysiology of several cardiometabolic diseases, such as heart failure, type 2 diabetes, and obesity [32,33]. In this endocrine system, angiotensinogen (Agt), mainly produced by liver and adipose tissue, is enzymatically cleaved by renin, which is released into circulation by juxtaglomerular epithelioid cells located in the walls of renal afferent arterioles [34], to Ang I. Ang I is then converted by angiotensin converting enzyme (ACE) in Ang II [35]. ...
Background:
The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system involved in controlling stress responses in humans under physiological and pathological conditions; cortisol is the main hormone produced by the HPA axis. It is known that calorie restriction acts as a stressor and can lead to an increase in cortisol production. Renin-angiotensin-aldosterone system (RAAS) is a complex endocrine network regulating blood pressure and hydrosaline metabolism, whose final hormonal effector is aldosterone. RAAS activation is linked to cardiometabolic diseases, such as heart failure and obesity. Obesity has become a leading worldwide pandemic, associated with serious health outcomes. Calorie restriction represents a pivotal strategy to tackle obesity. On the other hand, it is well known that an increased activity of the HPA may favour visceral adipose tissue expansion, which may jeopardize a successful diet-induced weight loss. Very low-calorie ketogenic diet (VLCKD) is a normoprotein diet with a drastic reduction of the carbohydrate content and total calorie intake. Thanks to its sustained protein content, VLCKD is extremely effective to reduce adipose tissue while preserving lean body mass and resting metabolic rate.
Purpose:
The purpose of this narrative review is to gain more insights on the effects of VLCKD on the HPA axis and RAAS, in different phases of weight loss and in different clinical settings.
... In recent years, other effector organs, as well as diseases, related to the MR were identified. There is evidence that the MR plays a role in the immune system (van der Heijden et al., 2018), in adipose tissue (Feraco et al., 2013) and in the liver (Li et al., 2020;Luo et al., 2012;Schreier et al., 2018). Thereby, the MRs contribute to the consequences of diseases such as diabetes mellitus (Chen et al., 2015;Luther et al., 2011;Wang et al., 2019) metabolic syndrome (Long et al., 2013) or liver cirrhosis and portal hypertension (Garcia-Pagan et al., 1994;Katsuta et al., 1993;Queisser et al., 2014;Schreier et al., 2018;Tandon et al., 2010). ...
Liver diseases are the fourth common death in Europe responsible for about 2 million death per year worldwide. Among the known detrimental causes for liver dysfunction are virus infections, intoxications and obesity.
The mineralocorticoid receptor (MR) is a ligand‐dependent transcription factor activated by aldosterone or glucocorticoids but also by pathological milieu factors. Canonical actions of the MR take place in epithelial cells of kidney, colon and sweat glands and contribute to sodium reabsorption, potassium secretion and extracellular volume homeostasis. The non‐canonical functions can be initiated by inflammation or an altered micro‐milieu leading to fibrosis, hypertrophy and remodelling in various tissues.
This narrative review summarizes the evidence regarding the role of MR in portal hypertension, non‐alcoholic fatty liver disease, liver fibrosis and cirrhosis, demonstrating that inhibition of the MR in vivo seems to be beneficial for liver function and not just for volume regulation. Unfortunately, the underlying molecular mechanisms are still not completely understood.
LINKED ARTICLES
This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone‐Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc
... La spécificité du lieu de production est due à une expression restreinte de l'aldostérone synthase. Toutefois, certaines études ont identifié une expression de l'aldostérone synthase dans le TA [209], [210] . Cela suppose la synthèse locale de minéralocorticoïdes [211], [212] , également induite par la leptine [208] . ...
L’obésité est une maladie pandémique caractérisée par un excès de tissu adipeux (TA), à l’origine de complications métaboliques et cardiovasculaires dont l’origine physiopathologique reste mal identifiée. Ce travail de thèse étudie le rôle du récepteur minéralocorticoïde (MR) dans la physiopathologie de l’obésité et de ses complications. Ce récepteur nucléaire, facteur de transcription, régule l’homéostasie hydrosodée rénale et colique. Il est également exprimé dans d’autres organes et cellules (vaisseaux sanguins, adipocytes, macrophages) et son expression est augmentée dans le TA des patients obèses. Notre hypothèse est que l’activation excessive du MR dans le TA induit un dysfonctionnement organique causé par un stress oxydant augmenté, des anomalies de la fonction mitochondriale et un vieillissement prématuré. À l’aide de modèles murins transgéniques spontanément obèses ou à l’obésité provoquée par un régime riche en lipides, et présentant une modification de l’expression du MR dans les adipocytes ou dans la lignée myéloïde, nous avons démontré que l’activation du MR dans le TA blanc viscéral induit une augmentation du stress oxydant liée à une altération de la respiration et du contrôle qualité mitochondriaux, ainsi qu’une sénescence prématurée. Nos données démontrent pour la première fois un lien entre activation du MR, dysfonction mitochondriale et vieillissement dans le TA blanc, permettant de mieux comprendre le rôle du MR dans l’obésité et de proposer de nouvelles pistes de recherche et stratégies thérapeutiques pour lutter contre les comorbidités qui y sont associées.
... This fact may be associated with the absence of hyperactivity of the renin angiotensin system, given that the animals evaluated did not present arterial hypertension. Among the adipokines released by adipose tissue, angiotensin II, a hypertensive hormone generated from the renin angiotensin system, is associated with the pathogenesis of oxidative stress; angiotensinogen, a precursor of angiotensin II, from adipose tissue, contributes about one third of circulating angiotensinogen in rodents and plays an important role in the function of this tissue through the modulation of adipogenesis and lipid metabolism [12,66,67]. The activity of angiotensin II is mediated through its connection with its plasma membrane receptors, among them, the AT1 receptor is the most related to its harmful actions in heart, including the increase in the production of ROS by stimulating NADPH oxidase [68]. ...
Background/aims:
Oxidative stress is associated with cardiometabolic alterations, and the involvement of excess glucose and fatty acids has been demonstrated in this process. Thus, the aim of this study was to investigate the effects of different hypercaloric diets on cardiac oxidative stress.
Methods:
Wistar rats were randomized into four groups: control (C), high-sucrose (HS), high-fat (HF), and high-fat with sucrose (HFS). Nutritional assessment, food profiles, histological analysis, comorbidities, and cardiovascular characteristics were determined. Cardiac oxidative stress was analyzed by malondialdehyde (MDA) and carbonylated proteins, and the cardiac protein expression levels of type 1 angiotensin receptor (AT-1), nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2), superoxide dismutase (SOD 1 e 2), glutathione peroxidase (GPX), and catalase (CAT) were determined by western blot.
Results:
The HF group showed an increase in adiposity; however, it did not present adipocyte hypertrophy and comorbidities. Cardiac MDA and carbonylated protein levels were higher in the HF and HFS compared with the C group. The levels of oxidant and antioxidant proteins showed no difference between the groups.
Conclusion:
HF and HFS dietary interventions promoted cardiac oxidative stress, in the presence and absence of obesity, respectively. However, this process was neither mediated by the pro-oxidants AT1 and Nox2, nor by the quantitative reduction of antioxidant enzymes.
... In humans and animal models of obesity, activation of the renin-angiotensin-aldosterone system (RAAS) has been observed to be associated with enhanced oxidative stress and inflammation in the vascular tissue [33]. The effect is mediated through inappropriate mineralocorticoid receptor activation in adipose tissue [34]. ...
The increasing burden of obesity plays an essential role in increased cardiovascular morbidity and mortality. The effects of obesity on the cardiovascular system have also been demonstrated in childhood, where prevention is even more important. Obesity is associated with hormonal changes and vascular dysfunction, which eventually lead to hypertension, hyperinsulinemia, chronic kidney disease, dyslipidemia and cardiac dysfunction—all associated with increased cardiovascular risk, leading to potential cardiovascular events in early adulthood. Several preventive strategies are being implemented to reduce the cardiovascular burden in children. This paper presents a comprehensive review of obesity-associated cardiovascular morbidity with the preventive diagnostic workup at our hospital and possible interventions in children.
... Aldosterone increases blood pressure, and activation of the mineralocorticoid receptor (MR) can affect cardiac function via induction of inflammation and fibrosis [52]. Moreover, MR is reportedly associated with adipocyte dysfunction and vascular abnormalities, which may lead to obesity and insulin resistance [53][54][55]. ...
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and may progress to cirrhosis or even hepatocellular carcinoma. A number of steroid hormones are important regulators of lipid homeostasis through fine tuning the expression of genes related to lipid synthesis, export, and metabolism. Dysregulation of such pathways has been implicated in the pathogenesis of NAFLD. The aim of this review is to clarify the potential impact of steroid hormones on NAFLD. We also highlight potential interventions through modulating steroid hormone levels or the activities of their cognate receptors as therapeutic strategies for preventing NAFLD.
... In summary, the majority of studies points to an increase in ACE2 expression after MRB treatment, mainly by counteracting aldosteroneinduced down regulation of ACE2. In addition, mitigation of the deleterious effects of obesity on the RAS, possibly reducing obesity-related COVID-19 complications (Feraco et al., 2013;Vecchiola et al., 2020) and direct anti-inflammatory and antiviral effects of MRBs, could be beneficial in the treatment of pulmonary COVID-19 complications (Cadegiani, Wambier, & Goren, 2020). Importantly, MRBs such as spironolactone possess a significant anti-androgenic activity, which may be beneficial in the context of SARS-CoV-2 infection, by inhibiting the androgen-dependent expression of "Transmembrane protease, serine 2" (TMPRSS2), a transmembrane protease crucial for SARS-CoV-2 entry (Liaudet & Szabo, 2020). ...
The recent emergence of coronavirus disease-2019 (COVID-19) as a global pandemic has prompted scientists to address an urgent need for defining mechanisms of disease pathology and treatment. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, employs angiotensin converting enzyme 2 (ACE2) as its primary target for cell surface attachment and likely entry into the host cell. Thus, understanding factors that may regulate the expression and function of ACE2 in the healthy and diseased body is critical for clinical intervention. Over 66% of all adults in the United States are currently using a prescription drug and while earlier findings have focused on possible upregulation of ACE2 expression through the use of renin angiotensin system (RAS) inhibitors, mounting evidence suggests that various other widely administered drugs used in the treatment of hypertension, heart failure, diabetes mellitus, hyperlipidemias, coagulation disorders, and pulmonary disease may also present a varied risk for COVID-19. Specifically, we summarize mechanisms on how heparin, statins, steroids and phytochemicals, besides their established therapeutic effects, may also interfere with SARS-CoV-2 viral entry into cells. We also describe evidence on the effect of several vitamins, phytochemicals, and naturally occurring compounds on ACE2 expression and activity in various tissues and disease models. This comprehensive review aims to provide a timely compendium on the potential impact of commonly prescribed drugs and pharmacologically active compounds on COVID-19 pathology and risk through regulation of ACE2 and RAS signaling.
... This model applies to those with severe infection, many of whom have preexisting conditions, such as obesity or being elderly, that lead to increased angiotensin II and AT1, or reduced ACE2 (Feraco et al. 2013;Hajifathalian et al. 2020;Chung et al. 2020). There appears, in contrast, to be a subset of Covid-19 patients who have mild symptoms and develop high antibody titers. ...
The response to viral infection generally includes an activation of the adaptive immune response to produce cytotoxic T cells and neutralizing antibodies. We propose that SARS-CoV-2 activates the innate immune system through the renin-angiotensin and kallikrein-bradykinin pathways, blocks interferon production and reduces an effective adaptive immune response. This model has therapeutic implications.
... In addition to the protection reported to be provided by spironolactone, specific actions against SARS-CoV-2 actions have been proposed, including increased availability of free circulating ACE2 in response to a hyperreninemic state induced by MR antagonism [98][99][100][101][102][103][104], reduction of TMPRSS2 expression due to antagonism of AR [105][106][107], reversal of RAAS abnormalities induced by obesity [108,109], and possible direct antiinflammatory and anti-viral actions that hamper lung injuries [110][111][112][113][114][115][116][117][118][119][120][121]. There are currently three ongoing clinical trials with spironolactone [122-124]. ...
Background
Coronavirus Disease 2019 (COVID-19) is a multi-systemic infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that has become a pandemic. Although its prevailing symptoms include anosmia, ageusia, dry couch, fever, shortness of brief, arthralgia, myalgia, and fatigue, regional and methodological assessments vary, leading to heterogeneous clinical descriptions of COVID-19. Aging, uncontrolled diabetes, hypertension, obesity, and exposure to androgens have been correlated with worse prognosis in COVID-19. Abnormalities in the renin-angiotensin-aldosterone system (RAAS), angiotensin-converting enzyme-2 (ACE2) and the androgen-driven transmembrane serine protease 2 (TMPRSS2) have been elicited as key modulators of SARS-CoV-2.
Main text
While safe and effective therapies for COVID-19 lack, the current moment of pandemic urges for therapeutic options. Existing drugs should be preferred over novel ones for clinical testing due to four inherent characteristics: 1. Well-established long-term safety profile, known risks and contraindications; 2. More accurate predictions of clinical effects; 3. Familiarity of clinical management; and 4. Affordable costs for public health systems. In the context of the key modulators of SARS-CoV-2 infectivity, endocrine targets have become central as candidates for COVID-19.
The only endocrine or endocrine-related drug class with already existing emerging evidence for COVID-19 is the glucocorticoids, particularly for the use of dexamethasone for severely affected patients. Other drugs that are more likely to present clinical effects despite the lack of specific evidence for COVID-19 include anti-androgens (spironolactone, eplerenone, finasteride and dutasteride), statins, N-acetyl cysteine (NAC), ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), and direct TMPRSS-2 inhibitors (nafamostat and camostat). Several other candidates show less consistent plausibility. In common, except for dexamethasone, all candidates have no evidence for COVID-19, and clinical trials are needed.
Conclusion
While dexamethasone may reduce mortality in severely ill patients with COVID-19, in the absence of evidence of any specific drug for mild-to-moderate COVID-19, researchers should consider testing existing drugs due to their favorable safety, familiarity, and cost profile. However, except for dexamethasone in severe COVID-19, drug treatments for COVID-19 patients must be restricted to clinical research studies until efficacy has been extensively proven, with favorable outcomes in terms of reduction in hospitalization, mechanical ventilation, and death.
... Unlike ACEi and ARB, that specifically increase lung membrane-attached ACE2 expression, spironolactone tend to disclose favorable patterns of ACE2 expression, including a more extensive increase of circulating ACE2 when compared to membrane-attached ACE2, enhancing its potential protective role in SARS-CoV-2, once plasma ACE2 may couple to SARS-CoV-2 and avoid its entry in the cells [50][51][52][53][54][55], and may downregulate the androgen-mediated TMPRSS2 due to its antiandrogenic activity [56][57][58], without the adverse events of male sexual castration. In addition, spironolactone has been demonstrated to mitigate the detrimental effects of obesity on the RAAS [58][59][60][61][62][63][64][65], including hyperactivation of the RAAS due to increased angiotensinogen production by adipose tissue and imbalance towards angiotensin-2-AT-1 axis, possibly reducing obesity-related COVID-19 complications, and has direct specific anti-inflammatory effects in the lungs, possibly reducing acute lung injuries [66][67][68][69][70][71][72][73]. ...
In coronavirus disease-19 (COVID-19), four major factors have been correlated with worse prognosis: aging, hypertension, obesity, and exposure to androgen hormones. Angiotensin-converting enzyme-2 (ACE2) receptor, regulation of the renin-angiotensin-aldosterone system (RAAS), and transmembrane serine protease 2 (TMPRSS2) action are critical for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) cell entry and infectivity. ACE2 expression and RAAS are abnormal in hypertension and obesity, while TMPRSS2 is overexpressed when exposed to androgens, which may justify why these factors are overrepresented in COVID-19.
Among therapeutic targets for SARS-CoV-2, we hypothesized that spironolactone, a long used and safe mineralocorticoid and androgen receptors antagonist, with effective anti-hypertensive, cardioprotective, nephroprotective, and anti-androgenic properties may offer pleiotropic actions in different sites to protect from COVID-19. Current data shows that spironolactone may concurrently mitigate abnormal ACE2 expression, correct the balances membrane-attached and free circulating ACE2 and between angiotensin II and Angiotensin-(1-7) (Ang-(1-7)), suppress androgen-mediated TMPRSS2 activity, and inhibit obesity-related RAAS dysfunctions, with consequent decrease of viral priming. Hence, spironolactone may provide protection from SARS-CoV-2, and has sufficient plausibility to be clinically tested, particularly in the early stages of COVID-19.
... Повышение концентрации альдостерона в сыворотке крови определяется при артериальной гипертензии, связанной с ожирением, и при метаболическом синдроме. Вероятно, в первую очередь это обусловлено повышением активности ренин-ангиотензин-альдостероновой системы (РААС) [48]. ...
The mechanisms of mutual influence of fat tissue and the hypothalamo-pituitary-adrenal (HPA) axis include the regulation of the metabolism of adipocytes by adrenal cortex hormones, on the one part, and the effect of adipocytes and adipocytokines on secretion, metabolism and action of steroid hormones in target cells - on the other part.Glucocorticoids contribute to the differentiation of preadipocytes into mature adipocytes; brown fat tissue transforms into white under the effect of GC. Mineralocorticoids are also involved in the process of adipocyte differentiation, regulate adipokine expression, and induce oxidative stress in fat tissue. There is evidence that suggest that circulating dehydroepiandrosterone sulfate (DHEAS), obesity, insulin sensitivity are associated with the presence of cardiovascular diseases.Orexigenic neuropeptides and inflammatory mediators, which trigger the synthesis of corticotropin-releasing hormone (CRH) in the hypothalamic paraventricular nuclei, are considered as possible mechanisms of (HPA) axis activation in obesity. Expression of 1ip-hydroxysteroid dehydrogenase type 1 (11P-HSD1) in fat tissue and the formation of cortisol from cortisone at the tissue level can be considered as one of the factors involved in development of insulin resistance. The autocrine and paracrine regulatory effect of these hormones on adipocyte function is the consequence of aldosterone production and aromatization of androgens by fat tissue.
... In this context, numerous studies elucidated the possible molecular mechanisms underlying the obesity-related hyperaldosteronism. First, the existence of a local adipose renin-angiotensin-aldosterone system has been documented (Feraco et al., 2013;Kalupahana & Moustaid-Moussa, 2012). In fact, all components of the renin-angiotensin-aldosterone system are expressed in adipose tissue (Kalupahana & Moustaid-Moussa, 2012), which represents the major extra-hepatic site of angiotensinogen production . ...
Mineralocorticoid receptor (MR) has been recently identified in adipose tissue, where its excessive activation contributes to several metabolic derangements often observed in obesity and metabolic syndrome. Recent findings support the existence of a bidirectional cross-talk between adipose tissue and adrenal glands, contributing to obesity-related hyperaldosteronism and subsequent adipocyte MR excessive activation. In this regard, MR pharmacological blockade has led to prevention of weight gain and metabolic benefits in murine models of genetic or diet-induced obesity. However, there is still a lack of knowledge on the potential metabolic effects of MR antagonists in clinical settings. Hence, larger clinical studies are deemed necessary to clarify the role of MR antagonism in obesity and metabolic syndrome in humans.
... In addition, there is evidence that RAAS activation is involved in insulin resistance in both skeletal muscle and adipose tissue. 38,39 Thus, the increase in RAAS that occurs with ResS, 40-42 could sodium chloride cotransporter (NCC) (B) in kidney were evaluated by real-time polymerase chain reaction. Each gene expression level was normalized by 18S rRNA expression level. ...
Background
We hypothesized that caloric restriction (CR) and salt restriction (ResS) would have similar effects on reducing cardiovascular risk markers and that combining CR and ResS would be synergistic in modulating these markers.
Methods and Results
To test our hypothesis, rats were randomized into 2 groups: ad libitum liberal salt diet (ad libitum/high‐sodium, 1.6% sodium) or ResS diet (ad libitum/ResS, 0.03% sodium). CR was initiated in half of the rats in each group by reducing caloric intake to 60% while maintaining sodium intake constant (CR/high‐sodium, 2.7% sodium or CR/ResS, 0.05% sodium) for 4 weeks. CR in rats on a high‐sodium diet improved metabolic parameters, renal transforming growth factor‐β and collagen‐1α1 and increased plasma adiponectin and renal visfatin and NAD⁺ protein levels. Although CR produced some beneficial cardiovascular effects (increased sodium excretion and reduced blood pressure), it also was associated with potentially adverse cardiovascular effects. Adrenal zona glomerulosa cell responsiveness and aldosterone levels and activation were inappropriately increased for the volume state of the rodent. Like CR on HS, CR on a ResS diet also produced relative increased zona glomerulosa responsiveness and an increased blood pressure with no improvement in metabolic parameters.
Conclusions
These results suggest that combining CR and ResS may decrease the beneficial effects of each alone. Furthermore, CR, regardless of dietary salt intake, inappropriately activates aldosterone production. Thus, caution should be used in combining ResS and CR because the combination may lead to increased cardiovascular risk.
... Both aldosterone and obesity play important roles in the pathogenesis of MS and cardiovascular disease; thus, the relationship between these conditions is of major clinical importance. Increased serum aldosterone levels have been observed in individuals with obesity-associated MS, and the mechanisms were thought to involve upregulation of the renin-angiotensin-aldosterone system in obesity and the identification of adipose-derived factors that can directly stimulate adrenal aldosterone production [29,30]. In addition, many studies have recently focused on the direct regulatory effects of aldosterone on adipocytes [15,16,31,32]. ...
Aldosterone plays a pivotal role in the pathogenesis of metabolic syndrome and cardiovascular disease; however, the underlying mechanisms have not been clarified. Chemerin has been characterized as an adipokine with crucial roles in obesity-associated disorders and cardiovascular homeostasis. The aim of the present study was to investigate the direct effects of aldosterone on chemerin expression and secretion in 3T3-L1 adipocytes and to identify the potential signalling pathways involved. Chemerin mRNA levels were measured using real-time PCR, whereas the levels of secreted chemerin in the culture media were determined using ELISA. Treatment with aldosterone induced time- and dose-dependent increases of chemerin gene expression and protein secretion, and effect that was mediated through the mineralocorticoid receptor. Signalling studies suggested that the NF-κB pathway is involved in aldosterone-induced chemerin expression. Taken together, our data demonstrate a direct interaction between aldosterone and chemerin in adipocytes, which may be an underlying mechanism linking aldosterone-associated metabolic abnormalities and cardiovascular disease.
... Of interest, the existence of a local and functional reninangiotensin-aldosterone system (RAAS) has been demonstrated also in adipose tissue (72,123,193). In fact, adipose tissue expresses high levels of angiotensinogen, together with other RAAS components essential for the production of angiotensin peptides and aldosterone (46,61,190) (Fig. 1). ...
Corticosteroids are secreted by the adrenal glands and control the functions of adipose tissue via the activation of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). In turn, adipocytes release a large variety of adipokines into the bloodstream, regulating the function of several organs and tissues, including the adrenal glands, hereby controlling corticosteroid production. In adipose tissue, the activation of the MR by glucocorticoids (GC) and aldosterone affects important processes such as adipocyte differentiation, oxidative stress, autophagic flux, adipokine expression as well as local production of GC through upregulation of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Notably, the proinflammatory responses induced by the MR are counteracted by activation of the GR, whose activity inhibits the expression of inflammatory adipokines. Both GR and MR are deeply involved in adipogenesis and adipose expansion; hence pharmacological blockade of these two receptors has proven effective against adipose tissue dysfunction in experimental models of obesity and metabolic syndrome (MetS), suggesting a potential use for MR and GR antagonists in these clinical settings. Importantly, obesity and Cushing's syndrome (CS) share metabolic similarities and are characterized by high levels of circulating corticosteroids, which in turn are able to deeply affect adipose tissue. In addition, pharmacological approaches aimed at reducing aldosterone and GC levels, by means of the inhibition of CYP11B2 (aldosterone synthase) or 11β-HSD1, represent alternative strategies to counter the detrimental effects of excessive levels of corticosteroids, which are often observed in obesity and, more general, in MetS. © 2017 American Physiological Society. Compr Physiol 7:1425-1447, 2017.
... In addition, MR antagonists have well-established beneficial effects at the vascular and cardiac levels, which supports the notion that MR antagonists act at a multisystemic level, reducing blood pressure, tissue fibrosis, oxidative stress, insulin resistance, and adipose mass expansion, with potential global protective effects on MetS (108). Indirect evidence emerges from clinical studies that demonstrate that the prevalence of MetS is higher in primary aldosteronism than in essential hypertension (109), mostly for a detrimental effect of aldosterone excess on glucose metabolism and on adipose tissue physiology (110,111). ...
The metabolic syndrome (MetS) is defined as a cluster of 3 or more metabolic and cardiovascular risk factors and represents a serious problem for public health. Altered function of adipose tissue has a significant impact on whole-body metabolism and represents a key driver for the development of these metabolic derangements, collectively referred as to MetS. In particular, increased visceral and ectopic fat deposition play a major role in the development of insulin resistance and MetS. A large body of evidence demonstrates that aging and MetS share several metabolic alterations. Of importance, molecular pathways that regulate lifespan affect key processes of adipose tissue physiology, and transgenic mouse models with adipose-specific alterations in these pathways show derangements of adipose tissue and other metabolic features of MetS, which highlights a causal link between dysfunctional adipose tissue and deleterious effects on whole-body homeostasis. This review analyzes adipose tissue-specific dysfunctions, including metabolic alterations that are related to aging, that have a significant impact on the development of MetS.-Armani, A., Berry, A., Cirulli, F., Caprio, M. Molecular mechanisms underlying metabolic syndrome: the expanding role of the adipocyte.
... Increased serum aldosterone levels have been observed with both obesity-associated hypertension and the metabolic syndrome. While several mechanisms may be at play, this finding is most likely due in large part to the upregulation of the renin-angiotensin-aldosterone system (RAAS) in obesity, a proposed mechanism linking hypertension with obesity that is reversed by weight loss [17]. ...
Adipose tissue and the adrenal glands both play fundamental roles in the regulation of normal physiology and in the development of metabolic pathology. There has been an increasing awareness of the complex interactions between adipose tissue and the adrenal glands. Adipose tissue-derived efferent signals are implicated in a variety of alterations in adrenal function. Adipocyte-derived secretory products such as adiponectin and leptin have direct effects on adrenfal steroidogenesis, glucocorticoid metabolism, adrenal medullary catecholamine output and hypothalamic-pituitary-adrenal (HPA) axis function. Moreover, glucocorticoids and mineralocorticoids likely play a crucial role in the development of obesity and insulin resistance through elaborate mechanisms. Augmenting the effects of adrenal steroid hormones on adipose tissue is the enhanced activity of the mineralocorticoid receptor in adipocytes. Elevated adrenal steroid levels have been associated with weight gain, changes in body fat distribution and alterations in circulating levels of several adipose tissue hormones, or “adipokines." In this chapter, we summarize the current literature regarding the two-way communication between the adrenal glands and adipose tissue; emphasizing the possible mechanisms of interactions between these two endocrine organs and its relevance to the pathogenesis of obesity and associated comorbidities, metabolic syndrome, and in primary adrenal disorders.
... [4][5][6][7] The proposed mechanisms for the aldosterone-induced abnormalities include adipocyte dysfunction, increased hepatic gluconeogenesis, overproduction of reactive oxygen species, and classic target-organ damage. [8][9][10] It is unclear, however, whether these effects are mediated by genomic or nongenomic MR effects and/or are secondary to alternative crosstalk among aldosterone, plasma membrane proteins, and other receptors. ...
Background
Overactivation of the aldosterone and mineralocorticoid receptor (MR) pathway is associated with hyperglycemia and dyslipidemia. Caveolin 1 (cav‐1) is involved in glucose/lipid homeostasis and may modulate MR signaling. We investigated the interplay between cav‐1 and aldosterone signaling in modulating insulin resistance and dyslipidemia in cav‐1–null mice and humans with a prevalent variant in the CAV1 gene. Methods and ResultsIn mouse studies, cav‐1 knockout mice exhibited higher levels of homeostatic model assessment of insulin resistance, cholesterol, and resistin and lower ratios of high‐ to low‐density lipoprotein (all P
... In fact, Ang II is one of the major pro-inflammatory adipokines produced in obese adipose tissue that may be critical in linking obesity, inflammation and IR [5,18,19,26,27]. Adipose Agt contributes to roughly one third of the circulating Agt in rodents and plays an important role in adipose tissue function through the modulation of adipogenesis or lipid metabolism [28]. The role of Agt was interrogated using mouse models where Agt was manipulated systemically. ...
Obesity is a complex disease characterized by excessive expansion of adipose tissue and is an important risk factor for chronic diseases such as cardiovascular disorders, hypertension and type 2 diabetes. Moreover, obesity is a major contributor to inflammation and oxidative stress, all of which are key underlying causes for diabetes and insulin resistance. Specifically, adipose tissue secretes bioactives molecules such as inflammatory hormone angiotensin II, generated in the Renin Angiotensin System (RAS) by its precursor angiotensinogen. Accumulated evidence suggests that RAS may serve as a strong link between obesity and insulin resistance. Dysregulation of RAS also occurs in several other tissues including those involved in regulation of glucose and whole body homeostasis as well as insulin sensitivity such as muscle, liver and pancreas and heart. Here we review the scientific evidence for these interactions and potential roles for oxidative stress, inflammation and mitochondrial dysfunction in these target tissues which may mediate effects of RAS in metabolic diseases.
... [9][10][11] Since the adipocyte is now appreciated as a "metabolically active cell" producing adipokines that stimulate hormonal changes, the increase in CV event rates may lie with how the adipocyte functions in the postmenopausal period. 12,13 One recent advance in our understanding of how abdominal obesity and hypertension are linked is the observation that aldosterone levels are correlated with the magnitude of central adiposity. 14,15 Elevated levels of aldosterone are present in obese patients with resistant hypertension, and weight loss improves hypertension and lowers aldosterone levels. ...
Increased abdominal obesity is associated with increased cardiovascular risk, especially in African American women. The adipocyte is documented to produce a number of inflammatory factors including the hormone aldosterone. There are very few data documenting aldosterone production from adipocytes of postmenopausal women as well as data demonstrating the effects of angiotensin receptor blockade (ARB) on its production in predominately African American women. The authors hypothesize that increased central adipocyte mass in obese postmenopausal women contributes to increased production of aldosterone that is suppressed with the ARB azilsartan medoxomil. The authors tested this hypothesis in a double-blind, placebo-controlled pilot study of 34 hypertensive postmenopausal women (mean age 57.5±7.5 years), 91% of whom were African American. Patients had a mean 24-hour ambulatory systolic blood pressure of 127±13 mm Hg off any blocker of the renin-angiotensin system but while taking other antihypertensive medications. The authors further validated aldosterone production in a nested cohort of women using fat cells from a fat pad biopsy. Azilsartan reduced 24-hour urinary aldosterone by 47.3% from baseline (P=.03), with between-groups differences in urine aldosterone of -5.3±52.3% placebo vs -47.3±32.9% azilsartan (P=.07) at 6 months. An adrenal cell line treated with adipocyte-conditioned media from subcutaneous abdominal adipocytes of postmenopausal women (n=3) showed an increase in aldosterone production blocked by an ARB (1948±1297 pg/mL fat alone vs 894±438 pg/mL fat + ARB; P=.022). The authors conclude that aldosterone is produced from subcutaneous adipocytes of obese postmenopausal women. Moreover, use of an ARB significantly reduces aldosterone production within 6 months of use in these women as well as in cells exposed to their adipocytes.
... MR is also expressed outside tight epithelia (1,6,7), leading to the notion that this receptor could have pleotropic effects both in physiological and pathological settings (8). It is now well established that among other multiple functions, MR affects vascular smooth muscle and endothelial pathophysiology (9), participates in differentiation and function of adipocytes and the epidermal barrier (10,11), mediates aldosterone/NaCl-induced cardiovascular damage (12), modulates central control of salt appetite and BP (13) and is involved in regulating neurogenesis and neuronal activity in the hippocampus (14). ...
The mineralocorticoid receptor (MR) is a member of the nuclear receptor superfamily that transduces the biological effects of corticosteroids. Its best-characterized role is to enhance transepithelial sodium reabsorption in response to increased aldosterone levels. In addition, MR participates in other aldosterone- or glucocorticoid-controlled processes such as cardiovascular homeostasis, adipocyte differentiation or neurogenesis and regulation of neuronal activity in the hippocampus. Like other steroid receptors, MR forms cytosolic heterocomplexes with heat shock protein 90 (Hsp90), Hsp70 and other proteins such as immunophilins. Interaction with Hsp90 is thought to maintain MR in a ligand-binding competent conformation and to regulate ligand-dependent and independent nucleocytoplasmatic shuttling. It has previously been shown that acetylation of residue K295 in Hsp90 regulates its interaction with the androgen receptor (AR) and glucocorticoid receptor (GR). In this work we hypothesized that Hsp90 acetylation provides a regulatory step to modulate MR cellular dynamics and activity. We used Hsp90 acetylation mimic mutant K295Q or non-acetylatable mutant K295R to examine whether MR nucleocytoplasmatic shuttling and gene transactivation are affected. Furthermore, we manipulated endogenous Hsp90 acetylation levels by controlling expression or activity of histone deacetylase 6 (HDAC6), the enzyme responsible for deacetylation of Hsp90-K295. Our data demonstrates that HDAC6-mediated Hsp90 acetylation regulates MR cellular dynamics but it does not alter its function. This stands in contrast to the downregulation of GR by HDAC6, suggesting that Hsp90 acetylation may play a role in balancing relative MR and GR activity when both factors are co-expressed in the same cell.
... Although it is clear that obesity is an important risk factor for HF development, data remain relatively scarce regarding the contribution of MRA in the prevention of the development of HF in obese patients. Given the proven role of MR activation in adipogenesis (Feraco et al., 2013); Guo et al., 2008), we hypothesised that early MRA treatment with eple, one of the most selective MRAs to date, may delay or attenuate the adverse cardiac remodelling and subsequently prevent HF progression preferentially in obese rats. ...
Background and purpose:
Mineralocorticoid receptor (MR) activation contributes to heart failure (HF) progression. Its over-activation in obesity is suggested to accelerate cardiac remodelling and HF development. Given that MR antagonists (MRA) are beneficial in chronic HF patients, we hypothesised that early MRA treatment may target obesity-related disorders and consequently delay the development of HF.
Experimental approach:
Twenty spontaneously hypertensive HF dyslipidemic obese SHHF(cp/cp) rats and eighteen non-dyslipidemic lean SHHF(+/+) controls underwent regular monitoring for their metabolic and cardiovascular phenotypes with or without MRA (eplerenone (eple), 100 mg.kg(-1) .day(-1) ) from 1.5 to 12.5 months of age.
Key results:
Eleven-months eple treatment in obese rats (SHHF(cp/cp) eple) reduced obesity-related metabolic disorders observed in untreated SHHF(cp/cp) rats by minimising weight gain (563 ± 43 vs. 634 ± 27 g), triglycerides (8.29 ± 1.93 vs. 20.50 ± 2.60 g.L(-1) ) and total cholesterol levels (2.67 ± 0.24 vs. 4.25 ± 0.33 g.L(-1) ) and by preserving adiponectinemia (22.7 ± 1.6 vs. 11.9 ± 0.7 µg. mL(-1) ). MRA treatment predominantly preserved diastolic and systolic functions in obese rats by alleviating eccentric cardiac hypertrophy observed in untreated SHHF(cp/cp) animals (left ventricular mass 1760 ± 72 vs. 2195 ± 73 mg) and preserving ejection fraction (70 ± 1 vs. 59 ± 1 %). MRA also improved survival independently of pressure effects.
Conclusion and implications:
Early chronic eple treatment resulted in a delay in cardiac remodelling and HF onset in both SHHF(+/+) and SHHF(cp/cp) rats whereas SHHF(cp/cp) rats further benefited from MRA treatment through reduction of their obesity and dyslipidemia. These findings suggest that preventive MRA therapy may provide greater derived benefits in obese patients with cumulating risk factors of developing cardiovascular complications. This article is protected by copyright. All rights reserved.
... 9 Interestingly, the effects of GCs in adipose tissue are not exclusively mediated by the GR, but also by the mineralocorticoid receptor (MR). 10 Recently, it has been found that the MR is expressed in white adipocytes as well as in brown adipocytes, 11,12 and has a key role in corticosteroid-induced adipogenesis. 13,14 The MR binds not only to aldosterone but also to GCs with equivalent affinity. ...
Background:
We have previously shown that antagonism of the mineralocorticoid receptor (MR) results in a potent antiadipogenic activity, in vitro and in vivo. Excessive glucocorticoid exposure is associated with obesity and related disorders in humans and mice.
Methods:
In this study responses to a novel combined glucocorticoid receptor (GR)/MR antagonist were investigated in a model of diet-induced obesity. Female 10-week-old C57BL/6J mice were fed with normal chow or a high fat diet (HFD) for 9 weeks. Mice fed a HFD were concomitantly treated for 9 weeks with the GR antagonist mifepristone (80 mg/kg/day) or the novel combined GR/MR antagonist CORT118335 (80 mg/kg/day). Male, juvenile 6-week-old C57BL/6J mice fed HFD were treated with CORT118335 for 4 weeks.
Results:
Mice fed a HFD showed a significant increase in total body weight and white fat mass, with impaired glucose tolerance and increased fat infiltration in livers. Interestingly, only CORT118335 completely prevented the HFD-induced weight gain and white fat deposition, whereas mifepristone showed no effect on body weight and modestly increased subcutaneous fat mass. Importantly, food intake was not affected by either treatment, and CORT118335 dramatically increased PGC-1α protein expression in adipose tissue, without any effect on UCP1. Both CORT118335 and mifepristone produced metabolic benefit, improving glucose tolerance, increasing adiponectin plasma levels, decreasing leptin and reducing mean adipocyte size. When tested in vitro, CORT118335 markedly reduced 3T3-L1 differentiation and reversed MR-mediated pro-adipogenic effects of aldosterone; differently, GR-mediated effects of dexamethasone were not antagonised by CORT118335, suggesting that it mostly acts as an antagonist of MR in cultured preadipocytes.
Conclusions:
Combined GR/MR pharmacological antagonism markedly reduced HFD-driven weight gain and fat mass expansion in mice through the increase in adipose PGC-1α, suggesting that both receptors represent strategic therapeutic targets to fight obesity. The effects of CORT118335 in adipocytes seem predominantly mediated by MR antagonism.International Journal of Obesity accepted article preview online, 02 February 2016. doi:10.1038/ijo.2016.13.
... In addition, aldosterone has been shown to potentiate the impact of Ang Ⅱ impairments in endothelium-dependent relaxation both directly and indirectly through increased vascular oxidative stress resulting in reductions in the bioavailable nitric oxide [86,[94][95][96] . Inappropriate mineralocorticoid receptor activation has been demonstrated to be a causal factor in several pathologic conditions such as vascular inflammation, endothelial dysfunction, insulin resistance and obesity [97] . ...
... Given that mineralocorticoids have a negative effect on BAT, it follows that aldosterone antagonists may represent a combined therapy for both hypertension and obesity (through possible activation of BAT). This also supports the findings that high aldosterone levels are noted in obesity-induced hypertension in humans, which reverses on weight loss [81]. ...
Recent observation of brown adipose tissue (BAT) being functional in adult humans provides a rationale for its stimulation to increase energy expenditure through ‘adaptive thermogenesis’ for an anti-obesity strategy. Many endocrine dysfunctions are associated with changes in metabolic rate that over time may result in changes in body weight. It is likely that human BAT plays a role in such processes.
In this brief review article, we explore the endocrine determinants of BAT activity, and discuss how these insights may provide a basis for future developments of novel therapeutic strategies for obesity management.
A review of electronic and print data comprising original and review articles retrieved from PubMed search up to December 2013 was conducted (Search terms: brown adipose tissue, brown fat, obesity, hormone). In addition, relevant references from the articles were screened for papers containing original data.
There is promising data to suggest that targeting endocrine hormones for BAT modulation can yield a cellular bioenergetics answer for successful prevention and management of human obesity. Further understanding of the physiological link between various endocrine hormones and BAT is necessary for the development of new therapeutic options.
... Increasing body weight has an important association with left atrial enlargement, 24 because it causes left ventricular hypertrophy 25 and elevated blood flow volume, 26 and increases the vulnerability of the atrium that triggers Table 2 footnote. AF. 27 The pathogenesis of increasing body weight is related to increasing BP, 28 and involves metabolic dysregulation, 29 the sympathetic nervous system, 30 renin-angiotensinaldosterone system activity, 31 and renal sodium reabsorption. 32 In the present study, we observed an interaction between BMI and BP for incident AF. ...
To prevent stroke, strategies for atrial fibrillation (AF) prevention and an early detection of AF by electrocardiogram are essential. However, only a limited prospective studies have examined the risk factors for AF, even in blood pressure (BP) and body mass index (BMI), which are not clear among general populations. We investigated the impacts of BP and BMI on the risk of incident AF in a general population.
A total of 6,906 participants (30-84 years) in the Suita Study were prospectively followed up for incident AF. Participants were diagnosed with AF if AF or atrial flutter was present on an electrocardiogram from a routine health examination (every 2 years) or if AF was indicated as a present illness from health examinations and/or medical records during follow-up. Adjusted Cox proportional hazard ratios (HRs) were calculated.
During the 12.8-year follow-up, 253 incident AF events occurred. Compared with the systolic BP (SBP) < 120mm Hg and normal-weight, the adjusted HRs (95% confidence intervals; CIs) of incident AF in the systolic hypertension and the overweight (BMI ≥ 25kg/m(2)) groups were 1.74 (1.22-2.49) and 1.35 (1.01-1.80), respectively. Compared with SBP < 120mm Hg and normal weight, the adjusted HRs (95% CIs) of incident AF in the SBP = 120-139mm Hg with overweight and the systolic hypertension with normal or overweight were 1.72 (1.01-2.91), 1.66 (1.10-2.50), and 2.31 (1.47-3.65), respectively (P for interaction = 0.04).
Systolic prehypertension and overweight are associated with incident AF in Japanese population. The association between SBP and AF may be evident by overweight.
© American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
... a) High plasma levels of aldo are positively correlated with fat mass [16] where weight loss decreases aldo levels [15] , suggesting that the association between plasma aldo levels on the one hand and obesity and insulin resistance on the other hand may be related to adipocyte biology [99 -101] . b) Aldo could impact on insulin resistance, oxidative stress, sodium retention and volume overload, increased sympathetic activity, levels of free fatty acids, or pro-inflammatory cytokines as well as adipokines [18,102,103] . ...
Abstract Crosstalk between adipose tissue and blood vessels is vital to vascular homeostasis and is disturbed in cardiovascular and metabolic diseases such as hypertension, diabetes and obesity. Cardiometabolic syndrome (CMS) refers to the clustering of obesity-related metabolic disorders such as insulin resistance, glucose and lipid profile alterations, hypertension and cardiovascular diseases. Mechanisms underlying these associations remain unclear. Adipose tissue associated with the vasculature [known as perivascular adipose tissue (PVAT)] has been shown to produce myriads of adipose tissue-derived substances called adipokines, including hormones, cytokines and reactive oxygen species (ROS), which actively participate in the regulation of vascular function and local inflammation by endocrine and/or paracrine mechanisms. As a result, the signaling from PVAT to the vasculature is emerging as a potential therapeutic target for obesity and diabetes-related vascular dysfunction. Accumulating evidence supports a shift in our understanding of the crucial role of elevated plasma levels of aldosterone in obesity, promoting insulin resistance and hypertension. In obesity, aldosterone/mineralocorticoid receptor (MR) signaling induces an abnormal secretion of adipokines, ROS production and systemic inflammation, which in turn contribute to impaired insulin signaling, reduced endothelial-mediated vasorelaxation, and associated cardiovascular abnormalities. Thus, aldosterone excess exerts detrimental metabolic and vascular effects that participate to the development of the CMS and its associated cardiovascular abnormalities. In this review, we focus on the physiopathological roles of corticosteroid receptors in the interplay between PVAT and the vasculature, which underlies their potential as key regulators of vascular function.
... Patients with cardiac cachexia show similar disruption of steroid hormone concentration [ 87 ]. Glucocorticoids and mineralocorticoids regulate AT and adipocyte biology to a large extent [ 88 ]. Aldosterone, which exerts a pro-inflammatory action on the AT, may do so by modulating mononuclear cells of the SVF, and the same authors mention that increased angiotensin production in obesity could be associated with inflammation. ...
Abstract Adipose tissue inflammation plays a role in the etiology of many chronic diseases, and has been the focus of much attention in the context of obesity and metabolic syndrome. Similarly, during cancer cachexia, a syndrome that markedly increases cancer-associated morbidity and mortality, local adipose inflammation is reported in animal models and in patients, potentially contributing to the chronic systemic inflammation that constitutes the hallmark of this condition. We discuss, on the basis of information generated by obesity-related studies, the possible relation between adipose tissue inflammation and compromised steroid hormone secretion and action in cachexia.
... Increased serum aldosterone levels have been observed with both obesity-associated hypertension and the metabolic syndrome. While several mechanisms may be at play, this finding is most likely due in large part to the upregulation of the renin-angiotensin-aldosterone system (RAAS) in obesity, a proposed mechanism linking hypertension with obesity that is reversed by weight loss [17]. ...
Hormones produced by the adrenal glands and adipose tissues have important roles in normal physiology and are altered in many disease states. Obesity is associated with changes in adrenal function, including increase in adrenal medullary catecholamine output, alterations of the hypothalamic-pituitary-adrenal (HPA) axis, elevations in circulating aldosterone together with changes in adipose tissue glucocorticoid metabolism, and enhanced adipocyte mineralocorticoid receptor activity. It is unknown whether these changes in adrenal endocrine function are in part responsible for the pathogenesis of obesity and related comorbidities or represent an adaptive response. In turn, adipose tissue hormones or "adipokines" have direct effects on the adrenal glands and interact with adrenal hormones at several levels. Here we review the emerging evidence supporting the existence of "cross talk" between the adrenal gland and adipose tissue, focusing on the relevance and roles of their respective hormones in health and disease states including obesity, metabolic syndrome, and primary disorders of the adrenals.
... Neurons in the hippocampus do not express this enzyme, thus MR should be mainly considered as a glucocorticoid-activated receptor in the central nervous system (CNS). This situation is similar in many other non-epithelial target cells such as in cardiomyocytes and adipocytes [8][9][10][11]. ...
Mineralocorticoid receptor (MR), a hormone-activated transcription factor belonging to the nuclear receptor superfamily, exerts widespread actions in many tissues such as tight epithelia, the cardiovascular system, adipose tissues and macrophages. In the mammalian brain, MR is present in the limbic areas where it is highly expressed in neurons of the hippocampus and mostly absent in other regions while the glucocorticoid receptor (GR) expression is ubiquitous. MR binds both aldosterone and glucocorticoids, the latter having a ten-fold higher affinity for MR than for the closely related GR. However, owing to the minimal aldosterone transfer across the blood brain barrier and the absence of neuronal 11β hydroxysteroid dehydrogenase type 2 as an intracellular gate-keeper, neuronal MR appears to be fully occupied even at low physiological glucocorticoid levels while GR activation only occurs at high glucocorticoid concentrations, i.e. at the peak of the circadian rhythm or under stress. This defined a one hormone/two receptors system that works in balance, modulating a large spectrum of actions in the central nervous system. MR and GR are involved in the stress responses, the regulation of neuron excitability, long term potentiation, neuroprotection and neurogenesis in the dentate gyrus. MR thus constitutes a key factor in the arising of higher cognitive functions such as memorization, learning and mood. This review presents an overview of various roles of MR in the central nervous system which are somewhat less studied than that of GR, in the light of recent data obtained using cellular models, animal models and clinical investigations.
... In mice adiponectin regulates vasodilation via induction of eNOS and NO and displays renoprotective properties by reversing loss of podocyte foot processes, through induction of AMPK activation and attenuation of Nox4 and ROS production [2]. In addition to the adipokines, adipose tissue also expresses the components of the renin-angiotensin (RAAS) system, locally affecting adipose glucose homeostasis, lipid metabolism and inflammation [17]. Obesity-induced upregulation of adipose RAAS may contribute to as much as 30% of circulating angiotensinogen, causing a paracrine effect linked to kidney disease and inflammation [18]. ...
Growing evidencehas described a correlation between aldosterone, obesity, and insulin resistance, suggesting that adipocyte-related factors and mineralocorticoid receptor (MR) overactivation may alter aldosterone secretion, potentially leading to obesity and glucose intolerance.
Preclinical studies showed that pharmacological antagonism of MR prevents white adipose tissue dysfunction(s) and expansion, activates brown adipose tissue, and improves glucose tolerance. The clinical use of nonsteroidal MR antagonists has been shown to reduce the risk of diabetic kidney disease progression and cardiovascular events in patients with diabetes. This review aims to summarize the effects of pharmacological MR blockade on obesity and its associated metabolic comorbidities, with a particular focus on the therapeutic implications of nonsteroidal MR antagonists in the management of patients with diabetes.
Introduction
At the onset of the COVID-19 pandemic, mortality following infection of severe acute respiratory coronavirus (SARS-CoV-2) was thought to be solely associated with aging and pre-existing conditions; however, as the pandemic ensued, several large scale epidemiological observations eluded to additional atypical risk factors, particularly hypertension, obesity, and male gender (1-11).
SARS-CoV-2: current knowledge on the mechanisms of action
The peculiarities and complexity of SARS-CoV-2 infection patterns precluded definitive findings regarding the mechanisms of infectivity. Current literature suggests that angiotensin-converting enzyme-2 (ACE2) receptor and transmembrane serine protease 2 (TMPRSS2) are the key for SARS-CoV-2 cell entry (12-20). While ACE2 is the coupling site of the spike protein of SARS-CoV-2, TMPRSS2 facilitates SARS-CoV-2 spikes and ACE2 for viral cell entry. Although ACE2 expression is present diffusely, up to 80% of its expression is located in the type-2 pneumocytes (12,17), which may explain why COVID-19 is predominantly pulmonary, although SARS-COV-2 may affect any organ and system. TMPRSS2 activity is modulated by androgens, which may justify why males are overrepresented among severe COVID-19 infected patients (21).
Current understanding of SARS-CoV-2 allows the division of COVID-19 into two phases (12-18). In a first, early phase, which corresponds to the period of SARS-CoV-2 cell entry, lung membrane-attached ACE2 expression seems to be positively correlated with virus infectivity, while the balance between circulating ACE2, that could protect from lung infectivity by coupling with SARS-CoV-2 and precluding from the entry into the pneumocytes (13-16)), and membrane-attached ACE2, may also be relevant.
In a second phase, represented by the inflammatory and immunological responses to SARS-CoV-2 infection, ACE2 is downregulated due to the entry into cell cytoplasm when coupled with the virus. In opposition to the first phase, in the second phase, lung-attached ACE2 expression may be positively correlated with better clinical outcomes, since ACE2 may limit the cytokine storm that underlies the Acute Respiratory Distress Syndrome (ARDS) in COVID-19, while the balance between proinflammatory angiotensin II - angiotensin receptor type 1 (AT1) axis, and the anti-inflammatory angiotensin 1-7 – G-coupled Mas receptor (angiotensin 1-7 receptor) axis may also be crucial for level of severity of the second phase (13,15-20).
SARS-CoV-2: the link between mechanisms of action and risk factors
The Renin-Angiotensin-Aldosterone System (RAAS) has been shown to be central in COVID-19, since three of the key modulators of SARS-CoV-2 infectivity - angiotensin 1-7, ACE2, and AT1 – belong to the RAAS, in addition to the TMPRSS2 expression (12-20).
Disruption of RAAS and ACE2 expression abnormalities are likely the underlying mechanism that links hypertension and obesity as important risk factors for COVID-19 (22-30). Conversely, TMPRSS2 overexpression in response to exposure to androgens may justify the higher occurrence of COVID-19 complications in males (31-34), which can be reinforced by the fact that males under androgen deprivation therapies such as for prostate cancer may experiment decreased risk for ARDS when compared to age-, sex-, and comorbidities-matched subjects (34).
A pro-thrombotic state, and endothelial, hematological, kidney, hepatic, cardiovascular, gonadal, neurological and gastrointestinal manifestations in COVID-19 are at least partially mediated by ACE2 and TMPRSS2 expressions (35-61).
In summary, aberrancies in ACE2 expression, unbalance between angiotensin II and angiotensin 1-7 levels, and overexpression of TMPRS22 seem to be key factors for the severity of clinical manifestations in COVID-19.
Spironolactone as a candidate against COVID-19
Drugs that address ACE2, any sight of the RAAS, or TMPRSS2 expression are potential candidates for COVID-19. In this context, the use of old drugs against COVID-19 may present major potential benefits over novel drugs for some reasons, including: 1. The well-established long-term safety profile 2. Extensively described risks and contraindications, which allows to prevent its use when contraindicated and monitor for risks directedly; and 3. The lower cost of old, non-patented drugs allows its massive use in public health systems, when clinically indicated.
These observations combined with our understanding of SARS-CoV-2 molecular mechanism of infectivity lead us to believe that spironolactone is an ideal candidate drug for the prophylactic treatment of SARS-CoV-2.
Spironolactone is a safe and well-tolerated anti-hypertensive and anti-androgenic drug used since 1959, that is effective to maintain normal blood levels (62-64), address heart function, and provide cardio- and renoprotection (65-69).
While spironolactone is a safe and unexpensive option, it may act in multiple sites against COVID-19, including: 1. Favorable patterns of ACE2 expression, including potential increase of circulating ACE2, enhancing its potential protective role in SARS-CoV-2, once plasma ACE2 may couple to SARS-CoV-2 and avoid its entry in the cells (70-76); 2. Downregulation of the androgen-mediated TMPRSS2 due to its antiandrogenic activity (77-79), without the adverse events of male sexual castration; 3. Mitigation of the deleterious effects of obesity on the RAAS, possibly reducing obesity-related COVID-19 complications (80,81); 4. Direct anti-inflammatory and anti-viral effects that could directly avoid pulmonary complications of COVID-19 (82-93).
Hence, spironolactone meets corresponding epidemiological data, mechanistical plausibility, and sufficient safety profile to become a candidate against COVID-19.
For the proper management of spironolactone during COVID-19, since spironolactone mostly targets the virus entry in the cells, which is the hallmark of the first phase of Covid-19, spironolactone should be preferably started during the earlier stages of the infection, prior to the complications of respiratory manifestations, but could also be employed in the second phase, when the inflammatory and immunologic responses become clinically relevant, due to its anti-inflammatory effects (94).
Conclusion
Abnormal ACE2 expression, angiotensin II and angiotensin 1-7 imbalance, and TMPRSS2 androgen-mediated overactivity seem to be key regulators of SARS-CoV-2 infectivity, in accordance with epidemiological observations of hypertension, obesity, and male sex as being major risk factors. Since spironolactone is a long used safe drug that exhibits concurrent actions in the modulation of ACE2 expression that could avoid SARS-CoV-2 cell entry, attenuation of the harms caused by the overexpression of angiotensin II-AT-1 axis, discloses anti-androgenic activity that can decrease viral priming through TMPRSS2 activity, and has anti-inflammatory effects in the lungs, spironolactone seems to be a plausible candidate for the prophylactic and early treatment of SARS-CoV-2
Background:
Obesity can be associated with increased cardio-metabolic risk, but some subjects with obesity do not show metabolic impairment and escape this association. Low-grade inflammation (i.e., high sensitivity C-reactive protein [hsCRP] > 3 mg/dL) is associated with high cardiovascular risk in obesity. We investigated renin-angiotensin system (RAS) activity in cultured circulating T-cells in subjects with obesity with and without angiotensin II (Ang II) stimulation in the presence or absence of low-grade inflammation.
Materials and methods:
We studied 18 subjects with obesity and 10 healthy subjects. After T-lymphocyte isolation, T-cell mRNAs for angiotensin converting enzyme (ACE) and AT1-receptor were quantified by reverse transcription polymerase chain reaction at baseline and after Ang II stimulation. hsCRP, plasma renin and ACE activity in the cell pellet and supernatant and Ang II T-cell content were also measured.
Results:
T-cell RAS in subjects with obesity with low-grade inflammation was more activated than in subjects with obesity without low-grade inflammation. The increase in RAS activation occurred both at baseline and after Ang II stimulation. Similarly, the release of ACE activity in the supernatant was significantly higher in subjects with obesity with hsCRP > 3 mg/dL than in subjects with hsCRP < 3 mg/dL and controls.
Conclusions:
Circulating T-cell based RAS is activated in subjects with obesity independently of low-grade inflammation that amplifies the T-cell RAS response to Ang II stimulation.
L’activation du récepteur minéralocorticoïde par l’aldostérone joue un rôle majeur dans le remodelage cardiovasculaire en participant à l’hypertension, à la fibrose et à l’inflammation. Notre laboratoire a récemment mis en évidence le rôle critique de la Neutrophil Gelatinase-Associated Lipocalin (NGAL), une nouvelle cible du MR, dans les effets délétères de son activation. Afin de mieux comprendre le rôle de NGAL dans ces effets, nous avons réalisé différents modèles profibrotiques chez des souris présentant une invalidation génique totale de NGAL ou une déplétion de NGAL dans leurs cellules immunitaires spécifiquement. Nos résultats démontrent un rôle primordial de la NGAL produite par les cellules immunitaires dans les lésions cardio-rénales induite par l’activation du MR. De plus, nos données suggèrent que le contexte inflammatoire pourrait être un élément déterminant de l’implication physiopathologique de NGAL.
L’utilisation d’antagonistes du récepteur aux minéralocorticoïdes (ARM) a prouvé son efficacité dans le traitement de l’insuffisance cardiaque (IC). Un des facteurs de risque majeur de l’IC, le syndrome métabolique (SMet), est également associé à une production augmentée d’aldostérone et une activation excessive de son récepteur. Dans ce contexte, nous avons émis l’hypothèse que l’utilisation des ARM pouvait être appliquée pour cibler les facteurs de risques du SMet et prévenir la progression subséquente vers l’IC. Dans ce projet, des rats Spontanément Hypertendus et développant une IC (rats SHHF) portant ou non une mutation du récepteur de la leptine (« cp ») conduisant à un SMet (respectivement SHHFcp/cp et SHHF+/+) ont été utilisés comme modèle expérimental. Les animaux ont reçu soit un placebo soit le traitement ARM (Eplérénone, Eplé) dès l’âge de 1.5 à 12.5 mois et leurs paramètres métaboliques et cardiovasculaires ont été régulièrement évalués. Les fonctions moléculaires altérées dans le coeur et le tissu adipeux lors du développement du SMet et la progression de l’IC, ainsi que celles modulées par l’action de l’Eplé ont été caractérisées par l’analyse du transcriptome et miRNome des animaux. Nos résultats montrent que les rats SHHFcp/cp développent à 12.5 mois une hypertrophie cardiaque excentrique associée à une dilatation du ventricule gauche (VG) et une fraction d’éjection diminuée comparés aux SHHF+/+. Alors que l’Eplé ne modifie pas les paramètres métaboliques et cardiovasculaires des SHHF+/+, Les rats Eple-SHHFcp/cp présentent une moindre prise de masse corporelle ainsi qu’une moindre dyslipidémie. Sans effet sur la pression artérielle (PA), ni le transcriptome et miRNome adipeux, les animaux SHHFcp/cp traités présentent en outre une moindre dilatation et hypertrophie de leur VG, une fraction d’éjection, un temps de relaxation isovolumique et un ratio E/A plus élevés. Les analyses du transcriptome et miRNome cardiaques révèlent que l’Eplé induit une diminution significative de l’expression de gènes impliqués dans le remodelage et l’inflammation myocardiques ainsi qu’une augmentation de l’expression de gènes relatifs à l’oxydation des acides gras dans le coeur. L’intégration et l’exploration bioinformatique des profils d’expression du transcriptome et du miRNome ont permis d’établir des réseaux de régulation de l’expression génique potentiellement impliqués dans les mécanismes physiopathologiques à l’oeuvre chez les rats SHHF obèses et dans ceux impactés par le traitement. Dans leur ensemble, nos données montrent que l’initiation d’un traitement ARM lors du développement du SMet permet d’atténuer l’obésité et la dyslipidémie et d’améliorer les paramètres de structure et fonction cardiaque. De façon intéressante, ces effets cardioprotecteurs sont obtenus via des mécanismes indépendants de la diminution de la PA, les analyses du transcriptome/miRNome cardiaque indiquent un mécanisme basé sur une diminution des processus de remodelage et d’inflammation ainsi qu’ une restauration de la fonction de métabolisme énergétique des acides gras au niveau myocardique
The overweight and obesity epidemic has led to an increase in the metabolic syndrome and associated cardiovascular disease (CVD). These abnormalities include insulin resistance, type 2 diabetes mellitus, vascular stiffness, hypertension, stroke, and coronary heart disease. Visceral white adipocyte tissue (WAT) expansion and associated fibrosis/stiffness of WAT promote insulin resistance and CVD through increases in proinflammatory adipokines, oxidative stress, activation of renin-angiotensin-aldosterone system, dysregulation of adipocyte apoptosis and autophagy, dysfunctional immune modulation, and adverse changes in the gut microbiome. The expansion of WAT is partly determined by activation of peroxisome proliferator-activated receptor gamma and mammalian target of rapamycin/ribosomal S6 kinase signaling pathways. Further, the chronic activation of these signaling pathways may not only induce adipocyte hypertrophy and fibrosis, but also contribute to systemic inflammation, and impairment of insulin metabolic signaling in fat, liver, and skeletal muscle tissue. Therefore, the interplay of adipocyte dysfunction, maladaptive immune and inflammatory responses, and associated metabolic disorders often coexist leading to systemic low-grade inflammation and insulin resistance that are associated with increased CVD in obese individuals. (C) 2017 American Physiological Society.
Next to epithelial tissues, mineralocorticoid receptors are also expressed in adipose tissue and are involved in the process of adipogenesis. Mineralocorticoid receptors in adipose tissue are likely to be activated mainly by glucocorticoids. The aim of the present study was to test the hypothesis that the processes related to adipogenesis are modified under the conditions associated with high circulating aldosterone. We have made advantage of a model of depression based on tryptophan depletion in which we have previously demonstrated that the elevation of serum aldosterone precedes that of corticosterone. Sixty adult female Sprague-Dawley rats were fed either a low tryptophan diet or control diet for 4 (elevation of aldosterone only), 7 and 14 days (broader neuroendocrine activation) respectively. Gene expression of several adipogenic factors, CD31, interleukin-6, adiponectin, resistin and leptin were evaluated. Levels of mRNAs coding for adipogenic, angiogenic and inflammatory factors in adipose tissue were elevated at 4 and 7 days of tryptophan depletion. Additionally, gene expression of aldosterone sensing 11-β-hydroxysteroid dehydrogenase 2 and mineralocorticoid receptors were elevated. All changes disappeared at 14 days of tryptophan depletion. Synchronously an increase of adipose tissue mass was observed. Although direct evidence is not provided, observed changes in gene expression may be related to the action of aldosterone on mineralocorticoid receptors. Our findings represent the first data on any changes in gene expression in adipose tissue in animal models of depression.
We aimed to evaluate mineralocorticoid receptor (MR) expression in rat bladder and the physiological role of the MR-epithelial sodium channel (ENaC) pathway in controlling bladder function in 10–12-week-old, male Sprague-Dawley rats. First, we examined the mRNA expression of MR and localization of MR and ENaC-α proteins in the urinary bladder. MR mRNA expression was observed in untreated-rat urinary bladders, and MR and ENaC-α proteins were localized in the epithelium. Next, rats were treated with vehicle (controls) or fludrocortisone (an MR agonist) for 3 days, and ENaC-α protein expression levels and bladder function were evaluated on day 4. ENaC-α protein expression was significantly higher in fludrocortisone-treated rats than in controls. In addition, cystometry was performed during intravesical infusion of saline and amiloride (an ENaC inhibitor). While intercontraction intervals (ICIs) during saline infusion were significantly shorter in the fludrocortisone group than in the controls, infusion of amiloride normalized the ICIs in the fludrocortisone group. However, no intra- or inter-group differences in maximum intravesical pressure were observed. Taken together, MR protein is localized in the rat urinary bladder epithelium, and may regulate ENaC expression and bladder afferent input. The MR-ENaC pathway may be a therapeutic target for ameliorating storage symptoms.
Primary aldosteronism, caused by autonomous secretion of aldosterone by the adrenals, is estimated to account for at least 5% of hypertension cases. Hypertension explains the considerable cardiovascular morbidity caused by aldosteronism only partly, calling for specific anti-aldosterone drugs. The pharmacology of aldosterone is complex due to high homology with other steroids, the resemblance of steroid receptors, and the common pathways of steroid synthesis. Classically, pharmacological treatment of aldosteronism relied on the mineralocorticoid receptor (MR) antagonist spironolactone, which is highly effective, but causes considerable, mainly sexual side-effects due to limited selectivity for the MR. New agents have been developed or are being developed that aim at higher selectivity for MR antagonists (eplerenone, dihydropyridine-derived calcium channel blockers (CCB)), or inhibition of aldosterone synthesis. Eplerenone is less potent than spironolactone, but causes fewer adverse effects due to its selectivity for the MR. Non-steroidal MR antagonists have been developed from dihydropyridine CCBs, having lost their CCB activity and being highly selective for the MR. The first clinical studies with these drugs are underway. Aldosterone synthase inhibitors are an attractive alternative, but are prone to interference with cortisol synthesis due to the inhibition of 11-β-hydroxylation, an essential step in both cortisol and aldosterone synthesis, and accumulation of mineralocorticoid precursors. In coming years clinical research will provide the answers as to which drugs and strategies to treat high-aldosterone states are the most effective.
Copyright © 2015. Published by Elsevier Inc.
Corticosteroid (glucocorticoids [GCs] and mineralcorticoids [MCs]) interact directly with cells of the cardiovascular system. Their signaling affects genomic and non-genomic receptors and comprises a multitude of alternative and interfering levels of interaction, which influence the physiological response. This review describes genomic and non-genomic pathways of steroid facilitation and portrays the current body of knowledge regarding corticosteroid-binding globulin (CBG). The latter is a carrier protein facilitating corticosteroid availability in the circulation and has recently been discovered intrinsically in cardiomyocytes. Thought experiments highlight potential areas of clinical research and hypotheses are presented for steroid-carrier interaction. Furthermore, this review comprises a conclusive overview of disease conditions and substances that influence CBG levels and summarizes the potential of CBG as a potential future biomarker.
Classical effects of mineralocorticoids include stimulation of Na(+) reabsorption and K(+) secretion in the kidney and other epithelia including colon and several glands. Moreover, mineralocorticoids enhance the excretion of Mg(2+) and renal tubular H(+) secretion. The renal salt retention following mineralocorticoid excess leads to extracellular volume expansion and hypertension. The increase of blood pressure following mineralocorticoid excess is, however, not only the result of volume expansion but may result from stiff endothelial cell syndrome impairing the release of vasodilating nitric oxide. Beyond that, mineralocorticoids are involved in the regulation of a wide variety of further functions, including cardiac fibrosis, platelet activation, neuronal function and survival, inflammation as well as vascular and tissue fibrosis and calcification. Those functions are briefly discussed in this short introduction to the special issue. Beyond that, further contributions of this special issue amplify on mineralocorticoid-induced sodium appetite and renal salt retention, the role of mineralocorticoids in the regulation of acid-base balance, the involvement of aldosterone and its receptors in major depression, the mineralocorticoid stimulation of inflammation and tissue fibrosis and the effect of aldosterone on osteoinductive signaling and vascular calcification. Clearly, still much is to be learned about the various ramifications of mineralocorticoid-sensitive physiology and pathophysiology. © 2014 S. Karger AG, Basel.
Objective:
Dysregulation of enzymes that control local tissue steroid metabolism has been implicated in the pathogenesis of obesity and insulin resistance; however, longitudinal changes in glucocorticoid metabolism have not been investigated. This study was performed to evaluate the role of glucocorticoid metabolism in the development of insulin resistance and obesity and to identify biomarkers for future development of metabolic disease.
Design:
This was a prospective longitudinal observation study conducted over 5 years.
Methods:
A 24-h collection was used to serially analyze urinary glucocorticoid and mineralocorticoid metabolites in 57 obese and overweight patients with no prior diagnosis of diabetes mellitus, recruited from the community.
Results:
Baseline higher 5α-reductase (5αR) activity, but not 11β-hydroxysteroid dehydrogenase type 1 activity, was predictive of increased fasting insulin at final visit (11.4 compared with 7.4 mU/l in subjects with lower 5αR activity, P<0.05), area under the curve insulin response to oral glucose tolerance test (176.7 compared with 89.1 mU/l.h, P<0.01), and homeostasis model assessment (HOMA2-IR; 1.3 compared with 0.8, P<0.01). Higher total glucocorticoid production was associated with abnormal glucose tolerance and increased BMI. During this study, systolic blood pressure increased (equivalent to ∼1 mmHg/year), as did plasma sodium levels; this evidence of increased mineralocorticoid activity was associated with increased aldosterone metabolites and decreased 11β-hydroxysteroid dehydrogenase type 2 activity.
Conclusions:
Increased 5αR activity and glucocorticoid secretion rate over time are linked with the development of metabolic disease, and may represent targets for therapeutic intervention, which merits further study.
Adipose tissue inflammation plays a role in the etiology of many chronic diseases, and has been the focus of much attention in the context of obesity and metabolic syndrome. Similarly, during cancer cachexia, a syndrome that markedly increases cancer-associated morbidity and mortality, local adipose inflammation is reported in ani-mal models and in patients, potentially contributing to the chronic systemic inflammation that constitutes the hallmark of this condition. We discuss, on the basis of information generated by obesity-related studies, the pos-sible relation between adipose tissue inflammation and compromised steroid hormone secretion and action in cachexia.
The prevalence of primary aldosteronism (PA) is around 3-15% in patients with hypertension. Hypertension is a frequent complication of type 2 diabetes mellitus (DM) because of the close etiological relationship between these two diseases. However, the possibility of PA in patients with DM and hypertension is often overlooked and the prevalence of PA in patients with DM and hypertension in Japan is unknown. We enrolled 124 hospitalized patients with both DM and hypertension. PA was diagnosed according to the modified criteria for Japanese patients. We examined the prevalence of PA and compared clinical characteristics between patients with and without PA. In another analysis of 43 patients with a confirmed diagnosis of PA, we compared the characteristics of patients with and without DM. Overall, 14/124 patients with DM and hypertension (11.3%) were diagnosed with PA. Multivariate logistic regression showed that the duration of DM was significantly shorter in the PA group. Fisher's direct probability test revealed that history of hypertension before the diagnosis of DM was a significant factor in patients with PA. Treatment with an angiotensin II receptor blocker (ARB) did not affect the diagnosis of PA in these patients. Among 43 patients with PA, those with DM were significantly older and the delay to the diagnosis of PA was significantly longer compared with patients without DM. In conclusion, almost 10% of patients with DM and hypertension actually have PA. More extensive screening for PA is recommended in patients with DM and hypertension, regardless of the use of ARBs.
Brown adipose tissue (BAT) is known to function in the dissipation of chemical energy in response to cold or excess feeding, and also has the capacity to modulate energy balance. To test the hypothesis that BAT is fundamental to the regulation of glucose homeostasis, we transplanted BAT from male donor mice into the visceral cavity of age- and sex-matched recipient mice. By 8-12 weeks following transplantation, recipient mice had improved glucose tolerance, increased insulin sensitivity, lower body weight, decreased fat mass, and a complete reversal of high-fat diet-induced insulin resistance. Increasing the quantity of BAT transplanted into recipient mice further improved the metabolic effects of transplantation. BAT transplantation increased insulin-stimulated glucose uptake in vivo into endogenous BAT, white adipose tissue (WAT), and heart muscle but, surprisingly, not skeletal muscle. The improved metabolic profile was lost when the BAT used for transplantation was obtained from Il6-knockout mice, demonstrating that BAT-derived IL-6 is required for the profound effects of BAT transplantation on glucose homeostasis and insulin sensitivity. These findings reveal a previously under-appreciated role for BAT in glucose metabolism.
Obesity, defined as excess fat mass, increases risks for multiple metabolic diseases, such as type 2 diabetes, cardiovascular disease and several types of cancer. Over and above fat mass per se, the pattern of fat distribution, android or truncal as compared to gynoid or peripheral, has a profound influence on systemic metabolism and hence risk for metabolic diseases. Increases in upper body adipose tissue (visceral and abdominal subcutaneous) confer an independent risk, while the quantity of gluteofemoral adipose tissue is protective. Variations in the capacity of different depots to store and release fatty acids and to produce adipokines are important determinants of fat distribution and its metabolic consequences. Depot differences in cellular composition and physiology, including innervation and blood flow, likely influence their phenotypic properties. A number of lines of evidence also support the idea that adipocytes from different anatomical depots are intrinsically different as a result of genetic or developmental events. In this chapter, we will review the phenotypic characteristics of different adipose depots and mechanisms that link their depot-specific biology to metabolic complications in men and women.
The main parenchymal cells of the adipose organ are adipocytes. White adipocytes store energy, whereas brown adipocytes dissipate energy for thermogenesis. These two cell types with opposing functions can both originate from endothelial cells, and co-exist in the multiple fat depots of the adipose organ - a feature that I propose is crucial for this organ's plasticity. This poster review provides an overview of the adipose organ, describing its anatomy, cytology, physiological function and histopathology in obesity. It also highlights the remarkable plasticity of the adipose organ, explaining theories of adipocyte transdifferentiation during chronic cold exposure, physical exercise or lactation, as well as in obesity. White-to-brown adipocyte transdifferentiation is of particular medical relevance, because animal data indicate that higher amounts of brown adipose tissue are positively associated with resistance to obesity and its co-morbidities, and that 'browning' of the adipose organ curbs these disorders.
The renin-angiotensin system (RAS) is classically known for its role in regulation of blood pressure, fluid and electrolyte balance. In this system, angiotensinogen (Agt), the obligate precursor of all bioactive angiotensin peptides, undergoes two enzymatic cleavages by renin and angiotensin converting enzyme (ACE) to produce angiotensin I (Ang I) and angiotensin II (Ang II), respectively. The contemporary view of RAS has become more complex with the discovery of additional angiotensin degradation pathways such as ACE2. All components of the RAS are expressed in and have independent regulation of adipose tissue. This local adipose RAS exerts important auto/paracrine functions in modulating lipogenesis, lipolysis, adipogenesis as well as systemic and adipose tissue inflammation. Mice with adipose-specific Agt overproduction have a 30% increase in plasma Agt levels and develop hypertension and insulin resistance, while mice with adipose-specific Agt knockout have a 25% reduction in Agt plasma levels, demonstrating endocrine actions of adipose RAS. Emerging evidence also points towards a role of RAS in regulation of energy balance. Because adipose RAS is overactivated in many obesity conditions, it is considered a potential candidate linking obesity to hypertension, insulin resistance and other metabolic derangements.
Aldosterone blockade reduces mortality and morbidity among patients with severe heart failure. We conducted a double-blind, placebo-controlled study evaluating the effect of eplerenone, a selective aldosterone blocker, on morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.
Patients were randomly assigned to eplerenone (25 mg per day initially, titrated to a maximum of 50 mg per day; 3319 patients) or placebo (3313 patients) [correction] in addition to optimal medical therapy. The study continued until 1012 deaths occurred. The primary end points were death from any cause and death from cardiovascular causes or hospitalization for heart failure, acute myocardial infarction, stroke, or ventricular arrhythmia.
During a mean follow-up of 16 months, there were 478 deaths in the eplerenone group and 554 deaths in the placebo group (relative risk, 0.85; 95 percent confidence interval, 0.75 to 0.96; P=0.008). Of these deaths, 407 in the eplerenone group and 483 in the placebo group were attributed to cardiovascular causes (relative risk, 0.83; 95 percent confidence interval, 0.72 to 0.94; P=0.005). The rate of the other primary end point, death from cardiovascular causes or hospitalization for cardiovascular events, was reduced by eplerenone (relative risk, 0.87; 95 percent confidence interval, 0.79 to 0.95; P=0.002), as was the secondary end point of death from any cause or any hospitalization (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.98; P=0.02). There was also a reduction in the rate of sudden death from cardiac causes (relative risk, 0.79; 95 percent confidence interval, 0.64 to 0.97; P=0.03). The rate of serious hyperkalemia was 5.5 percent in the eplerenone group and 3.9 percent in the placebo group (P=0.002), whereas the rate of hypokalemia was 8.4 percent in the eplerenone group and 13.1 percent in the placebo group (P<0.001).
The addition of eplerenone to optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.
The ability of mammals to resist body fat accumulation is linked to their ability to expand the number and activity of "brown adipocytes" within white fat depots. Activation of β-adrenergic receptors (β-ARs) can induce a functional "brown-like" adipocyte phenotype. As cardiac natriuretic peptides (NPs) and β-AR agonists are similarly potent at stimulating lipolysis in human adipocytes, we investigated whether NPs could induce human and mouse adipocytes to acquire brown adipocyte features, including a capacity for thermogenic energy expenditure mediated by uncoupling protein 1 (UCP1). In human adipocytes, atrial NP (ANP) and ventricular NP (BNP) activated PPARγ coactivator-1α (PGC-1α) and UCP1 expression, induced mitochondriogenesis, and increased uncoupled and total respiration. At low concentrations, ANP and β-AR agonists additively enhanced expression of brown fat and mitochondrial markers in a p38 MAPK-dependent manner. Mice exposed to cold temperatures had increased levels of circulating NPs as well as higher expression of NP signaling receptor and lower expression of the NP clearance receptor (Nprc) in brown adipose tissue (BAT) and white adipose tissue (WAT). NPR-C(-/-) mice had markedly smaller WAT and BAT depots but higher expression of thermogenic genes such as Ucp1. Infusion of BNP into mice robustly increased Ucp1 and Pgc-1α expression in WAT and BAT, with corresponding elevation of respiration and energy expenditure. These results suggest that NPs promote "browning" of white adipocytes to increase energy expenditure, defining the heart as a central regulator of adipose tissue biology.
Certain white adipose tissue (WAT) depots are readily able to convert to a "brown-like" state with prolonged cold exposure or exposure to β-adrenergic compounds. This process is characterized by the appearance of pockets of uncoupling protein 1 (UCP1)-positive, multilocular adipocytes and serves to increase the thermogenic capacity of the organism. We show here that fibroblast growth factor 21 (FGF21) plays a physiologic role in this thermogenic recruitment of WATs. In fact, mice deficient in FGF21 display an impaired ability to adapt to chronic cold exposure, with diminished browning of WAT. Adipose-derived FGF21 acts in an autocrine/paracrine manner to increase expression of UCP1 and other thermogenic genes in fat tissues. FGF21 regulates this process, at least in part, by enhancing adipose tissue PGC-1α protein levels independently of mRNA expression. We conclude that FGF21 acts to activate and expand the thermogenic machinery in vivo to provide a robust defense against hypothermia.
White and brown adipocytes are believed to occupy different sites in the body. We studied the anatomical features and quantitative histology of the fat depots in obesity and type 2 diabetes-prone C57BL/6J mice acclimated to warm or cold temperatures. Most of the fat tissue was contained in depots with discrete anatomical features, and most depots contained both white and brown adipocytes. Quantitative analysis showed that cold acclimation induced an increase in brown adipocytes and an almost equal reduction in white adipocytes; however, there were no significant differences in total adipocyte count or any signs of apoptosis or mitosis, in line with the hypothesis of the direct transformation of white into brown adipocytes. The brown adipocyte increase was accompanied by enhanced density of noradrenergic parenchymal nerve fibers, with a significant correlation between the density of these fibers and the number of brown adipocytes. Comparison with data from obesity-resistant Sv129 mice disclosed a significantly different brown adipocyte content in C57BL/6J mice, suggesting that this feature could underpin the propensity of the latter strain to develop obesity. However, the greater C57BL/6J browning capacity can hopefully be harnessed to curb obesity and type 2 diabetes in patients with constitutively low amounts of brown adipose tissue.
Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional co-activator PPAR-γ co-activator-1 α (PGC1-α). Here we show in mouse that PGC1-α expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in the blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise.
Clinical evidence shows that in males obesity is frequently associated with hypogonadism and vice versa; also, low testosterone levels have been considered a "hallmark" of metabolic syndrome in men. These observations indicate that there is a strict connection between anatomically and functionally distinct cell types such as white adipocytes and Leydig cells, that synthesize testosterone. Adipose tissue is able to control several functions of the testis through its products secreted in the bloodstream. On the other hand, circulating levels of testosterone and estradiol deeply affect adipocyte proliferation, differentiation, and fat mass distribution, hereby controlling critical metabolic functions, such as food intake, insulin sensitivity, vascular reactivity, and immunity. This paper highlights the existing clinical and experimental evidence linking androgens and adipose tissue and illustrates the consequences occurring when the balance between fat mass distribution and eugonadism is lost.
Aldosterone facilitates cardiovascular damage by increasing blood pressure and through different mechanisms that are independent of its effects on blood pressure. In this respect, recent evidence involves aldosterone in the pathogenesis of metabolic syndrome. Although this relationship is complex, there is some evidence suggesting that different factors may play an important role, such as insulin resistance, renin-angiotensin-aldosterone system, oxidative stress, sodium retention, increased sympathetic activity, levels of free fatty acids, or inflammatory cytokines and adipokines. In addition to the classical pathway by which aldosterone acts through the mineralocorticoid receptors leading to sodium retention, aldosterone also has other mechanisms that influence cardiovascular tissue remodelling. Finally, overweight and obesity promote the adrenal secretion of aldosterone, increasing the predisposition to type 2 diabetes mellitus. Further studies are needed to better establish therapeutic strategies that act on the blockade of mineralocorticoid receptor in the treatment and prevention of cardiovascular diseases related to the excess of aldosterone and the metabolic syndrome.
MR (mineralocorticoid receptor) activation by either administration of exogenous mineralocorticoids or by allowing endogenous glucocorticoids to activate the MR has been shown to produce oxidative stress and vascular inflammation at the earliest stages of the development of cardiac fibrosis in experimental animals. These studies suggest potential mechanisms for the benefits observed in recent large scale clinical trials investigating the cardioprotective effects of MR antagonists given in conjunction with current best practice therapy for moderate-to-severe heart failure and heart failure post-myocardial infarction. Given that few patients had elevated plasma aldosterone, novel mechanisms involved in activating the MR in the failing heart are now being investigated.
Aldosterone is a major regulator of salt balance and blood pressure, exerting its effects via the mineralocorticoid receptor (MR). To analyze the regulatory mechanisms controlling tissue-specific expression of the human MR (hMR) in vivo, we have developed transgenic mouse models expressing the SV40 large T antigen (TAg) under the control of each of the two promoters of the hMR gene (P1 or P2). Unexpectedly, all five P1-TAg founder animals died prematurely from voluminous malignant liposarcomas originating from brown adipose tissue, as evidenced by the expression of the mitochondrial uncoupling protein ucp1, indicating that the proximal P1 promoter was transcriptionally active in brown adipocytes. No such hibernoma occurred in P2-TAg transgenic mice. Appropriate tissue-specific usage of P1 promoter sequences was confirmed by demonstrating the presence of endogenous MR in both neoplastic and normal brown adipose tissue. Several cell lines were derived from hibernomas; among them, the T37i cells can undergo terminal differentiation into brown adipocytes, which remain capable of expressing ucp1 upon adrenergic or retinoic acid stimulation. These cells possess endogenous functional MR, thus providing a new model to explore molecular mechanisms of mineralocorticoid action. Our data broaden the known functions of aldosterone and suggest a potential role for MR in adipocyte differentiation and regulation of thermogenesis.
Aldosterone concentrations increase in obesity and predict the onset of diabetes. We investigated the effects of aldosterone on glucose homeostasis and insulin secretion in vivo and in vitro.
We assessed insulin sensitivity and insulin secretion in aldosterone synthase-deficient (As [also known as Cyp11b2](-/-)) and wild-type mice using euglycaemic-hyperinsulinaemic and hyperglycaemic clamps, respectively. We also conducted studies during high sodium intake to normalise renin activity and potassium concentration in As (-/-) mice. We subsequently assessed the effect of aldosterone on insulin secretion in vitro in the presence or absence of mineralocorticoid receptor antagonists in isolated C57BL/6J islets and in the MIN6 beta cell line.
Fasting glucose concentrations were reduced in As (-/-) mice compared with wild-type. During hyperglycaemic clamps, insulin and C-peptide concentrations increased to a greater extent in As (-/-) than in wild-type mice. This was not attributable to differences in potassium or angiotensin II, as glucose-stimulated insulin secretion was enhanced in As (-/-) mice even during high sodium intake. There was no difference in insulin sensitivity between As (-/-) and wild-type mice in euglycaemic-hyperinsulinaemic clamp studies. In islet and MIN6 beta cell studies, aldosterone inhibited glucose- and isobutylmethylxanthine-stimulated insulin secretion, an effect that was not blocked by mineralocorticoid receptor antagonism, but was prevented by the superoxide dismutase mimetic tempol.
We demonstrated that aldosterone deficiency or excess modulates insulin secretion in vivo and in vitro via reactive oxygen species and in a manner that is independent of mineralocorticoid receptors. These findings provide insight into the mechanism of glucose intolerance in conditions of relative aldosterone excess.
The mineralocorticoid receptor (MR) mediates aldosterone- and glucocorticoid-induced adipocyte differentiation. Drospirenone (DRSP) is a potent synthetic antimineralocorticoid with progestogenic and antiandrogenic properties, which is widely used for contraception and hormone replacement therapy. We investigated its potential role on adipocyte differentiation. The effects of DRSP were studied in murine preadipocyte cell lines and primary cultures of human preadipocytes. Differentiation markers and mechanisms underlying phenotypic variations in response to DRSP were explored. Early exposure to DRSP during differentiation led to a marked dose-dependent inhibition of adipose differentiation and triglyceride accumulation in 3T3-L1 and 3T3-F442A cells. DRSP also markedly inhibited adipose conversion of human primary preadipocytes derived from visceral (mesenteric and epicardial) and subcutaneous fat. This effect was MR-dependent and did not involve the glucocorticoid, androgen, or progesterone receptors. DRSP inhibited clonal expansion of preadipocytes and decreased expression of PPARγ, a key transcriptional mediator of adipogenesis, but had no effect on lipolysis, glucose uptake, and PPARγ binding to its ligands. DRSP exerts a potent antiadipogenic effect that is related to an alteration of the transcriptional control of adipogenesis via an antagonistic effect on the MR. Selective MR blockade therefore has promise as a novel therapeutic option for the control of excessive adipose tissue deposition and its related metabolic complications.
White adipose tissue (WAT) is no longer considered a depot for energy storage in the form of triglycerides, but is a secretory organ that releases factors, known as adipokines, capable of regulating several physiological processes. Alteration of WAT function with subsequent dysfunctional expression and secretion of adipokines plays a key role in the pathogenesis of obesity, diabetes, and other metabolic diseases. For this reason, a deeper understanding of the molecular mechanisms regulating adipocyte function is deemed necessary for planning strategies to treat and prevent obesity and its metabolic complications. This review examines cell culture models currently available for studying adipocyte biology. We focus on advantages, disadvantages and main differences between established preadipocyte cell lines and primary preadipocyte cultures. We revise protocols used to promote adipocyte differentiation and mature adipocytes dedifferentiation into preadipocytes. Finally, we briefly describe co-cultures of adipocytes with other cell types and three-dimensional adipocyte culture systems. These models allow investigation of cell-cell interactions with the cross-talk physiologically occurring between adipocytes and other cell types residing within or outside adipose tissue.
How can we decrease the body's energy efficiency? The answer to this could be used to fight the exploding obesity crisis.
Our ability to accumulate and retain energy reserves once provided a survival advantage. However, these ingrained energy-conservation
pathways are now driving unprecedented weight gain in modern societies where calorie-dense food pervades. Burning off excess
fuel (analogous to heating a house in winter with the windows open) may be an effective therapeutic avenue to reduce obesity
when diet and exercise are not enough. On page 1158 in this issue, Vegiopoulos et al. demonstrate that the fatty acid derivatives called prostaglandins encourage adipocytes (fat cells) to do exactly this—waste
energy through increased heat production (1).
The recent insight that brown adipocytes and muscle cells share a common origin and in this respect are distinct from white adipocytes has spurred questions concerning the origin and molecular characteristics of the UCP1-expressing cells observed in classic white adipose tissue depots under certain physiological or pharmacological conditions. Examining precursors from the purest white adipose tissue depot (epididymal), we report here that chronic treatment with the peroxisome proliferator-activated receptor gamma agonist rosiglitazone promotes not only the expression of PGC-1alpha and mitochondriogenesis in these cells but also a norepinephrine-augmentable UCP1 gene expression in a significant subset of the cells, providing these cells with a genuine thermogenic capacity. However, although functional thermogenic genes are expressed, the cells are devoid of transcripts for the novel transcription factors now associated with classic brown adipocytes (Zic1, Lhx8, Meox2, and characteristically PRDM16) or for myocyte-associated genes (myogenin and myomirs (muscle-specific microRNAs)) and retain white fat characteristics such as Hoxc9 expression. Co-culture experiments verify that the UCP1-expressing cells are not proliferating classic brown adipocytes (adipomyocytes), and these cells therefore constitute a subset of adipocytes ("brite" adipocytes) with a developmental origin and molecular characteristics distinguishing them as a separate class of cells.
Obesity is associated with chronic inflammation. Pro-inflammatory adipokines may promote metabolic disorders and cardiovascular morbidity. However, the key mechanisms leading to obesity-related inflammation are poorly understood. The corticosteroid metabolism in adipose tissue plays a crucial role in the pathogenesis of the metabolic syndrome. Both the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) mediate corticosteroid action in adipose tissue. The significance of the interplay of these receptors in mediating an inflammatory adipokine response is virtually unexplored. In the present study, we investigated the differential roles of the GR and MR in controlling the key adipose tissue functions including inflammatory adipokine expression and adipogenesis using selective stimulation with receptor agonists, acute receptor knockdown via RNA interference and newly generated knockout adipose cell lines. Selective GR stimulation of white adipocytes with dexamethasone inhibited the expression of interleukin 6 (IL6), monocyte chemoattractant protein-1 (MCP1 or CCL2 as listed in the MGI Database), tumour necrosis factor-alpha, chemerin and leptin. By contrast, selective MR stimulation with aldosterone promoted the expression of IL6, plasminogen activator inhibitor 1, chemerin and leptin. Furthermore, in the presence of an acute GR knockdown as well as in GR knockout adipocytes, corticosterone increased the gene expression of the pro-inflammatory adipokines IL6 and MCP1. Whereas GR knockout adipocytes displayed a mildly impaired adipogenesis during early differentiation, MR knockout cells completely failed to accumulate lipids. Taken together, our data demonstrate a critical role for the balance between gluco- and mineralocorticoid action in determining adipocyte responses implicated in obesity-associated inflammation and cardiovascular complications.
Gregoire, Francine M., Cynthia M. Smas, and Hei Sook Sul. Understanding Adipocyte Differentiation. Physiol. Rev. 78: 783–809, 1998. — The adipocyte plays a critical role in energy balance. Adipose tissue growth involves an increase in adipocyte size and the formation of new adipocytes from precursor cells. For the last 20 years, the cellular and molecular mechanisms of adipocyte differentiation have been extensively studied using preadipocyte culture systems. Committed preadipocytes undergo growth arrest and subsequent terminal differentiation into adipocytes. This is accompanied by a dramatic increase in expression of adipocyte genes including adipocyte fatty acid binding protein and lipid-metabolizing enzymes. Characterization of regulatory regions of adipose-specific genes has led to the identification of the transcription factors peroxisome proliferator-activated receptor-γ (PPAR-γ) and CCAAT/enhancer binding protein (C/EBP), which play a key role in the complex transcriptional cascade during adipocyte differentiation. Growth and differentiation of preadipocytes is controlled by communication between individual cells or between cells and the extracellular environment. Various hormones and growth factors that affect adipocyte differentiation in a positive or negative manner have been identified. In addition, components involved in cell-cell or cell-matrix interactions such as preadipocyte factor-1 and extracellular matrix proteins are also pivotal in regulating the differentiation process. Identification of these molecules has yielded clues to the biochemical pathways that ultimately result in transcriptional activation via PPAR-γ and C/EBP. Studies on the regulation of the these transcription factors and the mode of action of various agents that influence adipocyte differentiation will reveal the physiological and pathophysiological mechanisms underlying adipose tissue development.
The metabolic syndrome consists of a constellation of co-associated metabolic abnormalities such as insulin resistance, type 2 diabetes, dyslipidaemia, hypertension and visceral obesity. For many years endocrinologists have noted the striking resemblance between this disease state and that associated with Cushing’s syndrome. However, in the metabolic syndrome plasma cortisol levels tend to be normal or lower than in normal individuals. Nevertheless there is strong evidence that glucocorticoid action underlies metabolic disease, largely from rodent obesity models where removing glucocorticoids reverses obesity and its metabolic abnormalities. The apparent paradox of similar metabolic defects - despite the opposing plasma glucocorticoid profiles of Cushing’s and idiopathic metabolic syndrome - remained intriguing until the discovery that intracellular glucocorticoid reactivation was elevated in adipose tissue of obese rodents and humans. The enzyme that mediates this activation, conversion of cortisone (11-dehydrocorticosterone in rodents) to cortisol (corticosterone in rodents), locally within tissues is 11&Bgr; -hydroxysteroid dehydrogenase type 1 (11&Bgr; -HSD1). In order to determine whether elevated tissue 11&Bgr; -HSD1 contributed to obesity and metabolic disease, transgenic mice overexpressing 11&Bgr; -HSD1 in adipose tissue or liver were made. Adipose-selective 11&Bgr; -HSD1 transgenic mice exhibited elevated intra-adipose and portal, but not systemic corticosterone levels, abdominal obesity, hyperglycaemia, insulin resistance, dyslipidaemia and hypertension. In contrast, transgenic overexpression of 11&Bgr; -HSD1 in liver yielded an attenuated metabolic syndrome with mild insulin resistance, dyslipidaemia, hypertension and fatty liver, but not obesity or glucose intolerance. Together with early data using non-selective 11&Bgr; -HSD1 inhibitors to insulin sensitise humans, this corroborated the notion that the enzyme may be a good therapeutic target in the treatment of the metabolic syndrome. Further, a transgenic model of therapeutic 11&Bgr; -HSD1 inhibition, 11&Bgr; -HSD1 gene knock-out (11&Bgr; -HSD1-/-) mice, exhibited improved glucose tolerance, a ’cardioprotective’ lipid profile, reduced weight gain and visceral fat accumulation with chronic high-fat feeding. Recent evidence further suggests that high fat-mediated downregulation of adipose 11&Bgr; -HSD1 may be an endogenous pathway that underpins adaptive disease resistance in genetically predisposed mouse strains. This mechanism could feasibly make up a genetic component of innate obesity resistance in humans. The efficacy of 11&Bgr; -HSD1 inhibitors has recently been extended to include increased energy expenditure and reduction of arteriosclerosis, and therefore may be of significant therapeutic value in the metabolic syndrome, with complementary effects upon liver adipose tissue, muscle, pancreas and plaque-prone vessels.
Mineralocorticoid receptor antagonists (MRAs) are commonly used to reduce blood pressure, left-ventricular hypertrophy, and urinary albumin excretion in patients with essential hypertension or primary aldosteronism. Effects of MRAs on hypertensive organ damage seem to occur beyond what is expected from the mere reduction of blood pressure. This suggests that activation of the mineralocorticoid receptor plays a central role in the development of cardiac and renal abnormalities in hypertensive patients. However, broad use of classic MRAs such as spironolactone has been limited by significant incidence of gynecomastia and other sex-related adverse effects. To overcome these problems, new aldosterone blockers have been developed with different strategies that include use of nonsteroidal MRAs and inhibition of aldosterone synthesis. Both strategies have been designed to avoid the steroid receptor cross-reactivity of classic MRAs that accounts for most adverse effects. Moreover, inhibition of aldosterone synthesis could have an additional benefit due to blockade of the mineralocorticoid receptor-independent pathways that might account for some of the untoward effects of aldosterone. The new aldosterone blockers are currently having extensive preclinical evaluation, and one of these compounds has passed phase 2 trials showing promising results in patients with primary hypertension and primary aldosteronism. This narrative review summarizes the knowledge on the use of classic MRAs in hypertension and covers the evidence currently available on new aldosterone blockers.
Adipose tissue is an important site for lipid storage, energy homeostasis, and whole-body insulin sensitivity. It is important to understand the mechanisms involved in adipose tissue development and function, which can be regulated by the endocrine actions of various peptide and steroid hormones. Recent studies have revealed that white and brown adipocytes can be derived from distinct precursor cells. This review will focus on transcriptional control of adipogenesis and its regulation by several endocrine hormones. The general functions and cellular origins of adipose tissue and how the modulation of adipocyte development pertains to metabolic disease states will also be considered.
Brown fat generates heat via the mitochondrial uncoupling protein UCP1, defending against hypothermia and obesity. Recent data suggest that there are two distinct types of brown fat: classical brown fat derived from a myf-5 cellular lineage and UCP1-positive cells that emerge in white fat from a non-myf-5 lineage. Here, we report the isolation of "beige" cells from murine white fat depots. Beige cells resemble white fat cells in having extremely low basal expression of UCP1, but, like classical brown fat, they respond to cyclic AMP stimulation with high UCP1 expression and respiration rates. Beige cells have a gene expression pattern distinct from either white or brown fat and are preferentially sensitive to the polypeptide hormone irisin. Finally, we provide evidence that previously identified brown fat deposits in adult humans are composed of beige adipocytes. These data provide a foundation for studying this mammalian cell type with therapeutic potential. PAPERCLIP:
This review focuses on the expression of the key components of the renin-angiotensin-aldosterone axis in fat tissue. At the center of this report is the role of RAAS in normal and excessive fat mass enlargement, the leading etiology of insulin resistance. Understanding the expression and regulation of RAAS components in various fat depots allows insight not only into the processes by which these complex patterns are modified by the enlargement of adipose tissue, but also into their impact on local and systemic response to insulin.
Despite daily fasting and feeding, plasma glucose levels are normally maintained within a narrow range owing to the hormones insulin and glucagon. Insulin increases glucose uptake into fat and muscle cells through the regulated trafficking of vesicles that contain glucose transporter type 4 (GLUT4). New insights into insulin signalling reveal that phosphorylation events initiated by the insulin receptor regulate key GLUT4 trafficking proteins, including small GTPases, tethering complexes and the vesicle fusion machinery. These proteins, in turn, control GLUT4 movement through the endosomal system, formation and retention of specialized GLUT4 storage vesicles and targeted exocytosis of these vesicles. Understanding these processes may help to explain the development of insulin resistance in type 2 diabetes and provide new potential therapeutic targets.
Obesity is closely associated with the metabolic syndrome, a combination of disorders including insulin resistance, diabetes, dyslipidemia, and hypertension. A role for local glucocorticoid reamplification in obesity and the metabolic syndrome has been suggested. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active cortisol from inactive 11-keto forms, and aP2-HSD1 mice with relative transgenic overexpression of this enzyme in fat cells develop visceral obesity with insulin resistance and dyslipidemia. Here we report that aP2-HSD1 mice also have high arterial blood pressure (BP). The mice have increased sensitivity to dietary salt and increased plasma levels of angiotensinogen, angiotensin II, and aldosterone. This hypertension is abolished by selective angiotensin II receptor AT-1 antagonist at a low dose that does not affect BP in non-Tg littermates. These findings suggest that activation of the circulating renin-angiotensin system (RAS) develops in aP2-HSD1 mice. The long-term hypertension is further reflected by an appreciable hypertrophy and hyperplasia of the distal tubule epithelium of the nephron, resembling salt-sensitive or angiotensin II-mediated hypertension. Taken together, our findings suggest that overexpression of 1 11β-HSD1 in fat is sufficient to cause salt-sensitive hypertension mediated by an activated RAS. The potential role of adipose 11β-HSD1 in mediating critical features of the metabolic syndrome extends beyond obesity and metabolic complications to include the most central cardiovascular feature of this disorder.
Recent data suggest that mineralocorticoid receptor activation can affect insulin resistance independent of its effects on blood pressure. This review discusses new evidence linking mineralocorticoid receptor to insulin resistance and the underlying mechanisms of these effects.
Observational studies have shown mineralocorticoid activity to be associated with insulin resistance irrespective of race, blood pressure or body weight. Increased mineralocorticoid activity may be the common link between obesity, hypertension, dyslipidemia and insulin resistance, features that make up the metabolic syndrome. Treatment of primary aldosteronism is associated with a decrease in insulin resistance and provides one of the most convincing evidences in favor of the contribution of mineralocorticoid receptor to insulin resistance. Dietary salt restriction, which increases aldosterone levels, is also associated with an increase in insulin resistance. Potential mechanisms by which mineralocorticoid receptor may contribute to insulin resistance include a decreased transcription of the insulin receptor gene, increased degradation of insulin receptor substrates, interference with insulin signaling mechanisms, decreased adiponectin production and increased oxidative stress and inflammation. Advantages of mineralocorticoid receptor antagonists on insulin resistance have been demonstrated in animal models.
There may be a benefit of mineralocorticoid receptor antagonists in human insulin resistance states, but more clinical research is needed to explore these possibilities.
We reported aldosterone as a novel adipocyte-derived factor that regulates vascular function. We aimed to investigate molecular mechanisms, signaling pathways, and functional significance of adipocyte-derived aldosterone and to test whether adipocyte-derived aldosterone is increased in diabetes mellitus-associated obesity, which contributes to vascular dysfunction. Studies were performed in the 3T3-L1 adipocyte cell line and mature adipocytes isolated from human and mouse (C57BL/6J) adipose tissue. Mesenteric arteries with and without perivascular fat and mature adipocytes were obtained from obese diabetic db/db and control db/+ mice. Aldosterone synthase (CYP11B2; mRNA and protein) was detected in 3T3-L1 and mature adipocytes, which secrete aldosterone basally and in response to angiotensin II (Ang II). In 3T3-L1 adipocytes, Ang II stimulation increased aldosterone secretion and CYP11B2 expression. Ang II effects were blunted by an Ang II type 1 receptor antagonist (candesartan) and inhibitors of calcineurin (cyclosporine A and FK506) and nuclear factor of activated T-cells (VIVIT). FAD286 (aldosterone synthase inhibitor) blunted adipocyte differentiation. In candesartan-treated db/db mice (1 mg/kg per day, 4 weeks) increased plasma aldosterone, CYP11B2 expression, and aldosterone secretion were reduced. Acetylcholine-induced relaxation in db/db mesenteric arteries containing perivascular fat was improved by eplerenone (mineralocorticoid receptor antagonist) without effect in db/+ mice. Adipocytes possess aldosterone synthase and produce aldosterone in an Ang II/Ang II type 1 receptor/calcineurin/nuclear factor of activated T-cells-dependent manner. Functionally adipocyte-derived aldosterone regulates adipocyte differentiation and vascular function in an autocrine and paracrine manner, respectively. These novel findings identify adipocytes as a putative link between aldosterone and vascular dysfunction in diabetes mellitus-associated obesity.
Mineralocorticoid receptor (MR) blockade ameliorated insulin resistance with improvements in adipocytokine dysregulation, inflammation, and excess of reactive oxygen species (ROS) in obese adipose tissue and adipocytes, but its mechanism has not been clarified. The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), producing active glucocorticoids, is highly expressed in adipocytes and glucocorticoids bind to MR with higher affinity than to glucocorticoid receptor (GR). We investigated whether glucocorticoids effect on adipocytokines and ROS through MR in adipocytes. In addition, fat distributions of MR and GR were investigated in human subjects.
Corticoid receptors and their target genes were examined in adipose tissue of obese db/db mice. 3T3-L1 adipocytes were treated with glucocorticoids, H(2)O(2), MR antagonist eplerenone (EP), GR antagonist RU486 (RU), MR-siRNA, and/or N-acetylcysteine. Human adipose tissues were obtained from seven patients who underwent abdominal surgery. The mRNA levels of MR and its target gene were higher in db/db mice than in control db/m+mice. In 3T3-L1 adipocytes, glucocorticoids, similar to H(2)O(2), caused the dysregulation of mRNA levels of various genes related to adipocytokines and the increase of intracellular ROS. Such changes were rectified by MR blockade, not by GR antagonist. In human fat, MR mRNA level was increased in parallel with the increase of body mass index (BMI) and its increase was more significant in visceral fat, while there were no apparent correlations of GR mRNA level to BMI or fat distribution.
Glucocorticoid-MR pathway may contribute to the obesity-related adipocytokine dysregulation and adipose ROS.
Progress has been made in elucidating the cell-surface phenotype of primary adipose progenitors; however, specific functional markers and distinct molecular signatures of fat depot-specific preadipocytes have remained elusive. In this study, we label committed murine adipose progenitors through expression of GFP from the genetic locus for Zfp423, a gene controlling preadipocyte determination. Selection of GFP-expressing fibroblasts from either subcutaneous or visceral adipose-derived stromal vascular cultures isolates stably committed preadipocytes that undergo robust adipogenesis. Immunohistochemistry for Zfp423-driven GFP expression in vivo confirms a perivascular origin of preadipocytes within both white and brown adipose tissues. Interestingly, a small subset of capillary endothelial cells within white and brown fat also express this marker, suggesting a contribution of specialized endothelial cells to the adipose lineage. Zfp423(GFP) mice represent a simple tool for the specific localization and isolation of molecularly defined preadipocytes from distinct adipose tissue depots.
Adipose tissue expansion involves the enlargement of existing adipocytes, the formation of new cells from committed preadipocytes, and the coordinated development of the tissue vascular network. Here we find that murine endothelial cells (ECs) of classic white and brown fat depots share ultrastructural characteristics with pericytes, which are pluripotent and can potentially give rise to preadipocytes. Lineage tracing experiments using the VE-cadherin promoter reveal localization of reporter genes in ECs and also in preadipocytes and adipocytes of white and brown fat depots. Furthermore, capillary sprouts from human adipose tissue, which have predominantly EC characteristics, are found to express Zfp423, a recently identified marker of preadipocyte determination. In response to PPARγ activation, endothelial characteristics of sprouting cells are progressively lost, and cells form structurally and biochemically defined adipocytes. Together these data support an endothelial origin of murine and human adipocytes, suggesting a model for how adipogenesis and angiogenesis are coordinated during adipose tissue expansion.
The renin-angiotensin system (RAS) is classically known for its role in regulation of blood pressure, fluid and electrolyte balance. Recently, several local RASs in organs such as brain, heart, pancreas and adipose tissue have also been identified. Evidence from clinical trials suggests that in addition to anti-hypertensive effects, pharmacological inhibition of RAS also provides protection against the development of type-2 diabetes. Moreover, animal models with targeted inactivation of RAS genes exhibit improved insulin sensitivity and are protected from high-fat diet-induced obesity and insulin resistance. Because there is evidence for RAS overactivation in obesity, it is possible that RAS is a link between obesity and insulin resistance. This review summarizes the evidence and mechanistic insights on the associations between RAS, obesity and insulin resistance, with special emphasis on the role of adipose tissue RAS in the pathogenesis of metabolic derangements in obesity.
Although obesity is associated with overactivation of the white adipose tissue (WAT) renin-angiotensin system (RAS), a causal link between the latter and systemic insulin resistance is not established. We tested the hypothesis that overexpression of angiotensinogen (Agt) from WAT causes systemic insulin resistance via modulation of adipose inflammation. Glucose tolerance, systemic insulin sensitivity, and WAT inflammatory markers were analyzed in mice overexpressing Agt in the WAT (aP2-Agt mice). Proteomic studies and in vitro studies using 3T3-L1 adipocytes were performed to build a mechanistic framework. Male aP2-Agt mice exhibited glucose intolerance, insulin resistance, and lower insulin-stimulated glucose uptake by the skeletal muscle. The difference in glucose tolerance between genotypes was normalized by high-fat (HF) feeding, and was significantly improved by treatment with angiotensin-converting enzyme (ACE) inhibitor captopril. aP2-Agt mice also had higher monocyte chemotactic protein-1 (MCP-1) and lower interleukin-10 (IL-10) in the WAT, indicating adipose inflammation. Proteomic studies in WAT showed that they also had higher monoglyceride lipase (MGL) and glycerol-3-phosphate dehydrogenase levels. Treatment with angiotensin II (Ang II) increased MCP-1 and resistin secretion from adipocytes, which was prevented by cotreating with inhibitors of the nuclear factor-κB (NF-κB) pathway or nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In conclusion, we show for the first time that adipose RAS overactivation causes glucose intolerance and systemic insulin resistance. The mechanisms appear to be via reduced skeletal muscle glucose uptake, at least in part due to Ang II-induced, NADPH oxidase and NFκB-dependent increases in WAT inflammation.
Adipose tissue hypoxia is an early phenotype in obesity, associated with macrophage infiltration and local inflammation. Here we test the hypothesis that adipocytes in culture respond to a hypoxic environment with the release of pro-inflammatory factors that stimulate macrophage migration and cause muscle insulin resistance. 3T3-L1 adipocytes cultured in a 1% O2 atmosphere responded with a classic hypoxia response by elevating protein expression of HIF-1α. This was associated with elevated mRNA expression and peptide release of cytokines TNFα, IL-6 and the chemokine monocyte chemoattractant protein-1 (MCP-1). The mRNA and protein expression of the anti-inflammatory adipokine adiponectin was reduced. Conditioned medium from hypoxia-treated adipocytes (CM-H), inhibited insulin-stimulated and raised basal cell surface levels of GLUT4myc stably expressed in C2C12 myotubes. Insulin stimulation of Akt and AS160 phosphorylation, key regulators of GLUT4myc exocytosis, was markedly impaired. CM-H also caused activation of JNK and S6K, and elevated serine phosphorylation of IRS1 in the C2C12 myotubes. These effects were implicated in reducing propagation of insulin signaling to Akt and AS160. Heat inactivation of CM-H reversed its dual effects on GLUT4myc traffic in muscle cells. Interestingly, antibody-mediated neutralization of IL-6 in CM-H lowered its effect on both the basal and insulin-stimulated cell surface GLUT4myc compared to unmodified CM-H. IL-6 may have regulated GLUT4myc traffic through its action on AMPK. Additionally, antibody-mediated neutralization of MCP-1 partly reversed the inhibition of insulin-stimulated GLUT4myc exocytosis caused by unmodified CM-H. In Transwell co-culture, hypoxia-challenged adipocytes attracted RAW 264.7 macrophages, consistent with elevated release of MCP-1 from adipocytes during hypoxia. Neutralization of MCP-1 in adipocyte CM-H prevented macrophage migration towards it and partly reversed the effect of CM-H on insulin response in muscle cells. We conclude that adipose tissue hypoxia may be an important trigger of its inflammatory response observed in obesity, and the elevated chemokine MCP-1 may contribute to increased macrophage migration towards adipose tissue and subsequent decreased insulin responsiveness of glucose uptake in muscle.
Aldosterone controls blood pressure by binding to the mineralocorticoid receptor (MR), a ligand-activated transcription factor which regulates critical genes controlling salt and water homeostasis in the kidney. In recent years, inappropriate MR activation has been shown to trigger deleterious responses in various tissues, including vessels, heart and brain, hence promoting vascular inflammation, cardiovascular remodeling, endothelial dysfunction, and oxidative stress. Moreover, epidemiological studies have shown a clear association between aldosterone levels and the incidence of metabolic syndrome. In particular, recent work has revealed functional MRs in adipose tissue, where they mediate the effects of aldosterone and glucocorticoids, displaying important and specific functions involving adipose differentiation, expansion and proinflammatory capacity. This recent evidence finally moved MR out of the shadow of the glucocorticoid receptor (GR), which had previously been considered the only player mediating corticosteroid action in adipose tissue. This has opened a new era of research focusing on the complexity and selectivity of MR function in adipocyte biology. The aim of this review is to summarize the latest concepts on the role of MR in white and brown adipocytes, and to discuss the potential benefits of tissue-selective MR blockade in the treatment of obesity and metabolic syndrome.
In the last decade significant progress has been made in the understanding of mineralocorticoid receptor (MR) function and its implications for physiology and disease. The knowledge on the essential role of MR in the regulation of electrolyte concentrations and blood pressure has been significantly extended, and the relevance of excessive MR activation in promoting inflammation, fibrosis and heart disease as well as its role in modulating neuronal cell viability and brain function is now widely recognized. Despite considerable progress, the mechanisms of MR function in various cell-types are still poorly understood. Key modulators of MR function include the glucocorticoid receptor (GR), which may affect MR function by formation of heterodimers and by differential genomic and non-genomic responses on gene expression, and 11β-hydroxysteroid dehydrogenases (11β-HSDs), which determine the availability of intracellular concentrations of active glucocorticoids. In this review we attempted to provide an overview of the knowledge on MR expression with regard to the presence or absence of GR, 11β-HSD2 and 11β-HSD1/hexose-6-phosphate dehydrogenase (H6PDH) in various tissues and cell types. The consequences of cell-specific differences in the coexpression of MR with these proteins need to be further investigated in order to understand the role of this receptor in a given tissue as well as its systemic impact.
Phosphodiesterase type 5 (PDE5) is expressed in many tissues (e.g. heart, lung, pancreas, penis) and plays a specific role in hydrolyzing cyclic guanosine monophosphate (cGMP). In adipocytes, cGMP regulates crucial functions by activating cGMP-dependent protein kinase (PKG). Interestingly, PDE5 was recently identified in adipose tissue, although its role remains unclear. Its inhibition, however, was recently shown to affect adipose differentiation and aromatase function. This review summarizes evidence supporting a role for the PDE5-regulated cGMP/PKG system in adipose tissue and its effects on adipocyte function. A better elucidation of the role of PDE5 in the adipocyte could reveal new therapeutic strategies for fighting obesity and metabolic syndrome.
Angiotensin II is a peptide hormone with strong vasoconstrictive action, and recent reports have shown that Angiotensin II receptor type 1 antagonists (angiotensin II receptor blockers) also improve glucose metabolism. The angiotensin II receptor blocker telmisartan acts as an agonistic ligand of the peroxisome proliferator-activated receptor gamma (PPARγ). In this study, we investigated the effects of telmisartan on glucose uptake and insulin sensitivity in 3T3-L1 adipocytes and compared it with the action of other angiotensin II receptor blockers. Telmisartan treatment dose-dependently increased (from 1 μM) protein expression of PPARγ-regulated molecules such as fatty acid binding protein 4 (FABP4), insulin receptor, and glucose transporter 4 (GLUT4). Telmisartan increased glucose uptake both with and without insulin stimulation in 3T3-L1 adipocytes. Telmisartan increased the up-regulation of phosphorylated insulin receptor, insulin receptor substrate-1 (IRS-1) and Akt by insulin, suggesting that telmisartan increases insulin sensitivity. Furthermore, in the absence of insulin, telmisartan, but not candesartan, increased GLUT4 levels at the plasma membrane. These effects by 10 μM telmisartan were similar potency to those of 1 μM troglitazone, an activator of PPARγ. In addition, up-regulation of glucose uptake by telmisartan was inhibited by a PPARγ antagonist, T0070907 (2-chloro-5-nitro-N-4-pyridinyl-benzamide). These results indicate that telmisartan acts via PPARγ activation in adipose tissue and may be an effective therapy for the metabolic syndrome.
Mineralocorticoid receptors (MR), glucocorticoid receptors (GR), progesterone receptors (PR), and androgen receptors (AR) comprise a closely related subfamily within the human 49-member nuclear receptor family. These receptors and their cognate ligands play major roles in homeostasis, reproduction, growth, and development, despite which their evolution and diversification remains incompletely understood. Several conflicting models have been advanced for the evolution of this subfamily. We have thus undertaken Bayesian and maximum likelihood phylogenetic analyses of this subfamily. The Bayesian consensus and maximum likelihood trees support a basal position for MR, with the PR and AR forming a sister clade. We next performed analyses using topological constraints to directly contrast the likelihood of seven phylogenetic models. In these analyses, three models have similar support: one proposes two sister clades (MR and GR, PR and AR); the other two propose a different subfamily member (MR or GR) to be the first to have diverged. Ancestral state reconstructions at sites critical for physiological function show that the S810L mutation in the MR, which results in the MR being similar to estrogen receptors and the more distantly related retinoic acid receptor-α is likely to reflect the ancestral receptor sequence before the divergence of this subfamily and provides further support for MR having been the first of the subfamily to diverge. Finally, we drew on pathophysiological comparisons to help to distinguish the different models. On the basis of our phylogenetic analyses and pathophysiological considerations, we propose that the MR was the first to diverge from the ancestral gene lineage from which this subfamily derived.
The effect of the PPARγ agonistic action of an AT(1) receptor blocker, irbesartan, on adipose tissue dysfunction was explored using atherosclerotic model mice. Adult male apolipoprotein E-deficient (ApoEKO) mice at 9 weeks of age were treated with a high-cholesterol diet (HCD) with or without irbesartan at a dose of 50mg/kg/day for 4 weeks. The weight of epididymal and retroperitoneal adipose tissue was decreased by irbesartan without changing food intake or body weight. Treatment with irbesartan increased the expression of PPARγ in white adipose tissue and the DNA-binding activity of PPARγ in nuclear extract prepared from adipose tissue. The expression of adiponectin, leptin and insulin receptor was also increased by irbesartan. These results suggest that irbesartan induced activation of PPARγ and improved adipose tissue dysfunction including insulin resistance.
Obesity is a leading cause of death worldwide because of its associated inflammatory disorders such as hypertension, cardiovascular and kidney diseases, dyslipidemia, glucose intolerance, and certain types of cancer. Adipose tissue expresses all components of the renin-angiotensin system necessary to generate angiotensin (Ang) peptides for local function. The angiotensin type 1 (AT1) and type 2 (AT2) receptors mediate the effect of Ang II and recent studies have shown that both receptors may modulate fat mass expansion through upregulation of adipose tissue lipogenesis (AT2) and downregulation of lipolysis (AT1). Thus, both receptors may have synergistic and additive effects to promote the storage of lipid in adipose tissue in response to the nutrient environment. The production of angiotensinogen (AGT) by adipose tissue in rodents also contributes to one third of the circulating AGT levels. Increased adipose tissue AGT production in the obese state may be responsible in part for the metabolic and inflammatory disorders associated with obesity. This supports the notion that besides the traditional role of Ang II produced by the liver in the control of blood pressure, Ang II produced by the adipose tissue may more accurately reflect the role of this hormone in the regulation of fat mass and associated disorders.
The objective of the study was to assess the effect of high aldosterone levels on insulin sensitivity of adipose tissue in humans.
Visceral adipose tissue (VAT) was obtained from patients with aldosterone-producing adenoma (APA; n=14) and, as controls, nonfunctioning adenoma (NFA; n=14) undergoing laparoscopic adrenalectomy. Homeostasis model assessment index was higher and potassium was lower in APA than NFA (P<0.05). Immunohistochemistry, Western blotting, and real-time PCR were used to detect and quantify mineralocorticoid receptor (MR) expression. Transcript levels of peroxisome proliferative-activated receptor-gamma, insulin receptor, glucose transporter 4, insulin receptor substrate-1 and -2, leptin, adiponectin, IL-6, monocyte chemoattractant protein-1, glucocorticoid receptor (GR)-alpha, 11beta-hydroxysteroid dehydrogenase (HSD11B) type 1, and HSD11B2 were quantified. The effect of increasing aldosterone concentrations on 2-deoxy-[3H]d-glucose uptake was tested in human sc abdominal adipocytes.
Expression of MR was demonstrated in VAT, with no difference between APA and NFA as to mRNA levels of MR, GRalpha, HSD11B1, and glucose metabolism and inflammation factors. In cultured adipocytes, basal and insulin-stimulated glucose uptake were unaffected by 1-100 nM (normal/hyperaldosteronism) and impaired only by much higher, up to 10 microM, aldosterone concentrations. The impairment was prevented by RU486 but not by eplerenone.
Gene expression of insulin signaling/inflammatory molecules was similar in VAT of APA and NFA patients, not supporting an effect of aldosterone excess on insulin sensitivity of adipose tissues. Only at pharmacological concentrations and through GR activation, aldosterone reduced glucose uptake in adipocytes. Insulin resistance in primary aldosteronism might occur in compartments other than fat and/or depend on concurrent environmental factors.
The recent demonstration of considerable amounts of metabolically active brown adipose tissue (BAT) in many adult humans has renewed the scientific interest in the subject worldwide, mainly because of its antiobesity effects, documented in murine models. Genetic ablation of BAT or of all β-adrenergic receptors, which are responsible for its activation, induces obesity in mice (Lowell et al., 1993 and Bachman et al., 2002), whereas ectopic expression of UCP1—the protein-activating brown adipocyte thermogenesis uniquely found in BAT—in white adipose tissue (WAT) results in resistance to obesity (Kopecky et al., 1995). Accordingly, administration of drugs capable of increasing BAT activity curbs obesity and related disorders, such as type 2 diabetes, in animal models (Ghorbani and Himms-Hagen, 1997).