Analysis of Insulin Sensitivity in Adipose Tissue of Patients with Primary Aldosteronism

Urbanet, Riccardo; Pilon, Catia; Calcagno, Alessandra; Peschechera, Alessandro; Hubert, Edwige-Ludiwyne; Giacchetti, Gilberta; Gómez-Sánchez, Celso E.; Mulatero, Paolo; Toffanin, Mariacristina; Sonino, Nicoletta; Zennaro, Maria-Christina; Giorgino, Francesco; Vettor, Roberto; Fallo, Francesco

doi:10.1210/jc.2010-0097

Cited by 42 publications

(39 citation statements)

References 21 publications

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“…The targeted approach used in this study allowed us to assess the specific role of MR in adipocytes. Adipo-MROE mice exhibit in fact a moderate increase of fat MR expression, which mimics the fat MR increase we and others [6][7][8] have observed in several obese mouse models (db/db, ob/ob, and HFD) and in obese humans as reported here. …”

supporting

confidence: 88%

“…[6][7][8] The present findings suggest that this can be translated to humans, where MR expression is also enhanced in obese patients compared with lean individuals, and in VAT from obese subjects when compared with SAT from the same patient. Recent studies indicate that MR activation is involved in dysregulation of adipose tissue endocrine functions associated with genetic obesity and nutritional challenge and that MR antagonism improves metabolic status in these animal models.…”

Section: Mr and Metabolic Alterations: Potential Benefit Of Mr Antagosupporting

confidence: 57%

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Adipocyte Mineralocorticoid Receptor Activation Leads to Metabolic Syndrome and Induction of Prostaglandin D2 Synthase

et al. 2015

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M etabolic syndrome (MetS)1 is a disorder of energy use and storage, diagnosed by co-occurrence of at least 3 of 5 of the following medical conditions: abdominal (central) obesity, hypertension, elevated fasting-plasma glucose, high triglycerides, and low high-density lipoprotein cholesterol levels. Clinically, MetS is strongly associated with increased risk of cardiovascular disease and type-2 diabetes mellitus.Adipose tissue plays a central role in the metabolic alterations: adipose tissue is not only the energy store of the body but also influences food intake, insulin sensitivity and secretion, vascular function, systemic inflammation, and oxidative stress because of its hormonal functions.2 Understanding the molecular mechanisms regulating adipose tissue function and adipokine secretion is becoming increasingly important.The steroid hormone aldosterone (aldo) participates in blood pressure control through regulation of renal salt and water reabsorption via activation of the mineralocorticoid receptor (MR). The MR is a ligand-activated transcription factor with a widespread expression pattern. In the past decade, we and others demonstrated that MR expression and activation lead to major pathophysiological consequences in heart, vessels, brain, eye, and skin, extending the potential therapeutic use of pharmacological MR antagonists.3 These novel nonclassical targets also include adipose tissue where the role of the mineralocorticoid system is still debated. 4 Experimental and clinical studies have shown that aldo excess is a potential risk factor for type-2 diabetes mellitus, through mechanisms independent of its blood pressure effect. A high prevalence (10%-50%) of glucose intolerance or type-2 diabetes mellitus has been reported in primary aldosteronism, and metabolic disturbances are corrected by surgical removal of aldo-producing adenomas.5 Experimental studies performed in various rodent models, that is, db/db, ob/ob, or diet-induced obese mice, proposed a specific role of MR Abstract-Metabolic syndrome is a major risk factor for the development of diabetes mellitus and cardiovascular diseases.Pharmacological antagonism of the mineralocorticoid receptor (MR), a ligand-activated transcription factor, limits metabolic syndrome in preclinical models, but mechanistic studies are lacking to delineate the role of MR activation in adipose tissue. In this study, we report that MR expression is increased in visceral adipose tissue in a preclinical mouse model of metabolic syndrome and in obese patients. In vivo conditional upregulation of MR in mouse adipocytes led to increased weight and fat mass, insulin resistance, and metabolic syndrome features without affecting blood pressure. We identified prostaglandin D2 synthase as a novel MR target gene in adipocytes and AT56, a specific inhibitor of prostaglandin D2 synthase enzymatic activity, blunted adipogenic aldosterone effects. Moreover, translational studies showed that expression of MR and prostaglandin D2 synthase is strongly correlated in adipose tissues fro...

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supporting

confidence: 88%

Section: Mr and Metabolic Alterations: Potential Benefit Of Mr Antagosupporting

confidence: 57%

Adipocyte Mineralocorticoid Receptor Activation Leads to Metabolic Syndrome and Induction of Prostaglandin D2 Synthase

et al. 2015

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“…This should be interpreted in the light of previous studies showing that MR blockade by eplerenone reverses insulin resistance in genetically determined obese or diabetic mice (33) and prevents proinflammatory events prevailing in adipose depots (32). In addition, MR-mediated insulin resistance may be also supported by the higher prevalence of MetS and insulin resistance in patients with primary hyperaldosteronism (22, 23); however, this remains controversial (67). The relative resistance to HFD-induced obesity in hMRoverexpressing mice, which was associated with the lack of insulin sensitivity improvement, prompted us to further investigate properties of adipose depots that represent an essential insulin target and MR-expressing tissue.…”

Section: Tg Mice Are Protected Against Hfd-induced Obesitymentioning

confidence: 81%

Paradoxical resistance to high-fat diet-induced obesity and altered macrophage polarization in mineralocorticoid receptor-overexpressing mice

Kuhn

Bourgeois

Keo

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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vitro, yet its in vivo metabolic impact remains elusive. Wild type (WT) and transgenic (Tg) mice overexpressing human MR were subjected to standard chow (SC) or high-fat diet (HFD) for 16 wk. Tg mice had a lower body weight gain than WT animals and exhibited a relative resistance to HFD-induced obesity. This was associated with a decrease in fat mass, an increased population of smaller adipocytes, and an improved glucose tolerance compared with WT animals. Quantitative RT-PCR studies revealed decreased expression of PPAR␥2, a master adipogenic gene, and of glucocorticoid receptor and 11␤-hydroxysteroid dehydrogenase type 1, consistent with an impaired local glucocorticoid signaling in adipose tissues (AT). This paradoxical resistance to HFD-induced obesity was not related to an adipogenesis defect since differentiation capacity of Tg preadipocytes isolated from stroma-vascular fractions was unaltered, suggesting that other nonadipocyte factors might compromise AT development. Although AT macrophage infiltration was not different between genotypes, Tg mice exhibited a distinct macrophage polarization, as revealed by FACS analysis and CD11c/CD206 expression studies. We further demonstrated that Tg macrophage-conditioned medium partially impaired preadipocyte differentiation. Therefore, we propose that modification of M1/M2 polarization of hMR-overexpressing macrophages could account in part for the metabolic phenotype of Tg mice. Collectively, our results provide evidence that MR exerts a pivotal immunometabolic role by controlling adipocyte differentiation processes directly but also indirectly through macrophage polarization regulation. Our findings should be taken into account for the pharmacological treatment of metabolic disorders. adipocyte; glucocorticoid signaling; energy homeostasis; immunometabolism; mineralocorticoid receptor THE OBESITY PANDEMIC OF OUR INDUSTRIALIZED COUNTRIES is related to dramatic changes in nutritional and physical activities over the last decades. More recently, it was reported that obesity is a proinflammatory state characterized by adipose tissue (AT) inflammation, including AT infiltration by macrophages and lymphocytes, and local and systemic overproduction of cytokines, chemokines, and prothrombotic factors (3,11,16,25,27,35,36,63,64,72,73). There is likely a causal relationship between the obesity-associated remodeling of AT and the development of insulin resistance, type 2 diabetes, and cardiovascular diseases (14,36,74). Conversely, weight loss in obese patients decreases the magnitude of AT inflammation (7, 12, 15, 21, 62, 68a).The mineralocorticoid receptor (MR), a steroid receptor belonging to the nuclear receptor superfamily of transcription factors, plays a key role in hydroelectrolytic homeostasis in epithelial tissues such as kidney and colon. Because of similar affinity of the MR for aldosterone and cortisol (1, 24), the tissue selectivity of aldosterone effects is ensured by the presence of the 11␤-hydroxysteroid dehydrogenase type 2 (11HSD2), an enzyme that conve...

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“…Recently, comparing the ex vivo visceral adipose tissue of patients with APA and patients with non-functioning adrenal adenoma as controls, we have found no differences as to gene expression of insulin signalling/inflammatory molecules, not supporting an effect of aldosterone excess on fat insulin sensitivity. 14 In addition, only at very high pharmacological concentrations and through glucocorticoid receptor activation aldosterone was able to reduce glucose uptake in subcutaneous human adipocytes. 14 Altogether, a higher prevalence of metabolic syndrome in PA compared with EH is not consistently found, and the relative weight of single metabolic abnormalities is still undefined.…”

mentioning

confidence: 99%

“…14 In addition, only at very high pharmacological concentrations and through glucocorticoid receptor activation aldosterone was able to reduce glucose uptake in subcutaneous human adipocytes. 14 Altogether, a higher prevalence of metabolic syndrome in PA compared with EH is not consistently found, and the relative weight of single metabolic abnormalities is still undefined. The available data on potential differences in metabolic characteristics between APA and IHA patients are also conflicting.…”

mentioning

confidence: 99%

Metabolic syndrome and primary aldosteronism: time for reappraisal?

Fallo

Sonino

2010

J Hum Hypertens

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Recent studies have addressed the issue of an association of metabolic abnormalities with primary aldosteronism (PA). In a prospective study, we were the first to report a higher prevalence of metabolic syndrome, as defined by Adult Panel Treatment (ATP) III criteria, in a large population of patients with PA compared with patients with essential hypertension (EH) (41 vs 29%, Po0.05). 1 Distribution of each component of the metabolic syndrome showed a higher frequency of hyperglycaemia in PA than in EH, whereas there was no difference between the two populations as to blood pressure levels, abdominal obesity, body mass index and lipid levels. The occurrence of metabolic syndrome was similar in aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) subtypes. Ronconi et al. 2 confirmed a higher prevalence of the metabolic syndrome in PA compared with matched EH patients (45 vs 30%, Po0.05). Among their PA patients, the metabolic syndrome tended to be more frequent, though not significantly, in IHA than in APA (51 vs 32%). In the same line, Iacobellis et al. 3 have recently found, using the 2004 modified version of ATP III (high fasting glucose X100 mg per 100 ml), that PA was associated with metabolic syndrome more frequently than EH, and when PA subgroups were considered separately the metabolic syndrome was slightly prevalent in APA compared with IHA (29 vs 21%). The clinical relevance of all these observations is that aldosterone excess may lead to cardiovascular damage by mechanisms independent of its hypertensive effect, that is, an altered metabolic profile, suggesting that the reported higher rate of cardiovascular events in PA than in EH might be due to increased prevalence of the metabolic syndrome in the former condition. 4 However, the pathophysiology and characteristics of this association are still controversial and not fully elucidated.In this issue of the Journal of Human Hypertension, Somloova et al. 5 provide additional fuel to this matter with data on the metabolic phenotype of patients with PA, particularly as to the intriguing differences between the two main subtypes. The authors analysed retrospectively 100 patients with PA, 50 IHA and 50 APA, in comparison with 90 patients with EH matched for age and duration of hypertension. According to the 2009 International Diabetes Federation definition of the metabolic syndrome, its prevalence was similar in patients with PA and EH. Within PA and analysing metabolic syndrome individual components, fasting glucose level was similar in IHA and APA, whereas highdensity lipoprotein-cholesterol was markedly lower and body mass index and triglycerides were significantly higher in IHA than in APA. Overall, the metabolic syndrome was more prevalent in IHA than in APA (62 vs 36%, Po0.05). The results of Somloova et al. are partly in accordance with those of Matrozova et al. 6 who reported in a large controlled cross-sectional study that prevalence of carbohydrate and lipid metabolism disorders is similar in PA and in EH. However, Matrozova ...

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Analysis of Insulin Sensitivity in Adipose Tissue of Patients with Primary Aldosteronism

Cited by 42 publications

References 21 publications

Adipocyte Mineralocorticoid Receptor Activation Leads to Metabolic Syndrome and Induction of Prostaglandin D2 Synthase

Adipocyte Mineralocorticoid Receptor Activation Leads to Metabolic Syndrome and Induction of Prostaglandin D2 Synthase

Paradoxical resistance to high-fat diet-induced obesity and altered macrophage polarization in mineralocorticoid receptor-overexpressing mice

Metabolic syndrome and primary aldosteronism: time for reappraisal?

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