Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 11beta-hydroxysteroid dehydrogenase (11beta-HSD) exists in two isoforms, 11beta-HSD1 and 11beta-HSD2. 11beta-HSD1 generates active cortisol from cortisone and appears to be involved in insulin resistant states. 11beta-HSD2 protects the mineralocorticoid receptor from inappropriate activation by glucocorticoids and is important to prevent sodium retention and hypertension. The purposes of the present study were to develop two real-time PCR assays to assess 11beta-HSD1 and 11beta-HSD2 mRNA expression and to evaluate the tissue distribution of the two isoforms in dogs. Thirteen different tissues of 10 healthy dogs were evaluated. Both real-time PCR assays were highly specific, sensitive and reproducible. Highest 11beta-HSD1 mRNA expression was seen in liver, lung, and renal medulla; highest 11beta-HSD2 mRNA expression in renal cortex, adrenal gland, and renal medulla. Higher 11beta-HSD1 than 11beta-HSD2 mRNA levels were found in all tissues except adrenal gland, colon, and rectum. Our results demonstrate that the basic tissue distribution of 11beta-HSD1 and 11beta-HSD2 in dogs corresponds to that in humans and rodents. In a next step 11beta-HSD1 and 11beta-HSD2 expression should be assessed in diseases like obesity, hypercortisolism, and hypertension to improve our knowledge about 11beta-HSD activity, to evaluate the dog as a model for humans and to potentially find new therapeutic options.
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PMID:Quantitative real-time PCR for the measurement of 11beta-HSD1 and 11beta-HSD2 mRNA levels in tissues of healthy dogs. 1771 18

The development of diabetes associated with stress, obesity, and metabolic syndrome involves elevated plasma glucocorticoid levels. It has been shown that short-term (<1 day) exposure to glucocorticoids reduces insulin secretion from pancreatic islets by affecting several steps of glucose signaling in beta-cells. However, longer term direct effects of glucocorticoids on beta-cells remain to be established. In this study, single beta-cells isolated from rat islets were treated with glucocorticoids, mineralocorticoids, and their receptor agonists/antagonists for 3 days in culture, followed by assessment of the beta-cell responsiveness to glucose by measuring cytosolic Ca2+ concentration ([Ca2+]i) using fura-2. Following treatment with corticosterone at 10-500 ng/ml for 3 days, the first-phase [Ca2+]i response to 8.3 mM glucose in beta-cells was suppressed. Simultaneous administration of RU-486, a glucocorticoid receptor (GR) antagonist, prevented this suppression. RU-486 by itself promoted the beta-cell [Ca2+]i response to glucose. Conversely, dexamethasone (1000 ng/ml), a highly selective GR agonist, impaired beta-cell [Ca2+]i responses to glucose. A mineralocorticoid receptor (MR) antagonist spironolactone, co-administered with corticosterone, further depressed [Ca2+]i responses to glucose, while an MR ligand aldosterone attenuated the corticosterone inhibition of [Ca2+]i responses. Neither spironolactone nor aldosterone by itself affected [Ca2+]i responses. These results indicate that long-term treatment with corticosterone impairs beta-cell [Ca2+)]i responses to glucose. This effect is mediated by GR and attenuated partially by simultaneous MR stimulation by corticosterone. The results show a novel function of MR to protect islet beta-cells against deteriorating glucocorticoid action via GR.
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PMID:Sub-chronic stimulation of glucocorticoid receptor impairs and mineralocorticoid receptor protects cytosolic Ca2+ responses to glucose in pancreatic beta-cells. 1843 52

Beside their role in the control of water and electrolyte homeostasis, recent data clearly indicate that aldosterone and the mineralocorticoid receptor (MR) are involved in adipocyte biology. It has been recently shown that aldosterone promotes white and brown adipocyte differentiation in vitro through specific activation of the MR. In addition, a non-epithelial pro-inflammatory role for MR activation has been recently inferred from studies on mineralocorticoid/salt administration in experimental animal models and from clinical studies. The mineralocorticoid system could hence represent a potential target for new therapeutic strategies in obesity and the metabolic syndrome. Progesterone has high affinity for the MR and is a natural antagonist of aldosterone. Differently from classic synthetic progestins, which are devoid of antimineralocorticoid properties, progesterone and new progestogens show remarkable antimineralocorticoid effects. Here, we discuss the potential role of the antimineralocorticoid properties of progestogens in the control of body weight, adipose tissue proliferation and salt sensitivity; their therapeutic use in postmenopausal women, as well as in women affected by polycystic ovary syndrome, may open new and unexpected possibilities in the treatment of related metabolic disorders.
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PMID:Potential role of progestogens in the control of adipose tissue and salt sensitivity via interaction with the mineralocorticoid receptor. 1856 91

Resistant hypertension is defined as blood pressure that remains uncontrolled in spite of >or= 3 antihypertensive medications at effective doses, ideally including a diuretic. Although exact prevalence is unknown, clinical trials suggest that 20% to 30% of study participants are resistant. Hyperaldosteronism, obesity, refractory volume expansion, and obstructive sleep apnea are common findings in resistant hypertension patients. Multiple studies indicate that primary aldosteronism (PA) is common (approximately 20%) in patients with resistant hypertension. Screening for PA is recommended for most patients with resistant hypertension, ideally by measurement of 24-hour urinary aldosterone excretion, or by the plasma aldosterone/plasma renin activity ratio. Successful treatment of resistant hypertension is predicated on improvement of lifestyle factors; accurate diagnosis and treatment of secondary causes of hypertension; and use of effective multidrug regimens. A long-acting diuretic, specifically chlorthalidone, is recommended as part of the treatment regimen. Recent studies demonstrate that mineralocorticoid receptor antagonists provide substantial antihypertensive benefit when added to multidrug regimens, even in patients without demonstrable aldosterone excess.
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PMID:Resistant hypertension and hyperaldosteronism. 1895 38

Serum aldosterone level is clinically known to correlate with body weight and insulin resistance. Because the underlying molecular mechanism is largely unknown, we examined the effect of aldosterone on insulin-induced metabolic signaling leading to glucose uptake in 3T3-L1 adipocytes. Aldosterone reduced the amounts of insulin receptor substrate (IRS) 1 and IRS2 in a time- and dose-dependent manner. As a result, insulin-induced phosphorylation of Akt-1 and -2, and subsequent uptake of 2-deoxyglucose were decreased. Degradation of IRSs was effectively prevented by a glucocorticoid receptor antagonist and antioxidant N-acetylcysteine, but not by a mineralocorticoid receptor antagonist. Because aldosterone induced phosphorylation of IRS1 at Ser(307), responsible kinases were investigated, and we revealed that rapamycin and BMS345541, but neither SP600125 nor calphostin C, conferred for degradation of IRSs. Although lactacystin prevented the degradation of IRSs, glucose uptake was not preserved. Importantly, sucrose-gradient-sediment intracellular fraction analysis revealed that lactacystin did not effectively restore the reduction of IRS1 in the low-density microsome fraction, important for the transduction of insulin's metabolic signaling. These results indicate that aldosterone deteriorates metabolic action of insulin by facilitating the degradation of IRS1 and IRS2 via glucocorticoid receptor-mediated production of reactive oxygen species, and activation of IkappaB Kinase beta and target of rapamycin complex 1. Thus, aldosterone appears to be a novel key factor in the development of insulin resistance in visceral obesity.
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PMID:Aldosterone inhibits insulin-induced glucose uptake by degradation of insulin receptor substrate (IRS) 1 and IRS2 via a reactive oxygen species-mediated pathway in 3T3-L1 adipocytes. 1909 45

Obesity and obesity-associated kidney injuries have played an important role in the rising prevalence of chronic kidney disease (CKD). The link between obesity and kidney disease begins with obesity's well-known associations with diabetes and hypertension, the two leading etiologies of CKD. However, a growing body of evidence suggests that elevated aldosterone levels and expanded extracellular volume are key components of obesity-induced renal disease via aldosterone's non-epithelial effects on the kidney. Highlighting these blood pressure- and diabetes-independent mechanisms of kidney injury in obesity allows an exploration of whether mineralocorticoid receptor blockade, coupled with weight loss and salt restriction, is an optimal treatment for overweight CKD patients.
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PMID:Interaction of aldosterone and extracellular volume in the pathogenesis of obesity-associated kidney disease: a narrative review. 1929 92

The prevalence of obesity, diabetes, hypertension, and cardiovascular and chronic kidney disease is increasing in developed countries. Obesity, insulin resistance, and hypertension commonly cluster with other risk factors for cardiovascular and chronic kidney disease to form the metabolic syndrome. Emerging evidence supports a paradigm shift in our understanding of the renin-angiotensin-aldosterone system and in aldosterone's ability to promote insulin resistance and participate in the pathogenesis of the metabolic syndrome and resistant hypertension. Recent data suggest that excess circulating aldosterone promotes the development of both disorders by impairing insulin metabolic signaling and endothelial function, which in turn leads to insulin resistance and cardiovascular and renal structural and functional abnormalities. Indeed, hyperaldosteronism is associated with impaired pancreatic beta-cell function, skeletal muscle insulin sensitivity, and elevated production of proinflammatory adipokines from adipose tissue, which results in systemic inflammation and impaired glucose tolerance. Accumulating evidence indicates that the cardiovascular and renal abnormalities associated with insulin resistance are mediated in part by aldosterone acting on the mineralocorticoid receptor. Although we have known that mineralocorticoid receptor blockade attenuates cardiovascular and renal injury, only recently have we learned that mineralocorticoid receptor blockade improves pancreatic insulin release, insulin-mediated glucose utilization, and endothelium-dependent vasorelaxation. In summary, aldosterone excess has detrimental metabolic effects that contribute to the metabolic syndrome and endothelial dysfunction, which in turn contribute to the development of resistant hypertension as well as cardiovascular disease and chronic kidney disease.
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PMID:Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. 1948 12

Obesity hypertension and metabolic syndrome have become major public health concerns. Nowadays, aldosterone is recognized as an important mediator of cardiovascular and renal damage. In the kidney, aldosterone injures glomerular visceral epithelial cells (podocytes), the final filtration barrier to plasma macromolecules, leading to proteinuria and glomerulosclerosis. Mineralocorticoid receptor (MR) antagonists effectively ameliorate proteinuria in patients or in animal models of hypertension, diabetes mellitus and chronic kidney disease (CKD), as well as in patients who experience 'aldosterone breakthrough.' Recently, clinical and experimental studies have shown that plasma aldosterone concentration is associated with obesity hypertension and metabolic syndrome. We showed that spontaneously hypertensive rats (SHR)/cp, an experimental model of obesity hypertension and metabolic syndrome, are prone to glomerular podocyte injury, proteinuria and left ventricular diastolic dysfunction, especially when the animals are fed a high-salt diet. Inappropriate activation of the aldosterone/MR system underlies the renal and cardiac injuries. Adipocyte-derived aldosterone-releasing factors (ARFs), although still unidentified, may account for aldosterone excess and the resultant target organ complication in SHR/cp. On the other hand, recent studies have shown that MR activation triggers target organ disease even in normal or low aldosterone states. We identified a small GTP (guanosine triphosphate)-binding protein, Rac1, as a novel activator of MR, and showed that this ligand-independent MR activation by Rac1 contributes to the nephropathy of several CKD models. We expect that ARFs and Rac1 can be novel therapeutic targets for metabolic syndrome and CKD. Future large-scale clinical trials are awaited to prove the efficacy of MR blockade in patients with obesity hypertension and metabolic syndrome.
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PMID:Mineralocorticoid receptor activation in obesity hypertension. 1952 18

Experiments in Cushing patients and healthy control subjects receiving adrenocorticotropic hormone (ACTH) indicate that transient renal sodium retention may contribute to the generation of hypertension. Here we have investigated the effect of chronic ACTH infusion on renal sodium handling in adult male C57BL/6J mice using selective antagonists to dissect mineralocorticoid and glucocorticoid receptor-mediated pathways. Mice were infused via osmotic minipump with ACTH (2.5 microg/d) or saline for 2 weeks before being anesthetized for renal function experiments. ACTH caused an increase in blood pressure and a reduction in fractional sodium excretion associated with enhanced activity of the epithelial sodium channel. Given separately, spironolactone and RU38486 blunted the pressor response to ACTH and the increased epithelial sodium channel activity; combined mineralocorticoid and glucocorticoid receptor blockade was required to resolve the response to ACTH excess. Dietary sodium depletion also prevented ACTH-induced hypertension. The effect of increased sodium reabsorption in the distal nephron is offset by downregulation of Na-K-Cl cotransport in the loop of Henle. Sodium excretion is normalized chronically, but blood pressure remains high; acute blockade of V1 receptors and alpha1 adrenoceptors in combination restored blood pressure to control values. In summary, ACTH excess promotes renal sodium reabsorption, contributing to the increased blood pressure; both glucocorticoid and mineralocorticoid receptor pathways are involved. These data are relevant to conditions associated with overactivity of the hypothalamic-pituitary-adrenal axis, such as obesity and chronic stress.
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PMID:Mineralocorticoid and glucocorticoid receptors stimulate epithelial sodium channel activity in a mouse model of Cushing syndrome. 1963 86

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.
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PMID:The balance between gluco- and mineralo-corticoid action critically determines inflammatory adipocyte responses. 1993 12


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