UMLS:C0948265 - FACTA Search

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Query: UMLS:C0948265 (metabolic syndrome)
24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In utero overexposure to glucocorticoids may explain the association between low birth weight and subsequent development of the metabolic syndrome. We previously showed that prenatal dexamethasone (dex) exposure in the rat lowers birth weight and programs adult fasting and postprandial hyperglycemia, associated with increased hepatic gluconeogenesis driven by elevated liver glucocorticoid receptor (GR) expression. This study aimed to determine whether prenatal dex (100 microg/kg per day from embryonic d 15 to embryonic d 21) programs adult GR expression in skeletal muscle and/or adipose tissue and whether this contributes to altered peripheral glucose uptake or metabolism. In utero dex-exposed rats remained lighter until 6 months of age, despite some early catch-up growth. Adults had smaller epididymal fat pads, with a relative increase in muscle size. Although glycogen storage was reduced in quadriceps, 2-deoxyglucose uptake into extensor digitorum longus muscle was increased by 32% (P < 0.05), whereas uptake in other muscles and adipose beds was unaffected by prenatal dex. GR mRNA was not different in most muscles but selectively reduced in soleus (by 23%, P < 0.05). However, GR mRNA was markedly increased specifically in retroperitoneal fat (by 50%, P < 0.02). This was accompanied by a shift from peroxisomal proliferator-activated receptor gamma 1 to gamma 2 expression and a reduction in lipoprotein lipase mRNA (by 28%, P < 0.02). Adipose leptin, uncoupling protein-3 and resistin mRNAs, muscle GLUT-4, and circulating lipids were not affected by prenatal dex. These data suggest that hyperglycemia in 6-month-old rats exposed to dexamethasone in utero is not due to attenuated peripheral glucose disposal. However, increased GR and attenuated fatty acid uptake specifically in visceral adipose are consistent with insulin resistance in this crucial metabolic depot and could indirectly contribute to increased hepatic glucose output.
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PMID:Programming of rat muscle and fat metabolism by in utero overexposure to glucocorticoids. 1258 77

Two isoforms of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) interconvert the active glucocorticoid, cortisol, and inactive cortisone. 11beta-HSD1 acts predominantly as an oxo-reductase in vivo using NADP(H) as a cofactor to generate cortisol. In contrast, 11beta-HSD2 is a NAD-dependent dehydrogenase inactivating cortisol to cortisone, thereby protecting the mineralocorticoid receptor from occupation by cortisol. In peripheral tIssues, both enzymes serve to control the availability of cortisol to bind to corticosteroid receptors. 11beta-HSD2 protects the mineralocorticoid receptor from cortisol excess; mutations in the HSD11B2 gene explain an inherited form of hypertension, the syndrome of 'apparent mineralocorticoid excess', in which 'Cushing's disease of the kidney' results in cortisol-mediated mineralocorticoid excess. Inhibition of 11beta-HSD2 explains the mineralocorticoid excess state seen following liquorice ingestion and more subtle defects in enzyme expression might be involved in the pathogenesis of 'essential' hypertension. 11beta-HSD1 by generating cortisol in an autocrine fashion facilitates glucocorticoid receptor-mediated action in key peripheral tIssues including liver, adipose tissue, bone and the eye. 'Cushing's disease of the omentum' has been proposed as an underlying mechanism in the pathogenesis of central obesity and raises the exciting possibility of selective 11beta-HSD1 inhibition as a novel therapy for patients with the metabolic syndrome. 'Pre-receptor' metabolism of cortisol via 11beta-HSD isozymes is an important facet of corticosteroid hormone action. Aberrant expression of these isozymes is involved in the pathogenesis of diverse human diseases including hypertension, insulin resistance and obesity. Modulation of enzyme activity may offer a future therapeutic approach to treating these diseases whilst circumventing the endocrine consequences of glucocorticoid excess or deficiency.
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PMID:Tissue-specific Cushing's syndrome, 11beta-hydroxysteroid dehydrogenases and the redefinition of corticosteroid hormone action. 1294 16

Glucocorticoids have a broad array of life-sustaining functions and play an important role in the therapy of many diseases. Thus, changes of tissue sensitivity to glucocorticoids may be associated with and influence the course and treatment of many pathologic states. Such tissue sensitivity changes may present on either side of an optimal range, respectively as glucocorticoid resistance or hypersensitivity, and may be generalized or tissue-specific. Familial/sporadic glucocorticoid resistance syndrome caused by inactivating mutations of the glucocorticoid receptor (GR) gene is a classic monogenic disorder associated with congenital, generalized glucocorticoid insensitivity, while several autoimmune, inflammatory and allergic diseases are often associated with resistance of the inflamed tissues to glucocorticoids. On the other hand, glucocorticoid hypersensitivity has been suggested in visceral obesity-related insulin resistance associated with components of the metabolic syndrome, and in the acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus type-1 (HIV-1) infection. Here, we have reviewed the molecular analyses of five familial and three sporadic cases of the familial/sporadic glucocorticoid resistance syndrome and discussed the possible contribution of newly identified molecules, such as HIV-1 accessory proteins Vpr and Tat, FLICE-associated huge protein (FLASH) and chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), on the molecular regulation of GR activity, as well as their possible contribution to changes in tissue sensitivity to glucocorticoids in pathologic conditions.
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PMID:Tissue glucocorticoid resistance/hypersensitivity syndromes. 1294 36

Glucocorticoids (GCs) are a vital class of steroid hormones that are secreted by the adrenal cortex and that are regulated by ACTH largely under the control of the hypothalamic-pituitary-adrenal axis. GCs mediate profound and diverse physiological effects in vertebrates, ranging from development, metabolism, neurobiology, anti-inflammation and programmed cell death to many other fuctions. Multiple factors "downstream" of GC secretion, such as glucocorticoid receptor (GR) number and the abundance of plasma binding proteins have originally been considered as modulators of GC action. However, in the last decade the role of tissue-specific GC activating and inactivating enzymes have been identified as additional determinants in GC signalling pathways. On the cellular level, they function as important pre-receptor regulators by acting as "molecular switches" for receptor-active and receptor-inactive GC hormones. According to their biologic activity to catalyze the interconversion of C11-hydroxyl and C11-oxo GCs these enzymes have been named 11beta-hydroxysteroid dehydrogenase (11beta-HSD; EC 1.1.1.146). Two isoforms of 11beta-HSD have been cloned and characterized so far. 11beta-HSD type 1 is found in a wide range of tissues, acts predominantly as a reductase in intact cells and tissues by regenerating active cortisol from cortisone, and has been described to regulate GC access to the GR. 11beta-HSD type 2 is found mainly in mineralocorticoid target tissues such as kidney and colon, acts only as a dehydrogenase by producing inactive cortisone, and has been found to protect the mineralocorticoid receptor from high levels of receptor-active cortisol. Recently, 11beta-HSD 1 has become highly topical due to the finding that 11beta-HSD 1 plays a pivotal role in the pathogenesis of central obesity and the appearance of the metabolic syndrome. This review provides an overview on the components involved in GC signalling of 11beta-HSD type 1 as an important pre-receptor control enzyme that modulates activation of the GR.
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PMID:Enzymology and molecular biology of glucocorticoid metabolism in humans. 1460 13

Fatty acid metabolism is abnormal in insulin-resistant states that increase the risk of atherosclerosis such as type 2 diabetes and the metabolic syndrome. How fatty acids promote vascular disease is poorly understood, but lipoprotein lipase and peroxisome proliferator-activated receptor alpha (PPARalpha)-physiologically related proteins involved in fatty acid metabolism-may be involved. Glucocorticoid metabolism is also abnormal in insulin-resistant states and may promote several components of the metabolic syndrome. Recent studies have shown that hepatic fatty acid metabolism is required for the development of insulin resistance and hypertension caused by glucocorticoid excess, suggesting that crosstalk between glucocorticoid receptor-and PPARalpha-dependent pathways may contribute to vascular disease.
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PMID:Fatty acid metabolism and vascular disease. 1503 Jul 93

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) interconverts inactive cortisone and active cortisol. Although bidirectional, in vivo it is believed to function as a reductase generating active glucocorticoid at a prereceptor level, enhancing glucocorticoid receptor activation. In this review, we discuss both the genetic and enzymatic characterization of 11beta-HSD1, as well as describing its role in physiology and pathology in a tissue-specific manner. The molecular basis of cortisone reductase deficiency, the putative "11beta-HSD1 knockout state" in humans, has been defined and is caused by intronic mutations in HSD11B1 that decrease gene transcription together with mutations in hexose-6-phosphate dehydrogenase, an endoluminal enzyme that provides reduced nicotinamide-adenine dinucleotide phosphate as cofactor to 11beta-HSD1 to permit reductase activity. We speculate that hexose-6-phosphate dehydrogenase activity and therefore reduced nicotinamide-adenine dinucleotide phosphate supply may be crucial in determining the directionality of 11beta-HSD1 activity. Therapeutic inhibition of 11beta-HSD1 reductase activity in patients with obesity and the metabolic syndrome, as well as in glaucoma and osteoporosis, remains an exciting prospect.
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PMID:11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. 1546 42

In humans, a hyperactivity of glucocorticoid metabolism was postulated to be involved in the intrauterine programming of the metabolic syndrome in adulthood. We studied in rats the effects of overfeeding, obtained by reducing the size of the litter in the immediate postnatal period, a time crucial for neuroendocrine maturation such as late gestation in humans. Overfeeding induced early-onset obesity and accelerated the maturation of the hypothalamo-pituitary-adrenal (HPA) axis together with an upregulation of adipose tissue glucocorticoid receptor (GR) mRNA. In adulthood, neonatally overfed rats presented with moderate increases in basal and stress-induced corticosterone secretion and striking changes in visceral adipose tissue glucocorticoid signaling, that is, enhanced GR and 11beta-hydroxysteroid dehydrogenase type 1 mRNA levels. The above-mentioned alterations in the endocrine status of overfed rats were accompanied by a moderate overweight status and significant metabolic disturbances comparable to those described in the metabolic syndrome. Our data demonstrate for the first time that postnatal overfeeding accelerates the maturation of the HPA axis and leads to permanent upregulation of the HPA axis and increased adipose tissue glucocorticoid sensitivity. Thus, the experimental paradigm of postnatal overfeeding is a powerful tool to understand the pathophysiology of glucocorticoid-induced programming of metabolic axes.
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PMID:Postnatal diet-induced obesity in rats upregulates systemic and adipose tissue glucocorticoid metabolism during development and in adulthood: its relationship with the metabolic syndrome. 1561 29

Patients with cortisol excess, Cushing's syndrome, develop a classical phenotype characterized by central obesity, hypertension, and increased cardiovascular mortality. Whilst this observation points to the importance of glucocorticoids, circulating cortisol excess is rare and does not explain the pathogenesis of many common conditions. At a tissue specific level, the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) locally regenerates active cortisol from inactive cortisone amplifying glucocorticoid receptor activation in the context of normal circulating cortisol levels. Increased 11beta-HSD1 activity and expression have been implicated in the pathogenesis of many common conditions including, obesity, insulin resistance, the metabolic syndrome, polycystic ovarian syndrome, osteoporosis and glaucoma. Furthermore, selective 11beta-HSD1 inhibition has been proposed as a novel therapeutic strategy in many of these conditions. Here we review the role of 11beta-HSD1 in human disease and discuss the impact of selective 11beta-HSD1 inhibition.
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PMID:11Beta-hydroxysteroid dehydrogenase type 1 in human disease: a novel therapeutic target. 1587 12

Glucocorticoids (GCs) increase hepatic gluconeogenesis and play an important role in the regulation of hepatic glucose output. Whereas systemic GC inhibition can alleviate hyperglycemia in rodents and humans, it results in adrenal insufficiency and stimulation of the hypothalamic-pituitary-adrenal axis. In the present study, we used optimized antisense oligonucleotides (ASOs) to cause selective reduction of the glucocorticoid receptor (GCCR) in liver and white adipose tissue (WAT) and evaluated the resultant changes in glucose and lipid metabolism in several rodent models of diabetes. Treatment of ob/ob mice with GCCR ASOs for 4 weeks resulted in approximately 75 and approximately 40% reduction in GCCR mRNA expression in liver and WAT, respectively. This was accompanied by approximately 65% decrease in fed and approximately 30% decrease in fasted glucose levels, a 60% decrease in plasma insulin concentration, and approximately 20 and 35% decrease in plasma resistin and tumor necrosis factor-alpha levels, respectively. Furthermore, GCCR ASO reduced hepatic glucose production and inhibited hepatic gluconeogenesis in liver slices from basal and dexamethasone-treated animals. In db/db mice, a similar reduction in GCCR expression caused approximately 40% decrease in fed and fasted glucose levels and approximately 50% reduction in plasma triglycerides. In ZDF and high-fat diet-fed streptozotocin-treated (HFD-STZ) rats, GCCR ASO treatment caused approximately 60% reduction in GCCR expression in the liver and WAT, which was accompanied by a 40-70% decrease in fasted glucose levels and a robust reduction in plasma triglyceride, cholesterol, and free fatty acids. No change in circulating corticosterone levels was seen in any model after GCCR ASO treatment. To further demonstrate that GCCR ASO does not cause systemic GC antagonism, normal Sprague-Dawley rats were challenged with dexamethasone after treating with GCCR ASO. Dexamethasone increased the expression of GC-responsive genes such as PEPCK in the liver and decreased circulating lymphocytes. GCCR ASO treatment completely inhibited the increase in dexamethasone-induced PEPCK expression in the liver without causing any change in the dexamethasone-induced lymphopenia. These studies demonstrate that tissue-selective GCCR antagonism with ASOs may be a viable therapeutic strategy for the treatment of the metabolic syndrome.
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PMID:Reduction of hepatic and adipose tissue glucocorticoid receptor expression with antisense oligonucleotides improves hyperglycemia and hyperlipidemia in diabetic rodents without causing systemic glucocorticoid antagonism. 1591 8

Angiogenesis restores blood flow to healing tissues, a process that is inhibited by high doses of glucocorticoids. However, the role of endogenous glucocorticoids and the potential for antiglucocorticoid therapy to enhance angiogenesis is unknown. Using in vitro and in vivo models of angiogenesis in mice, we examined effects of (i) endogenous glucocorticoids, (ii) blocking endogenous glucocorticoid action with the glucocorticoid receptor antagonist RU38486, and (iii) abolishing local regeneration of glucocorticoids by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1). Glucocorticoids, administered at physiological concentrations, inhibited angiogenesis in an in vitro aortic ring model and in vivo in polyurethane sponges implanted s.c. RU38486-enhanced angiogenesis in s.c. sponges, in healing surgical wounds, and in the myocardium of mice 7 days after myocardial infarction induced by coronary artery ligation. 11betaHSD1 knockout mice showed enhanced angiogenesis in vitro and in vivo within sponges, wounds, and infarcted myocardium. Endogenous glucocorticoids, including those generated locally by 11betaHSD1, exert tonic inhibition of angiogenesis. Inhibition of 11betaHSD1 in liver and adipose has been advocated to reduce cardiovascular risk in the metabolic syndrome: these data suggest that 11betaHSD1 inhibition offers a previously uncharacterized therapeutic approach to improve healing of ischemic or injured tissue.
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PMID:Preventing local regeneration of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1 enhances angiogenesis. 1609 20

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