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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As obesity reaches epidemic levels in the United States there is an urgent need to understand the developmental pathways leading to this condition. Obesity increases the risk of hypertension and diabetes, symptoms of which are being seen with increased incidence in children. Adipocyte development begins in the fetus and, in contrast to all other tissues whose growth ceases in late juvenile life, it has the capacity for "unlimited" growth. In normal healthy individuals, the increase in fat mass with age is accompanied by a parallel increase in cortisol sensitivity, i.e., increased glucocorticoid receptor abundance and increased activity of the enzyme 11beta hydroxysteroid dehydrogenase type 1. Enhanced adipocyte sensitivity to cortisol is promoted in offspring born to mothers that were nutrient-restricted in utero in conjunction with increased peroxisome proliferator activated receptor alpha. This adaptation only appears to be associated with greater fat mass in the offspring when maternal nutrient restriction is confined to late gestation, coincident with the period of maximal fetal growth. In these offspring, increased fat mass is accompanied by glucose intolerance and insulin resistance, in conjunction with an adipose tissue specific reduction in glucose transporter 4 abundance. In conclusion, changes in maternal and, therefore, fetal nutrient supply at specific stages of gestation have the potential to substantially increase the risk of those offspring becoming obese in later life. The extent to which changes in dietary habits, both during pregnancy and in later life, may act to contribute to the current explosion in childhood and adult obesity remains a scientific and public health challenge to us all.
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PMID:Maternal nutritional programming of fetal adipose tissue development: long-term consequences for later obesity. 1618 15

Medroxyprogesterone acetate (MPA), a widely used synthetic progestational contraceptive, occasionally leads to Cushingoid side effects such as hypertension, fluid retention, and centripetal obesity. We investigated the effect of MPA on classic mineralocorticoid target genes, alpha-epithelial Na channel (ENaC) and sgk1, in the collecting duct. In adrenalectomized mice, aldosterone, dexamethasone, and MPA increased alpha-ENaC mRNA levels in kidney cortex. MPA and dexamethasone, but not progesterone, dose dependently increased alpha-ENaC and sgk1 mRNA in M-1 and in Madin-Darby canine kidney-C7 cells, both collecting duct cell lines. The stimulatory effect of MPA and dexamethasone on alpha-ENaC expression was inhibited by RU-38486, a combined glucocorticoid receptor (GR) and progesterone receptor (PR) antagonist, but not by Org31710, a pure PR antagonist. MPA and dexamethasone dose dependently increased alpha-ENaC promoter-driven luciferase activity in M-1 cells, which was not inhibited by Org31710, indicating that MPA regulates alpha-ENaC in a PR-independent manner. When tested in HT29 cells, MPA could only stimulate alpha-ENaC-driven reporter activity when GR was coexpressed, confirming the requirement for functional GR in the transcriptional effect of MPA. The activation of steroid receptors such as GR can explain the apparent glucocorticoid effects of MPA, independent of PR activation.
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PMID:Medroxyprogesterone acetate binds the glucocorticoid receptor to stimulate alpha-ENaC and sgk1 expression in renal collecting duct epithelia. 1618 95

Hypothalamo-pituitary-adrenal axis has been reported to influence fat mass distribution in obesity. We investigated the hypothesis that corticosteroid-binding globulin (CBG) polymorphism could influence obesity, metabolic, or hypothalamo-pituitary adrenal (HPA) axis activity parameters. In 44 obese pre-menopausal women, a microsatellite located within the CBG gene was analyzed, providing three genotypes: 86/86 (n = 29), 86/90 (n = 14), and 90/90 (n = 1). No significant difference was found for obesity, metabolic, and HPA axis activity parameters between the genotypes 86/86 and 86/90. Looking for differences in correlations between HPA axis activity parameters and obesity or metabolic parameters between the two genotypes, genotype 86/90 showed a strong correlation between salivary cortisol after dexamethasone (0.25 mg) suppression test and waist-to-hip ratio (r = -0.84, p = 0.0007), whereas this correlation was weaker for genotype 86/86 (r = -0.34, p = 0.09). These data were completed with an analysis of the BclI polymorphism of the glucocorticoid receptor (GR) gene. There was an association between this GR polymorphism and both awakening salivary cortisol and postdexamethasone salivary cortisol but no association for obesity or metabolic parameters. We concluded that CBG gene polymorphisms might modulate the influence of the HPA axis on the fat mass distribution in this population.
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PMID:Corticosteroid binding globulin gene polymorphism influences cortisol driven fat distribution in obese women. 1622 46

Low birth weight is strongly predictive of hypertension, cardiovascular diseases, obesity, insulin resistance and diabetes. The mechanisms by which fetal undernutrition and, hence, low birth weight increase the risk of developing these diseases are unclear. To investigate the hypothesis of a primary defect in beta-cell development, we designed a rat model of undernutrition, involving an overall reduction in maternal food intake. In this model, fetuses with intrauterine growth retardation have a decreased beta-cell mass, which persists into adulthood and ultimately causes glucose intolerance, thereby mimicking features of the metabolic syndrome. Maternal undernutrition causes elevations in glucocorticoid concentrations, which, in turn, cause a reduction in beta-cell mass in the fetus. Our data also suggest a key role of glucocorticoids when nutrient supply is normal. By combining in-vitro studies with in-vivo investigations in mice lacking the glucocorticoid receptor in the whole organism or in specific pancreatic cell populations, we have shown that the glucocorticoid receptor is critical for ensuring pancreatic architecture and survival, as well as for beta-cell mass expansion during a critical developmental window. Glucocorticoids act on precursor cells before the onset of hormone gene expression and are likely to programme beta-cell differentiation by modifying the balance of specific transcription factors, mostly Pdx-1. Glucocorticoids should therefore be considered as important hormones in pancreatic development, in situations of both normal nutrition and undernutrition. To investigate whether this is also the case in human pancreatic development, we studied the expression of the glucocorticoid receptor and that of the transcription factor Pdx-1 on pancreatic specimens from very early to late stages of development of the human embryo. In terms of beta-cell ontogeny, expression of the glucocorticoid receptor in the pancreas coincides with that of the transcription factor Pdx-1 in beta cells. These results are consistent with a possible role for glucocorticoids during human pancreatic development.
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PMID:Nutrition, glucocorticoids and pancreas development. 1661 21

Excessive glucocorticoid exposure (Cushing's syndrome) results in increased adiposity associated with dysmetabolic features (including insulin resistance, hyperlipidaemia, and hypertension). Circulating cortisol levels are not elevated in idiopathic obesity, although cortisol production and clearance are increased. However, tissue glucocorticoid exposure may be altered independently of circulating levels by 11beta-hydroxysteroid dehydrogenase type 1 (11HSD1), an enzyme which generates active glucocorticoid within tissues, including in adipose tissue. Transgenic overexpression of 11HSD1 in mice causes obesity. In human obesity, 11HSD1 is altered in a tissue-specific manner with reduced levels in liver but elevated levels in adipose, which may lead to glucocorticoid receptor activation and contribute to the metabolic phenotype. The reasons for altered 11HSD1 in obesity are not fully understood. Although some polymorphisms have been demonstrated in intronic and upstream regions of the HSD11B1 gene, the functional significance of these is not clear. In addition, there is mounting evidence that 11HSD1 may be dysregulated secondarily to factors that are altered in obesity, including substrates for metabolism, hormones, and inflammatory mediators. 11HSD1 is a potential therapeutic target for the treatment of the metabolic syndrome. 11HSD1 knockout mice are protected from diet-induced obesity and associated metabolic dysfunction. Although many specific inhibitors of 11HSD1 have now been developed, and published data support their efficacy in the liver to reduce glucose production, their efficacy in enhancing insulin sensitivity in adipose tissue remains uncertain. The therapeutic potential of 11HSD1 in human obesity therefore remains highly promising but as yet unproven.
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PMID:Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 in obesity. 1662 97

Asthma and obesity are prevalent disorders, each with a significant public health impact, and a large and growing body of literature suggests an association between the two. The systemic inflammatory milieu in obesity leads to metabolic and cardiovascular complications, but whether this environment alters asthma risk or phenotype is not yet known. Animal experiments have evaluated the effects of leptin and obesity on airway inflammation in response to both allergic and nonallergic exposures and suggest that airway inflammatory response is enhanced by both endogenous and exogenous leptin. Cross-sectional and prospective cohort studies of humans have shown a modest overall increase in asthma incidence and prevalence in the obese, although body mass index does not appear be a significant modifier of asthma severity. Studying the obesity-asthma relationship in large cohorts, in which self-reports are frequently used to ascertain the diagnosis of asthma, has been complicated by alterations in pulmonary physiology caused by obesity, which may lead to dyspnea or other respiratory symptoms but do not fulfill accepted physiologic criteria for asthma. Recent investigations toward elucidating a shared genetic basis for these two disorders have identified polymorphisms in specific regions of chromosomes 5q, 6p, 11q13, and 12q, each of which contains one or more genes encoding receptors relevant to asthma, inflammation, and metabolic disorders, including the beta(2)-adrenergic receptor gene ADRB2 and the glucocorticoid receptor gene NR3C1. Further research is warranted to synthesize these disparate observations into a cohesive understanding of the relationship between obesity and asthma.
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PMID:Obesity and asthma. 1662 66

The nuclear receptor constitutive androstane receptor (CAR), a key transcription factor for the expression of cytochrome P450 (CYP) 2B genes, resides in the cytoplasm under untreated conditions and translocates into the nucleus upon xenobiotic exposure. CAR forms a multiprotein complex including heat shock protein 90 in the cytoplasm as the glucocorticoid receptor, and it is likely that protein phosphatase 2A plays a critical role in the first step of CAR nuclear translocation. In addition to the xenobiotic induction of CYP2Bs, our recent studies have indicated that CAR is important for sex and strain differences and obesity/diabetes-associated changes in the expression of CYP2B genes. These results have raised the hypothesis that the expression of nuclear receptors varies depending on the physiologic condition, leading to the dysregulation of CYP expression. In obese mice fed a high-fat diet, however, hepatic CYP3A levels are drastically decreased without any significant changes in the expression of nuclear receptors including the pregnane X receptor and hepatocyte nuclear factor-4, which are known to be key transcription factors in the expression of CYP3A genes. These results indicate that it is important to investigate the mechanism of the transcriptional regulation of nuclear receptor genes as well as the activation of nuclear receptors to understand the CYP expression system fully.
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PMID:[Roles of nuclear receptors in the gene expression of drug-metabolizing enzymes under various physiological conditions]. 1667 42

The glucocorticoid receptor (GR) may be a common link between human obesity/metabolic syndrome and Cushing's syndrome. The effects of glucocorticoids are mediated through the functional isoform, GRalpha. An alternative isoform, GRbeta, behaves as a dominant negative inhibitor of GRalpha and has been implicated as a contributing factor to glucocorticoid resistance. A naturally occurring ATTTA to GTTTA single nucleotide polymorphism (A3669G) located in the 3' end of exon 9beta results in increased stability of GRbeta mRNA and increased GRbeta protein expression. Enhanced GRbeta expression may result in greater inhibition of GRalpha transcriptional activity, resulting in glucocorticoid insensitivity. To test the hypothesis that the 3669G allele would result in a phenotype less likely to express features of glucocorticoid excess, we studied the prevalence of this polymorphism and its relationship with obesity and features of the metabolic syndrome in 322 Europid and 262 South-Asian subjects in northeast England. We report evidence that 3669G allele is associated with reduced central obesity in Europid women and a more favorable lipid profile in Europid men. These data suggest that the 3669G allele may attenuate the undesirable effects of glucocorticoids on fat distribution and lipid metabolism, although its penetrance may vary in different ethnic groups.
Obesity (Silver Spring) 2006 May
PMID:Association of glucocorticoid receptor polymorphism A3669G in exon 9beta with reduced central adiposity in women. 1685 82

Metabolic syndrome, with its attendant cardiovascular complications, is reaching epidemic proportions worldwide; hence, there is intense interest in understanding the pathogenesis of and developing therapy for these common disorders. Recent studies have suggested that metabolic syndrome may be a stress response, with an underlying abnormality in the enzyme 11beta-hydroxysteroid dehydrogenase. At the cellular level, the enzyme hydroxysteroid dehydrogenase type 1 (HSD1) locally regenerates active cortisol from inactive cortisone, amplifying glucocorticoid receptor activation and promoting preadipocyte differentiation and adipocyte hypertrophy. Although initial studies in transgenic mice and humans are encouraging, more data are required to conclusively prove the hypothesis that the adipose-tissue-specific overexpression of HSD1 and the resultant increase in tissue-specific cortisol concentrations result in human obesity, insulin resistance, high blood pressure, and metabolic syndrome. Currently, selective inhibitors of HSD1 are not available for human use; however, their development is under way. The use of potent and selective HSD1 inhibitors will finally confirm or refute this hypothesis and may turn out to be an effective strategy for combating these common maladies.
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PMID:Enhanced 11beta-hydroxysteroid dehydrogenase activity, the metabolic syndrome, and systemic hypertension. 1689 15

The hypothalamic paraventricular nucleus (PVN) is a major integrative site for the control of homeostasis, including energy balance, through coordinated regulation of neuroendocrine and autonomic outputs. However, cross-talk regulation of PVN neuroendocrine and preautonomic systems is poorly understood. The stress response invokes the coordinated control of motor, hormonal, and vegetative systems to establish homeostasis after an environmental perturbation. Elevated stress levels of circulating glucocorticoids give rise to multiple, complex physiological effects. The complexity of the glucocorticoid actions is caused by the wide range of glucocorticoid target tissues and to the broad time scale over which the actions occur. Recent studies have revealed rapid glucocorticoid actions in the hypothalamus that may provide an integrative signal linking stress with the regulation of energy and fluid homeostasis. Glucocorticoids inhibit PVN and supraoptic nucleus neurons by stimulating a rapid synthesis and retrograde release of endocannabinoids, which suppress synaptic excitation through presynaptic CB1 receptor activation. The glucocorticoid-induced endocannabinoid synthesis is mediated apparently by a novel membrane-associated glucocorticoid receptor found in multiple subpopulations of hypothalamic neuroendocrine cells. It may, therefore, represent a mechanism for rapid glucocorticoid control of activity among different neuroendocrine systems to coordinate a global response to stress. In support of this, leptin, a circulating adipose signal that regulates food intake and energy expenditure through central actions, blocks the glucocorticoid-mediated endocannabinoid release in the PVN. This represents a means by which the regulation of stress and feeding may interface in the PVN, thus providing a possible mechanism for the integration of multiple homeostatic functions.
Obesity (Silver Spring) 2006 Aug
PMID:Rapid glucocorticoid actions in the hypothalamus as a mechanism of homeostatic integration. 1702 78


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