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

Obesity is associated with an increased risk of diabetes type 2, dyslipidemia, and atherosclerosis. These cardiovascular and metabolic abnormalities are exacerbated by excessive dietary fat, particularly cholesterol and its metabolites. High adipose tissue glucocorticoid levels, generated by the intracellular enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), are also implicated in the pathogenesis of obesity, metabolic syndrome, and atherosclerosis. 11beta-HSD1 also interconverts the atherogenic oxysterols 7-ketocholesterol (7KC) and 7beta-hydroxycholesterol (7beta-HC). Here, we report that 11beta-HSD1 catalyzes the reduction of 7KC to 7beta-HC in mature 3T3-L1 and 3T3-F442A adipocytes, leading to cellular accumulation of 7beta-HC. Approximately 73% of added 7KC was reduced to 7beta-HC within 24 h; this conversion was prevented by selective inhibition of 11beta-HSD1. Oxysterol and glucocorticoid conversion by 11beta-HSD1 was competitive and occurred with a physiologically relevant IC(50) range of 450 nm for 7KC inhibition of glucocorticoid metabolism. Working as an inhibitor of 11beta-reductase activity, 7KC decreased the regeneration of active glucocorticoid and limited the process of differentiation of 3T3-L1 preadipocytes. 7KC and 7beta-HC did not activate liver X receptor in a transactivation assay, nor did they display intrinsic activation of the glucocorticoid receptor. However, when coincubated with glucocorticoid (10 nm), 7KC repressed, and 7beta-HC enhanced, glucocorticoid receptor transcriptional activity. The effect of 7-oxysterols resulted from the modulation of 11beta-HSD1 reaction direction, and could be ameliorated by overexpression of hexose 6-phosphate dehydrogenase, which supplies reduced nicotinamide adenine dinucleotide phosphate to 11beta-HSD1. Thus, the activity and reaction direction of adipose 11beta-HSD1 is altered under conditions of oxysterol excess, and could impact upon the pathophysiology of obesity and its complications.
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PMID:7-oxysterols modulate glucocorticoid activity in adipocytes through competition for 11beta-hydroxysteroid dehydrogenase type. 1902 97

Aberrant accumulation of lipids in the liver ("fatty liver" or hepatic steatosis) represents a hallmark of the metabolic syndrome and is tightly associated with obesity, type II diabetes, starvation, or glucocorticoid (GC) therapy. While fatty liver has been connected with numerous abnormalities of liver function, the molecular mechanisms of fatty liver development remain largely enigmatic. Here we show that liver-specific disruption of glucocorticoid receptor (GR) action improves the steatotic phenotype in fatty liver mouse models and leads to the induction of transcriptional repressor hairy enhancer of split 1 (Hes1) gene expression. The GR directly interferes with Hes1 promoter activity, triggering the recruitment of histone deacetylase (HDAC) activities to the Hes1 gene. Genetic restoration of hepatic Hes1 levels in steatotic animals normalizes hepatic triglyceride (TG) levels. As glucocorticoid action is increased during starvation, myotonic dystrophy, and Cushing's syndrome, the inhibition of Hes1 through the GR might explain the fatty liver phenotype in these subjects.
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PMID:The glucocorticoid receptor controls hepatic dyslipidemia through Hes1. 1876 22

Glucocorticoid receptors (GRs) are cytoplasmaticreceptors regulating the expression of cortisol and bind to specific sites on chromatin. The glucocorticoid receptor gene (GRL) is located on chromosome 5q31 and encodes for either a 777-amino acid (GRalpha) or a 742-amino acid (GRbeta) polypeptide. The objective of the current study was to examine the prospective association of 3 polymorphisms-a Tth111I restriction fragment in the promoter region, a BclI polymorphism in intron 2, and an A/G polymorphism in exon 2-of the GRL gene on estimates of obesity, hypertension, and diabetes in 163 unrelated Swedish men born in 1944. These data showed a significant increase in body weight, body mass index, abdominal obesity, fasting glucose, insulin, and homeostasis model assessment over the 5-year follow-up among homozygotes for the rare BclI allele. In contrast, no significant associations with the Tth111I or A/G polymorphism were detected. It is concluded that the genetic information about GRL would be useful for further genetic study of obesity, diabetes, and related metabolic diseases.
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PMID:A 5-year follow-up study of 3 polymorphisms in the human glucocorticoid receptor gene in relation to obesity, hypertension, and diabetes. 1898 27

Glucocorticoids (GCs) exert profound influences on many physiologic functions by virtue of their diverse roles in growth, development, and maintenance of homeostasis. We previously created a novel gain of function in the human glucocorticoid receptor (hGR), hGRM604L, which is active at GC concentrations 5-10-fold lower than wild-type GR. To gain a greater insight into GC physiology in vivo, we inserted this mutant GR (GRM610L in mice) into mice via homologous recombination. Mice expressing the allele are phenotypically normal with respect to GC function. However, corticosterone levels, ACTH levels, and adrenocortical size are markedly reduced, suggesting they are phenotypically normal because the mutant GR alters the basal regulation of the hypothalamic-pituitary-adrenal axis. We demonstrate via physiologic and immunologic studies that GRM610L mice have increased sensitivity to GCs in vivo. Sensitivity to the actions of endogenous GCs may be an important factor underlying the development of many human diseases including hypertension, obesity, and diabetes. Our model may provide a new and powerful tool for the study of GC physiological and pathological processes in vivo.
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PMID:Characterization of a novel gain of function glucocorticoid receptor knock-in mouse. 1901 39

Androgens modulate adipocyte function and affect the size of adipose tissue compartments in humans. Aldo-keto reductase 1C (AKR1C) enzymes, especially AKR1C2 and AKR1C3, through local synthesis and inactivation of androgens, may be involved in the fine regulation of androgen availability in adipose tissue. This review article summarizes recent findings on androgen metabolism in adipose tissue. Primary culture models and whole tissue specimens of human adipose tissue obtained from the abdominal subcutaneous and intra-abdominal (omental) fat compartments were used in our studies. The non-aromatizable androgen dihydrotestosterone (DHT) inhibits adipocyte differentiation in subcutaneous and omental adipocytes in humans. This inhibitory effect is partially reversed by anti-androgens. Activity and mRNA expression of AKR1C1, 2 and 3 were detected in SC and OM adipose tissue, in men and women, with higher levels in the SC depot than the omental depot of both sexes. The abundance of AKR1C enzyme mRNAs was particularly elevated compared to other steroid-converting enzymes. Significant positive associations were observed between AKR1C enzyme mRNA levels or DHT inactivation rates and visceral fat accumulation as well as OM adipocyte size in women and in men, at least in the normal weight to moderately obese range. Mature adipocytes had significantly higher DHT inactivation rates compared to preadipocytes. Accordingly, adipocyte differentiation significantly increased AKR1C enzyme expression and DHT inactivation rates. Treatment of preadipocytes with dexamethasone alone led to significant increases in the formation of 5alpha-androstan-3alpha,17beta-diol. This stimulation was completely abolished by RU486, suggesting that androgen inactivation is stimulated by a glucocorticoid receptor-dependent mechanism. In conclusion, higher AKR1C activity and expression in mature adipocytes may explain the associations between these enzymes and obesity. We speculate that glucocorticoid-induced androgen inactivation could locally decrease the exposure of adipose cells to active androgens and partially remove their inhibitory effect on adipogenesis. We hypothesize that body fat distribution patterns likely emerge from the local adipose tissue balance between active androgens and glucocorticoids in each fat compartment.
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PMID:Androgen metabolism in adipose tissue: recent advances. 1902 38

Thirteen candidate genes for human obesity were selected for cytogenetic mapping by FISH in the pig genome. Among them, 6 genes were assigned to chromosomes for the first time (NR3C1, GNB3, ADRB1, ADRB2, ADRB3 and UCP1). Location of the other 7 genes (INSIG2, LIPIN1, PLIN, NAMPT, ADIPOQ, UCP2 and UCP3), earlier mapped by somatic cell hybridization or with the use of a radiation hybrid panel, was verified (INSIG2) or more precisely described. The genes were assigned to the following chromosomes: INSIG2 to SSC15q12, LIPIN1 to SSC3q26, NR3C1 to SSC2q29, PLIN to SSC7q15, GNB3 to SSC5q21, NAMPT to SSC9q23, ADIPOQ to SSC13q41, ADRB1 to SSC14q28, ADRB2 to SSC2q29, ADRB3 to SSC15q13-14, UCP1 to SSC8q21-22, and both UCP2 and UCP3 to SSC9p24. Most of the genes were located within known QTL for pig fatness traits.
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PMID:Chromosomal localization of 13 candidate genes for human obesity in the pig genome. 1902 85

Adipocyte plays an important role in lipid regulation in mammals. Understanding of adipocyte differentiation becomes a key issue for the development of anti-obesity agent. Glucocorticoids (GCs) regulate lipid metabolism through promoting lipogenesis in adipose tissue. Ginsenoside Rh2, with a similar chemical structure as GCs, shows antidiabetic, anti-inflammatory, and anticancer actions both in vivo and in vitro. However, effect of Rh2 on glucocorticoid receptor (GR) for an increase of adipogenesis like GCs remains unclear. In the present study, we employed ginsenoside Rh2 to investigate the changes in adipogenetic process of 3T3-L1, one of the widely used preadipocytes, through activating GR or not. In leuciferase assay, we found that ginsenoside Rh2 induced GRs transitivity in a way as dexamethasone, which was deleted by RU486 at concentrations sufficient to block GR. Moreover, 3T3-L1 preadipocytes were differentiated into adipocytes by adipogenic induction medium containing 0.01 to 1 microM of ginsenoside Rh2. Also, RU486 blocked this adipogenesis induced by ginsenoside Rh2 or dexamethasone. The obtained results suggest that ginsenoside Rh2 can promote preadipocytes differentiation through activating GR. This finding seems helpful for the understanding of ginsenosides in the regulation of lipid metabolism.
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PMID:Increase of adipogenesis by ginsenoside (Rh2) in 3T3-L1 cell via an activation of glucocorticoid receptor. 1904 55

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

Recent investigations have demonstrated that activation of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in liver and adipose tissue is closely related to the pathogenesis of obesity and diabetes. However, the relationship between alteration of 11beta-HSD1 and the pathogenesis of type 2 diabetes in skeletal muscle is still unclear. A rat model of Type 2 diabetes was developed by high fat diet feeding combined with multiple low dose streptozotocin injection (30 mg/kg, i.p. twice). Intraperitoneal glucose tolerance test, insulin tolerance test were performed. Fasting blood glucose, fasting insulin, total cholesterol, triglyceride were measured. The protein and mRNA level of 11beta-HSD1 and glucocorticoid receptor in gastrocnemius muscle were determined. The alteration of insulin signaling pathway related protein was investigated. We found that the protein levels of 11beta-HSD1 and glucocorticoid receptor were significantly increased (P < 0.05); the mRNA level of 11beta-HSD1 was also elevated (P < 0.05); the mRNA level of glucocorticoid receptor was decreased (P < 0.05). After insulin stimulation, diabetic rats had no significant changes in the level of the insulin receptor beta-subunit (IR-beta), AKT, as in phosphorylated AKT in the gastrocnemius muscle compared to its basal state. Similar results were observed in the protein expression level of glucose transporter 4 (GLUT4). Our data indicate that the alteration of 11beta-HSD1 at protein and mRNA level may be related to the abnormality of insulin signal pathway in skeletal muscle, this effect may be mediated by glucocorticoid receptor.
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PMID:Alteration of 11beta-hydroxysteroid dehydrogenase type 1 in skeletal muscle in a rat model of type 2 diabetes. 1911 9

Layer and broiler chickens demonstrate striking differences in body weight and body composition. However, the mechanism underlying such difference is elusive. Hypothalamus-pituitary-adrenal (HPA) axis regulates energy homeostasis and body size in mammals, but information in birds is scarce. Here we test the hypothesis that such breed difference is more associated with hypothalamic expression of genes related to HPA axis, rather than orexigenic neuropeptides. Broiler chicks exhibit significantly higher body weight and food intake at day (D) 7 posthatching, but the food intake relative to body weight gain was actually lower. No breed differences were observed for hypothalamic expression of neuropeptide Y (NPY), agouti-related protein (AGRP), proopiomelanocortin (POMC), orexin (ORX), leptin receptor (LEPR), acetyl-CoA carboxylase (ACC) or fatty acid synthase (FAS). However, broiler chicks expressed significantly higher glucocorticoid receptor (GR) mRNA (P<0.05) and protein (P<0.01) in hypothalamus compared to layer chicks, which is associated with lower corticotropin-releasing hormone (CRH) mRNA (P<0.05) yet higher accumulation of CRH peptide in hypothalamus, suggesting an augmented GR-mediated negative feedback regulation of CRH transcription and release in broiler chicks. Furthermore, fat mass and obesity associated (FTO) gene was also more highly expressed in hypothalamus of broiler chicks (P<0.05). These results suggest that the genes related to energy homeostasis and obesity, such as GR, CRH and FTO, rather than orexigenic neuropeptides, are impacted by the genetic selection practices and play a role in breed-specific body weight setpoint regulation in the chicken.
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PMID:Layer and broiler chicks exhibit similar hypothalamic expression of orexigenic neuropeptides but distinct expression of genes related to energy homeostasis and obesity. 1934 99


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