Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase in Adipose Tissue

Seckl, Jonathan R.

doi:10.1210/rp.59.1.359

Cited by 214 publications

(164 citation statements)

References 147 publications

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“…11b-HSDs catalyze the interconversion between active glucocorticoids (cortisol, corticosterone) and their inert 11-keto forms (cortisone, 11-dehydrocorticosterone, 11-DHC). 11b-HSD type 1 (11b-HSD-1) is an NADP(H)-dependent isoenzyme, predominantly acting as a reductase in vivo, converting inactive into active glucocorticoids (for a review, see, Seckl et al 38 ). It is expressed in most peripheral tissues, as well as in hippocampal neurons, 39,40 and in neurons of the arcuate and paraventricular hypothalamic nuclei.…”

Section: Glucocorticoids and Neuropeptide Ymentioning

confidence: 99%

Role of glucocorticoids in the physiopathology of excessive fat deposition and insulin resistance

2004

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Glucocorticoids are important hormones in the regulation of metabolic homeostasis. We infused normal rats with dexamethasone given intracerebroventricularly (i.c.v.) for 3 days. This resulted in hyperphagia, hyperinsulinemia, and marked insulin resistance. Similar metabolic defects were observed following i.c.v. infusion of neuropeptide Y (NPY) in normal rats. As central dexamethasone infusion enhanced NPY content in the arcuate nucleus, it suggested that its metabolic effects are mediated by NPY. Moreover, due to the lack of effects observed in vagotomized animals, activation of the parasympathetic nervous system by central dexamethasone infusion is proposed. Glucocorticoid action is known to involve prereceptor metabolism by enzymes such as 11b-HSD-1 that converts inactive into active glucocorticoids. Mice overexpressing 11b-HSD-1 in adipose tissue were shown to be obese and insulin resistant. We recently observed that adipose tissue 11b-HSD-1 mRNA expression is increased at the onset of high-fat diet-induced obesity and positively correlated with the degree of hyperglycemia. In human obesity, increased adipose tissue 11b-HSD-1 expression and activity were also reported. Resistin is a new adipose tissue-secreted hormone shown to play a role in glucose homeostasis by increasing hepatic glucose production and inhibiting muscle and adipose tissue glucose utilization. We observed increased adipose tissue resistin expression in the early phase of highfat diet-induced obesity as well as decreased resistin expression in response to leptin. A positive correlation between glycemia and adipose tissue resistin expression further suggested a role of this hormone in the development of insulin resistance. The melanocortin system is another important player in the regulation of energy balance. Peripheral administration of a melanocortin agonist decreased food intake and body weight and favored lipid oxidation, effects that were more marked in obese than in lean rats. It is proposed that both resistin and melanocortin agonists may influence adipose tissue 11b-HSD-1, thereby decreasing or enhancing glucose metabolism.

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Section: Glucocorticoids and Neuropeptide Ymentioning

confidence: 99%

Role of glucocorticoids in the physiopathology of excessive fat deposition and insulin resistance

2004

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“…9 The enzyme generates active GC (cortisol in humans and corticosterone in the rat) from inactive forms (cortisone and 11-dehydrocorticosterone), and it plays a central role in regulating intracellular GC concentration and action in adipose tissue and liver. 17 Overexpression of 11b-HSD1 in adipose tissue results in a phenotype resembling the metabolic syndrome, whereas whole-body specific inhibition of 11b-HSD1 by genetic or pharmacologic means results in overall metabolic improvement. 17 Because of the potential importance of local modulation of GC action in adipose tissue lipid metabolism, the present study aimed to assess whether defeating the PPARg-induced reduction in adipose tissue GC amplification via 11b-HSD1, achieved through introduction of an exogenous source of GC, would impact the beneficial global metabolic actions of PPARg agonism, namely insulin sensitization and reduction in lipemia.…”

Section: Introductionmentioning

confidence: 99%

“…17 Overexpression of 11b-HSD1 in adipose tissue results in a phenotype resembling the metabolic syndrome, whereas whole-body specific inhibition of 11b-HSD1 by genetic or pharmacologic means results in overall metabolic improvement. 17 Because of the potential importance of local modulation of GC action in adipose tissue lipid metabolism, the present study aimed to assess whether defeating the PPARg-induced reduction in adipose tissue GC amplification via 11b-HSD1, achieved through introduction of an exogenous source of GC, would impact the beneficial global metabolic actions of PPARg agonism, namely insulin sensitization and reduction in lipemia. In addition, because the GC and PPARg pathways share several common targets in adipose lipid metabolism, the study also aimed at investigating their interactions on the expression of major genes of adipose tissue lipid uptake, storage, lipolysis, recycling, and oxidation.…”

Section: Introductionmentioning

confidence: 99%

Metabolic action of peroxisome proliferator-activated receptor γ agonism in rats with exogenous hypercorticosteronemia

et al. 2007

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Objective: The beneficial metabolic actions of peroxisome proliferator-activated receptor g (PPARg) agonism are associated with modifications in adipose tissue metabolism that include a reduction in local glucocorticoid (GC) production by 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1). This study aimed to assess the contribution of GC attenuation to PPARg agonism action on gene expression in visceral adipose tissue and global metabolic profile. Design: Rats were treated (2 weeks) with the PPARg agonist rosiglitazone (RSG, 10 mg/kg/day) with concomitant infusion of vehicle (cholesterol implant) or corticosterone (HiCORT, 75 mg/implant/week) to defeat PPARg-mediated GC attenuation. Measurements: mRNA levels of enzymes involved in lipid uptake (and lipoprotein lipase activity), storage, lipolysis, recycling, and oxidation in retroperitoneal white adipose tissue (RWAT). Serum glucose, insulin and lipids, and lipid content of oxidative tissues. Results: Whereas HiCORT did not alter RWAT mass, RSG increased the latter ( þ 33%) independently of the corticosterone status. Both HiCORT and RSG increased lipoprotein lipase activity, the mRNA levels of the de novo lipogenesis enzyme fatty acid synthase, and that of the fatty acid retention-promoting enzyme acyl-CoA synthase 1, albeit in a nonadditive fashion. Expression level of the lipolysis enzyme adipose triglyceride lipase was increased additively by HiCORT and RSG. PPARg agonism increased mRNA of the fatty acid recycling enzymes glycerol kinase and cytosolic phosphoenolpyruvate carboxykinase and those of the fatty acid oxidation enzymes muscle-type carnitine palmitoyltransferase 1 and acyl-CoA oxidase, whereas HiCORT remained without effect. HiCORT resulted in liver steatosis and hyperinsulinemia, which were abrogated by RSG, whereas the HiCORTinduced elevation in serum nonesterified fatty acid levels was only partially prevented. The hypotriglyceridemic action of RSG was maintained in HiCORT rats. Conclusion: The GC and PPARg pathways exert both congruent and opposite actions on specific aspects of adipose tissue metabolism. Both the modulation of adipose gene expression and the beneficial global metabolic actions of PPARg agonism are retained under imposed high ambient GC, and are therefore independent from PPARg effects on 11b-HSD1-mediated GC production.

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“…The ratio of 17␤ hydroxysteroid dehydrogenase to aromatase increases in obesity and has been associated with insulin resistance and hyperlipidemia in menopausal women (9). The oxidoreductase, 11␤ hydroxysteroid dehydrogenase type 1, mediates the conversion of cortisone to cortisol in humans and 11-dehydrocorticosterone to corticosterone in mice (10). Excess local production of active glucocorticoids has been implicated in central obesity, elevated glucose, and lipid levels and cardiovascular morbidity (10 -15).…”

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confidence: 99%

Brain Adipocytokine Action and Metabolic Regulation

et al. 2006

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Adipose tissue secretes factors that control various physiological systems. The fall in leptin during fasting mediates hyperphagia and suppresses thermogenesis, thyroid and reproductive hormones, and immune system. On the other hand, rising leptin levels in the fed state stimulate fatty acid oxidation, decrease appetite, and limit weight gain. These divergent effects of leptin occur through neuronal circuits in the hypothalamus and other brain areas. Leptin also regulates the activities of enzymes involved in lipid metabolism, e.g., AMP-activated protein kinase and stearoyl-CoA desaturase-1, and also interacts with insulin signaling in the brain. Adiponectin enhances fatty acid oxidation and insulin sensitivity, in part by stimulating AMP-activated protein kinase phosphorylation and activity in liver and muscle. Moreover, adiponectin decreases body fat by increasing energy expenditure and lipid catabolism. These effects involve peripheral and possibly central mechanisms. Adipose tissue mediates interconversion of steroid hormones and secretes proinflammatory cytokines, vasoactive peptides, and coagulation and complement proteins. Understanding the actions of these "adipocytokines" will provide insight into the pathogenesis and treatment of obesity and related diseases. Diabetes 55 (Suppl. 2): S145-S154, 2006 ADIPOSE TISSUE

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Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase in Adipose Tissue

Cited by 214 publications

References 147 publications

Role of glucocorticoids in the physiopathology of excessive fat deposition and insulin resistance

Role of glucocorticoids in the physiopathology of excessive fat deposition and insulin resistance

Metabolic action of peroxisome proliferator-activated receptor γ agonism in rats with exogenous hypercorticosteronemia

Brain Adipocytokine Action and Metabolic Regulation

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