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Following extensive suprasellar operations for excision of hypothalamic tumors, some patients develop morbid obesity despite receiving replacement doses of glucocorticoids. Urine analysis of cortisol and cortisone metabolites show that 11-OH/11-oxo ratios are significantly higher in patients with hypothalamic obesity, indicating enhanced 11beta-HSD1 activity. This correlates with the visceral-to-subcutaneous fat ratio. The consequence of increased 11beta-HSD1 activity and a shift of the steroid inter-conversion towards cortisol may contribute to the effects of the latter in adipose tissue. The message from the hypothalamus to adipocyte 11beta-HSD-1 involves hormones, the sympathetic nervous system and cytokines. CRH and ACTH downregulate 11beta-HSD-1 activity and induce lipolysis. Tumor necrosis factor-alpha and interleukin-1beta upregulate 11beta-HSD-1 expression and activity, while enhancing lipolysis. The sympathetic nervous system exerts its effects through beta-adrenergic upregulation and alpha-adrenergic downregulation of 11beta-HSD-1 activity. Inhibition of 11beta-HSD-1 suppresses preadipocyte differentiation into mature adipocytes, and may provide a therapeutic tool.  相似文献   

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Mechanisms regulating adipocyte expression of resistin   总被引:29,自引:0,他引:29  
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In humans, oxoreducing 11beta-HSD-1 activity appears to be related to body fat distribution in male-type central obesity, but not in female-type peripheral obesity. We postulated that inhibition of 11beta-HSD-1 might have clinical therapeutic significance in oxoreducing mostly visceral fat and its metabolic activity. Our current study investigated the consequence at the cellular level of such inhibition. As an inhibitor of 11beta-HSD-1 activity, we used the licorice derivative carbenoxolone. Carbenoxolone has an inhibitory effect on the activity of both oxidizing 11beta-HSD-2, which converts cortisol to cortisone, and oxoreducing 11beta-HSD-1; yet, preadipocytes and adipocytes only express the latter. Preadipocytes were retrieved from omental and subcutaneous fat from healthy non-obese individuals and differentiated in vitro to mature adipocytes. Activity of 11beta-HSD-1 was assayed by measuring conversion of added 500 nM cortisone to cortisol. Expression of 11beta-HSD-1 mRNA was determined by real-time PCR, while lipolytic effects were determined by measuring glycerol and triglyceride concentration in the culture medium. Carbenoxolone decreased 11beta-HSD-1 activity in a dose-dependent manner with an IC-50 of 5X10 -6 M, but did not affect the expression of 11beta-HSD-1 mRNA. Cortisone stimulated subcutaneous, but not omental preadipocytes proliferation, an effect that was not abolished by carbenoxolone. Dexamethasone had a stimulatory effect on the maturation of both omental and subcutaneous preadipocytes. Carbenoxolone per se, either with or without cortisone, had a negative effect on preadipocyte maturation. Inhibiting 11beta-HSD-1 activity by carbenoxolone had no impact on leptin secretion. Thus, carbenoxolone has no effect on preadipocyte proliferation, but a dramatic inhibitory effect on preadipocyte differentiation into mature adipocytes. The mechanism is only partly related to its inhibitory effect on 11beta-HSD-1 activity. The present observations lend support to the presence of an intracrine loop of a hormone that is both produced from a precursor and active within the preadipocyte and adipocyte.  相似文献   

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Glutathione peroxidase 3 (GPx3) accounts for the major antioxidant activity in the plasma. Here, we demonstrate that down-regulation of GPx3 in the plasma of obese subjects is associated with adipose GPx3 dysregulation, resulting from the increase of inflammatory signals and oxidative stress. Although GPx3 was abundantly expressed in kidney, lung, and adipose tissue, we observed that GPx3 expression was reduced selectively in the adipose tissue of several obese animal models as decreasing plasma GPx3 level. Adipose GPx3 expression was greatly suppressed by prooxidative conditions such as high levels of TNFalpha and hypoxia. In contrast, the antioxidant N-acetyl cysteine and the antidiabetic drug rosiglitazone increased adipose GPx3 expression in obese and diabetic db/db mice. Moreover, GPx3 overexpression in adipocytes improved high glucose-induced insulin resistance and attenuated inflammatory gene expression whereas GPx3 neutralization in adipocytes promoted expression of proinflammatory genes. Taken together, these data suggest that suppression of GPx3 expression in the adipose tissue of obese subjects might constitute a vicious cycle to expand local reactive oxygen species accumulation in adipose tissue potentially into systemic oxidative stress and obesity-related metabolic complications.  相似文献   

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Abdominal visceral tissue (VAT) and subcutaneous adipose tissue (SAT), comprised of superficial‐SAT (sSAT) and deep‐SAT (dSAT), are metabolically distinct. The antidiabetic agents thiazolidinediones (TZDs), in addition to their insulin‐sensitizing effects, redistribute SAT suggesting that TZD action involves adipose tissue depot‐specific regulation. We investigated the expression of proteins key to adipocyte metabolism on differentiated first passage (P1) preadipocytes treated with rosiglitazone, to establish a role for the diverse depots of abdominal adipose tissue in the insulin‐sensitizing effects of TZDs. Adipocytes and preadipocytes were isolated from sSAT, dSAT, and VAT samples obtained from eight normal subjects. Preadipocytes (P1) left untreated (U) or treated with a classic differentiation cocktail (DI) including rosiglitazone (DIR) for 9 days were evaluated for strata‐specific differences in differentiation including peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) and lipoprotein lipase (LPL) expression, insulin sensitivity via adiponectin and glucose transport‐4 (GLUT4), glucocorticoid metabolism with 11β‐hydroxysteroid dehydrogenase type‐1 (11βHSD1), and alterations in the adipokine leptin. While depot‐specific differences were absent with the classic differentiation cocktail, with rosiglitazone sSAT had the most potent response followed by dSAT, whereas VAT was resistant to differentiation. With rosiglitazone, universal strata effects were observed for PPAR‐γ, LPL, and leptin, with VAT in all cases expressing significantly lower basal expression levels. Clear dSAT‐specific changes were observed with decreased intracellular GLUT4. Specific sSAT alterations included decreased 11βHSD1 whereas secreted adiponectin was potently upregulated in sSAT with respect to dSAT and VAT. Overall, the subcompartments of SAT, sSAT, and dSAT, appear to participate in the metabolic changes that arise with rosiglitazone administration.  相似文献   

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PPARgamma activators such as rosiglitazone (RSG) stimulate adipocyte differentiation and increase subcutaneous adipose tissue mass. However, in addition to preadipocyte differentiation, adipose tissue expansion requires neovascularization to support increased adipocyte numbers. Paradoxically, endothelial cell growth and differentiation is potently inhibited by RSG in vitro, raising the question of how this drug can induce an increase in adipose tissue mass while inhibiting angiogenesis. We find that adipose tissue from mice treated with RSG have increased capillary density. To determine whether adipose tissue angiogenesis was stimulated by RSG, we developed a novel assay to study angiogenic sprout formation ex vivo. Angiogenic sprout formation from equally sized adipose tissue fragments, but not from aorta rings, was greatly increased by obesity and by TZD treatment in vivo. To define the mechanism involved in RSG-stimulated angiogenesis in adipose tissue, the expression of proangiogenic factors by adipocytes was examined. Expression of VEGFA and VEGFB, as well as of the angiopoietin-like factor-4 (ANGPTL4), was stimulated by in vivo treatment with RSG. To define the potential role of these factors, we analyzed their effects on endothelial cell growth and differentiation in vitro. We found that ANGPTL4 stimulates endothelial cell growth and tubule formation, albeit more weakly than VEGF. However, ANGPTL4 mitigates the growth inhibitory actions of RSG on endothelial cells in the presence or absence of VEGF. Thus, the interplay between VEGF and ANGPTL4 could lead to a net expansion of the adipose tissue capillary network, required for adipose tissue growth, in response to PPARgamma activators.  相似文献   

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Clinical observations have highlighted the link between glucocorticoids and obesity. While exogenous glucocorticoids in excess predispose to the development of central obesity, we have focused on cortisol metabolism within human adipose tissue. 11beta-hydroxysteroid dehydrogenase (11beta-HSD) inter-converts the active glucocorticoid, cortisol, and inactive cortisone. 11beta-HSD1, the only isoform expressed in adipose tissue, acts predominantly as an oxoreductase to generate cortisol. Expression is higher in omental compared to subcutaneous preadipocytes and activity and expression are potently regulated by growth factors and cytokines. Mice over-expressing 11beta-HSD1 specifically within adipocytes develop central obesity. However, the situation is less clear in humans. Globally, there appears to be inhibition of the enzyme, but expression in human obesity is still not fully characterized; its functional role in adipocyte biology remains to be elucidated. In vitro, 11beta-HSD1 appears to function in promoting adipocyte differentiation and limiting preadipocyte proliferation, but the impact of these effects in vivo upon the regulation of fat mass remains to be defined. Clinical studies utilizing selective 11beta-HSD1 inhibitors may help to answer this question.  相似文献   

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To better define the mechanism of action of the thiazolidinediones, we incubated freshly isolated human adipocytes with rosiglitazone and investigated the changes in mRNA expression of genes encoding key proteins of adipose tissue functions. Rosiglitazone (10(-6) M, 4 h) increased p85alphaphosphatidylinositol 3-kinase (p85alphaPI-3K) and uncoupling protein-2 mRNA levels and decreased leptin expression. The mRNA levels of insulin receptor, IRS-1, Glut 4, lipoprotein lipase, hormone-sensitive lipase, acylation-stimulating protein, fatty acid transport protein-1, angiotensinogen, plasminogen activator inhibitor-1, and PPARgamma1 and gamma2 were not modified by rosiglitazone treatment. Activation of RXR, the partner of PPARgamma, in the presence of rosiglitazone, increased further p85alphaPI-3K and UCP2 mRNA levels and produced a significant augmentation of Glut 4 expression. Because p85alphaPI-3K is a major component of insulin action, the induction of its expression might explain, at least in part, the insulin-sensitizing effect of the thiazolidinediones.  相似文献   

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