RU-486 (Mifepristone) ameliorates diabetes but does not correct deficient β-adrenergic signalling in adipocytes from mature C57BL/6J-ob/ob mice

Gettys, Thomas W.; Watson, Patricia M.; Taylor, Ian L.; Collins, Sheila

doi:10.1038/sj.ijo.0800479

Cited by 46 publications

(30 citation statements)

References 22 publications

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“…Glucocorticoids have been shown to repress the transcription of the b 1 AR and b 3 AR genes in adipocyte cell lines 38 (and our unpublished observations) and increase transcription of the b 2 AR gene. 39 Because adrenalectomy or treatment with RU-486 ameliorates the obesity in obaob mice and Zucker fatty rat, 40 ± 42 and more recently has been shown to substantially restore expression of b 3 AR, 43,44 it suggests that this endocrine feature contributes signi®cantly to the overall severity of the defects in adipocyte bAR expression in these animals. However, hypercorticism clearly does not account for the impaired bAR expression in the other mice we have studied, since their glucocorticoid concentrations are normal.…”

Section: Discussionmentioning

confidence: 99%

Depressed expression of adipocyte β-adrenergic receptors is a common feature of congenital and diet-induced obesity in rodents

1999

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OBJECTIVE: To determine whether the dramatic reduction in expression and functional activity of the b 3 -adrenergic receptor (AR) and b 1 AR subtypes originally observed in adipose tissue of the C57BLa6J Lep ob a Lep ob (`obese') mouse are general features of all models of obesity, and whether obesity-related differences in bAR subtype expression occur between adipose depots. DESIGN: Survey of adipose tissue bAR expression from four mouse models of congenital obesity: the`obese' mouse (C57BLa6J Lep ob a Lep ob ), the`diabetic' mouse (C57BLaKsJ LepR db aLepR db ), the`tubby' mouse (C57BLa6J tubatub) and the`fat' mouse (C57BLaKsJ Cpe fat aCpe fat ), and in a model of high-fat diet-induced obesity in C57BLa6J mice. MEASUREMENTS: Expression of the bAR subtypes was measured by Northern blot hybridization in white and brown adipose depots. RESULTS: In the severely obese Lep ob and LepR db mice, mRNA concentrations of b 3 AR and b 1 AR in white adipose tissue (WAT) were decreased by b 99% and by b 70%, respectively. More modest effects on b 3 AR expression were observed in brown adipose tissue (BAT, decreased by 20 ± 30%). In less severe forms of obesity, as found in the tubby and carboxypeptidase (Cpe) fat mice, and in diet-induced obese B6 mice, b 3 AR expression was decreased in WAT by up to 90%, with more modest decreases in interscapular BAT (IBAT). Changes in b 1 AR mRNA concentrations were more variable. b 2 AR mRNA levels did not differ in most cases, with the exception that there was a 3 ± 5-fold increase in BAT for both Lep ob and LepR db mice. CONCLUSIONS: Impaired expression of adipocyte bAR subtypes is a general feature of both genetic and dietary obesity in mice. The degree of obesity is correlated with the extent of loss of b 3 AR and b 1 AR expression in WAT. The distinct endocrine abnormalities associated with these obesity models may be responsible for the degree of impaired adipocyte bAR expression.

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Section: Discussionmentioning

confidence: 99%

Depressed expression of adipocyte β-adrenergic receptors is a common feature of congenital and diet-induced obesity in rodents

1999

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“…The plasma corticosterone level is significantly increased in diabetic mice and STZ-injected rats [31,32]. In addition, the increased BGL was recovered by mifepristone (RU486), a glucocorticoid receptor antagonist, in db/db mice [33,34,35]. In an attempt to examine whether the glucocorticoid system is involved in the hypoglycemic effect induced by i.t.…”

Section: Discussionmentioning

confidence: 99%

Pertussis Toxin Administered Spinally Induces a Hypoglycemic Effect on Normal and Diabetic Mice

et al. 2014

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Background/Aims: To show whether intrathecal (i.t.) treatment with pertussis toxin (PTX) produces a hypoglycemic effect in ICR, db/db and streptozotocin-treated mice. Methods: The blood glucose level (BGL) was measured after i.t. treatment with PTX, AB₅ toxins and PTX subunits. Insulin or leptin levels were measured after PTX injection. The effect of PTX on the BGL was examined in adrenalectomized (ADX) mice. Glucose transporter (GLUT) levels were determined by Western blotting. Results: PTX attenuated the elevated BGL in the D-glucose-fed model in a long-term manner. Heat-labile toxin (HLT), HLT subunit B or Shiga toxin, which belong to the AB₅ toxins, administered i.t. did not affect the BGL. PTX A protomer (PTX-A) or PTX B oligomers (PTX-B) injected i.t. did not have an effect on the BGL as well. However, combined treatment with PTX-A and PTX-B subunits caused a hypoglycemic effect. The leptin level was gradually reduced by PTX for up to 6 days, without affecting the insulin level. PTX administered i.t. significantly decreased the BGL further in ADX mice. Moreover, GLUT-2 (hypothalamus and pituitary gland), GLUT-4 (muscle) and GLUT-3 (adrenal gland) expression levels were increased, whereas GLUT-1 (brain cortex, liver, muscle and spinal cord), GLUT-2 (liver) and GLUT-3 (brain cortex and pituitary gland) expression levels were decreased. Discussion: Our data suggest that PTX administered spinally produces a hypoglycemic effect in a long-term manner, and PTX-induced hypoglycemia appears to be mediated by the reduction in activity of the glucocorticoid system. Furthermore, PTX may modulate the insulin level during hypoglycemia. Among GLUTs, GLUT-4 in muscle, GLUT-2 in the liver, hypothalamus and pituitary gland as well as GLUT-1 in the adrenal gland may be responsible for PTX-induced hypoglycemia.

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“…A potential role for RU486 in obesity and related disorders such as diabetes and hypertension has been suggested on the basis of its anti-glucocorticoid effect [2,4,10,11,14] and not on a possible direct action on adipose tissue. However, in a previous study, in which RU486 was used as a tool for inhibiting progesterone effects, we showed a possible direct effect in vitro on the expression of uncoupling proteins (UCPs) in brown adipocytes [19].…”

Section: Introductionmentioning

confidence: 99%

The steroid RU486 induces UCP1 expression in brown adipocytes

Rodríguez

Palou

2004

Pflugers Arch - Eur J Physiol

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RU486 (mifepristone), a potent antagonist at progesterone and glucocorticoid receptors (PR and GR), is well known for its use in the termination of unwanted pregnancies, the potential development of oral contraceptives, treatment of certain cancers and other activities. Potentially, it could also play a role in obesity control, although the few studies that have addressed this aspect have focused mainly on its central and anti-glucocorticoid effects. We have shown previously that it could have a direct effect on brown adipocytes in culture when administered together with progesterone. The aim of the present work was to analyse the effects of RU486 on the expression of uncoupling proteins (UCPs) in brown adipocytes. In culture-grown, differentiated brown adipocytes, placed in a serum-free medium to exclude the presence of progesterone or glucocorticoids, RU486 stimulated UCP1 expression at both the mRNA and protein levels. These effects could be mediated by PR, GR or other unknown mechanisms but do not seem to be due to its anti-progestin or anti-glucocorticoid actions. The results suggest that the steroid RU486 has a direct action on adipocytes which could be useful for stimulating non-shivering BAT thermogenesis and therefore is of interest in obesity studies.

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RU-486 (Mifepristone) ameliorates diabetes but does not correct deficient β-adrenergic signalling in adipocytes from mature C57BL/6J-ob/ob mice

Cited by 46 publications

References 22 publications

Depressed expression of adipocyte β-adrenergic receptors is a common feature of congenital and diet-induced obesity in rodents

Depressed expression of adipocyte β-adrenergic receptors is a common feature of congenital and diet-induced obesity in rodents

Pertussis Toxin Administered Spinally Induces a Hypoglycemic Effect on Normal and Diabetic Mice

The steroid RU486 induces UCP1 expression in brown adipocytes

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