Effects of antiglucocorticoid RU 486 on development of obesity in obese fa/fa Zucker rats

Langley, Simon C.; York, David A.

doi:10.1152/ajpregu.1990.259.3.r539

Cited by 65 publications

(63 citation statements)

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“…31 Similar conclusions were reached in studies using the glucocorticoid receptor antagonist, RU-486, in that receptor blockade at or near weaning prevented development of the obese phenotype, while administration at later ages was ineffective. 12,14 Findings from the present study are consistent with both sets of studies in the sense that RU-486 treatment did not lessen the severity of obesity in ob/ob mice, but did correct their hyperglycemia and reduce insulin concentrations by 50%. One might question why hyperinsulinemia persisted despite the correction of hyperglycemia.…”

Section: Discussionsupporting

confidence: 86%

“…This vehicle and dosage have previously been shown to produce effective glucocorticoid receptor blockade in rodents. 14,15 All animals were killed on day 22 and blood samples were obtained for assay of glucose and insulin as previously described. 16 …”

Section: Experimental Animal Protocolmentioning

confidence: 99%

“…48 Thus, the failure of RU-486 to fully correct hyperinsulinemia in ob/ob mice may have prevented complete restoration of b 3 -AR expression. Given that adrenalectomy or RU-486 treatment at younger ages is more effective in correcting hyperinsulinemia in obese rodents, 10,11,14,31 it will be interesting to see if a similar experimental approach will fully restore b 3 -AR expression. Recent work has shown that b 3 -AR expression is also modulated by thyroid status.…”

Section: Ru-486 Ameliorates Diabetesmentioning

confidence: 99%

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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

et al. 1997

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OBJECTIVE: To investigate the role of hypercorticism in the development of compromised b-adrenergic signalling in adipocytes of mature C57BL/6J-ob/ob mice. DESIGN AND EXPERIMENTAL UNITS: Mature male ob/ob mice and their lean littermates were treated with vehicle or the speci®c glucocorticoid receptor (GR) antagonist, RU-486 (30 mg/kg bw/d) for 21 d. MEASUREMENTS: Blood glucose, serum insulin, adipocyte Glut-4 expression, adipocyte G s a expression, adenylylcyclase activation by b-adrenergic receptor (b-AR) agonists in adipocyte membranes and mRNA levels for b 1 -, b 2 -and b 3 -adrenergic receptor subtypes in adipocytes. RESULTS: RU-486 reduced blood glucose levels in ob/ob mice to levels that were not different from lean mice. RU-486 also reduced serum insulin by approximately 50% in ob/ob mice, but failed to restore depressed G s a or GLUT-4 expression in adipocytes of ob/ob mice. RU-486 produced a two-fold increase in b 3 -AR mRNA in ob/ob mice and a small but signi®cant improvement in isoprenaline-mediated adenylylcyclase activation. CONCLUSIONS: The present results indicate that glucocorticoid antagonism ameliorates diabetic symptoms of the mature ob/ob mouse, but does not lessen their obesity or fully reverse de®cient expression and function of components of the adipocyte b-adrenergic signalling cascade.

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Section: Discussionsupporting

confidence: 86%

Section: Experimental Animal Protocolmentioning

confidence: 99%

Section: Ru-486 Ameliorates Diabetesmentioning

confidence: 99%

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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

et al. 1997

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“…Adrenalectomy and corticosterone replacement failed to normalize fed glucose values in the ob/ob mouse 18 . Similar results were observed following treatment with the glucocorticoid receptor antagonist RU486 in the Zucker (fa/fa) rat, with no effect of antiglucocorticoid treatment on fed glucose levels 19 . In contrast, treatment with antisense oligonucleotides directed against the glucocorticoid receptor restored normal fasting glucose levels in Zucker diabetic rats 20 .…”

Section: Discussionsupporting

confidence: 72%

Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons

et al. 2008

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Multiple organ systems are adversely affected by diabetes, including the brain, which undergoes changes that may increase the risk of cognitive decline. Although diabetes influences the hypothalamic-pituitary-adrenal axis, the role of this neuroendocrine system in diabetes-induced cognitive dysfunction remains unexplored. Here we demonstrate that, in both insulin-deficient rats and insulin-resistant mice, diabetes impairs hippocampus-dependent memory, perforant path synaptic plasticity and adult neurogenesis, and the adrenal steroid corticosterone contributes to these adverse effects. Rats treated with streptozocin have reduced levels of insulin, and exhibit hyperglycemia, increased levels of corticosterone, and impairments in hippocampal neurogenesis, synaptic plasticity and learning. Similar deficits are observed in db/db mice, which are characterized by insulin resistance, elevated corticosterone levels and obesity. Changes in hippocampal plasticity and function in both models are reversed when normal physiological levels of corticosterone are maintained, suggesting that cognitive impairment in diabetes may result from glucocorticoidmediated deficits in neurogenesis and synaptic plasticity. Keywords glucocorticoid; dentate gyrus; streptozotocin; water maze; object recognition As a result of high calorie diets and sedentary lifestyles, diabetes is rapidly becoming more prevalent in Western societies 1 . In addition to its well-known adverse effects on the cardiovascular and peripheral nervous systems, diabetes also appears to negatively impact the brain, increasing the risk of depression and dementia2 , 3 . Human subjects with either type 1 (caused by insulin deficiency) or type 2 (mediated by insulin resistance) diabetes typically exhibit impaired cognitive function compared to age-matched non-diabetic subjects 3,4 . Cognitive deficits have also been documented in studies of rodent models of diabetes. For Supplementary Information accompanies this paper.Competing interests statement. The authors declare that they have no competing financial interests. Conflict of Interest:The authors declare no conflict of interest. NIH Public Access Author ManuscriptNat Neurosci. Author manuscript; available in PMC 2010 August 25. Published in final edited form as:Nat Neurosci. 2008 March ; 11(3): 309-317. doi:10.1038/nn2055. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript example, rats rendered diabetic by treatment with the pancreatic β-cell toxin streptozocin (STZ; a model of type 1 diabetes) exhibit impaired performance in tests of spatial learning ability 5, 6. Similar deficits have been reported in the db/db mouse7, a model of Type 2 diabetes in which obesity, hyperglycemia, and elevations in circulating corticosterone levels arise from a mutation that inactivates the leptin receptor 8 . However, the mechanism(s) responsible for cognitive dysfunction in diabetes has not been established.Within the hippocampus, changes in the strength of synapses between groups of neurons play a critic...

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“…7). RU486 treatment in mammals often causes elevations in plasma corticosterone due to inhibition of negative feedback in the hypothalamus and pi-tuitary (Langley and York 1990;Cooney and Dinan 1996). Thus, data from this study suggest that negative feedback in the red knot may be independent of GR occupation.…”

Section: Discussionmentioning

confidence: 59%

Role of the Low‐Affinity Glucocorticoid Receptor in the Regulation of Behavior and Energy Metabolism in the Migratory Red KnotCalidris canutus islandica

Landys¹,

Piersma²,

Ramenofsky³

et al. 2004

Physiological and Biochemical Zoology

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Role of the low-affinity glucocorticoid receptor in the regulation of behavior and energy metabolism in the migratory red knot Calidris canutus islandica Landys, MM; Piersma, Theun; Ramenofsky, M; Wingfield, JC; Wingfield, John C. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. ABSTRACTPlasma corticosterone increases in association with migratory flight in the red knot Calidris canutus islandica, suggesting that corticosterone may promote migratory activity and/or energy mobilization in this species. This hypothesis is supported by general effects of glucocorticoids, which include stimulation of locomotion and the mobilization of energy depots. We experimentally examined the role of elevated corticosterone levels in the migratory red knot by comparing foraging behavior, flight frequency, and plasma metabolites between vehicle-injected controls and birds treated with RU486, an antagonist to the genomic low-affinity glucocorticoid receptor (GR). We predicted that RU486 treatment would interfere with energy mobilization. However, we expected no effects on flight activity because recent studies suggest that glucocorticoids affect locomotion through a nongenomic receptor. Finally, because glucocorticoids exert permissive effects on food intake, we postulated that RU486 treatment in the red knot would interfere with feeding. Results were consistent with the latter prediction, suggesting that the GR participates in the promotion of hyperphagia, the intense feeding state that is characteristic of the migratory condition. RU486 treatment did not affect flight fre- quency, suggesting that corticosterone may support migratory activity through a receptor other than the GR. Energy metabolism (as determined through plasma metabolites) was also unaffected by RU486, possibly because energetic demands experienced by captive birds were low.

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Effects of antiglucocorticoid RU 486 on development of obesity in obese fa/fa Zucker rats

Cited by 65 publications

References 0 publications

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

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

Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons

Role of the Low‐Affinity Glucocorticoid Receptor in the Regulation of Behavior and Energy Metabolism in the Migratory Red KnotCalidris canutus islandica

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