Selective Glucocorticoid Receptor (GR-II) Antagonist Reduces Body Weight Gain in Mice

Asagami, Tomoko; Belanoff, Joseph K.; Azuma, Junya; Blasey, Christine; Clark, Robin D.; Tsao, Philip S.

doi:10.1155/2011/235389

Cited by 28 publications

(24 citation statements)

References 23 publications

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“…Interestingly, clear antagonist effects on the brain were accompanied by lack of negative-feedback inhibition of the HPA axis, which in itself suggests the possibility of antagonizing a number of GR effects without affecting systemic basal glucocorticoid levels and the associated change in activity of, for example, MR-dependent processes (33). C108297 is expected to have selective modulator effects also in peripheral tissues that we did not examine here (34). We did not determine binding to MRs and PRs or specific MR/PR readouts here, but previous studies showed 0% displacement from MR and 26% from PR at 10 μM C108297, i.e., over a 1000-fold selectivity for GR (18).…”

Section: Discussionmentioning

confidence: 95%

Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator

Zalachoras

Houtman²,

Atucha

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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104

137

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Glucocorticoid receptor (GR) antagonism may be of considerable therapeutic value in stress-related psychopathology such as depression. However, blockade of all GR-dependent processes in the brain will lead to unnecessary and even counteractive effects, such as elevated endogenous cortisol levels. Selective GR modulators are ligands that can act both as agonist and as antagonist and may be used to separate beneficial from harmful treatment effects. We have discovered that the high-affinity GR ligand C108297 is a selective modulator in the rat brain. We first demonstrate that C108297 induces a unique interaction profile between GR and its downstream effector molecules, the nuclear receptor coregulators, compared with the full agonist dexamethasone and the antagonist RU486 (mifepristone). C108297 displays partial agonistic activity for the suppression of hypothalamic corticotropin-releasing hormone (CRH) gene expression and potently enhances GR-dependent memory consolidation of training on an inhibitory avoidance task. In contrast, it lacks agonistic effects on the expression of CRH in the central amygdala and antagonizes GR-mediated reduction in hippocampal neurogenesis after chronic corticosterone exposure. Importantly, the compound does not lead to disinhibition of the hypothalamus-pituitary-adrenal axis. Thus, C108297 represents a class of ligands that has the potential to more selectively abrogate pathogenic GR-dependent processes in the brain, while retaining beneficial aspects of GR signaling.HPA axis | neuroendocrinology | steroid pharmacology | transcription regulation | NCoA1

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Section: Discussionmentioning

confidence: 95%

Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator

Zalachoras

Houtman²,

Atucha

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

104

137

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“…In fact, the absolute masses of all three fat depots were significantly reduced in the mifepristone post-WL group vs. the placebotreated animals. Previously, it had been shown that mifepristone treatment reduced adipose tissue mass gain and body weight gain in rodent models of diet-induced obesity (3,28,56). In addition, 2-4 wk of mifepristone treatment reduced risperidone-and olanzapine-induced weight gain in healthy men (23,24).…”

Section: Adiposity Rebound After Daily Exercise and Cr Is Stoppedmentioning

confidence: 98%

Glucocorticoid antagonism limits adiposity rebound and glucose intolerance in young male rats following the cessation of daily exercise and caloric restriction

Teich

Dunford

Porras

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Teich T, Dunford EC, Porras DP, Pivovarov JA, Beaudry JL, Hunt H, Belanoff JK, Riddell MC. Glucocorticoid antagonism limits adiposity rebound and glucose intolerance in young male rats following the cessation of daily exercise and caloric restriction. Am J Physiol Endocrinol Metab 311: E56 -E68, 2016. First published May 3, 2016 doi:10.1152/ajpendo.00490.2015.-Severe caloric restriction (CR), in a setting of regular physical exercise, may be a stress that sets the stage for adiposity rebound and insulin resistance when the food restriction and exercise stop. In this study, we examined the effect of mifepristone, a glucocorticoid (GC) receptor antagonist, on limiting adipose tissue mass gain and preserving whole body insulin sensitivity following the cessation of daily running and CR. We calorically restricted male Sprague-Dawley rats and provided access to voluntary running wheels for 3 wk followed by locking of the wheels and reintroduction to ad libitum feeding with or without mifepristone (80 mg·kg Ϫ1 ·day Ϫ1 ) for 1 wk. Cessation of daily running and CR increased HOMA-IR and visceral adipose mass as well as glucose and insulin area under the curve during an oral glucose tolerance test vs. pre-wheel lock exercised rats and sedentary rats (all P Ͻ 0.05). Insulin sensitivity and glucose tolerance were preserved and adipose tissue mass gain was attenuated by daily mifepristone treatment during the post-wheel lock period. These findings suggest that following regular exercise and CR there are GC-induced mechanisms that promote adipose tissue mass gain and impaired metabolic control in healthy organisms and that this phenomenon can be inhibited by the GC receptor antagonist mifepristone. exercise; caloric restriction; glucocorticoid antagonism; glucose intolerance; adiposity rebound REPEATED BOUTS OF WEIGHT LOSS and weight regain, termed weight cycling, have been associated with a greater risk for developing cardiovascular disease and type 2 diabetes over time (5,20,26). Although caloric restriction (CR) and regular exercise reduce body fat content and improve metabolic health (74), a key component to their success is adherence. Following weight loss from CR in overweight or obese individuals, nearly one-half of the weight is regained within one year (16). This weight regain is associated with a marked deterioration in whole body insulin sensitivity, which may occur via increased adipose tissue hypertrophy and hyperplasia, changes in neuroendocrine inputs to adipose tissue (43), and reductions in skeletal muscle insulin sensitivity (32). Although regular exercise attenuates the metabolic drive to regain weight after long-term weight loss in animal models (44), humans tend to relapse toward more sedentary behavior after lifestyle interventions (79). Humans (1, 25, 31, 52, 57, 73) and rodents (13, 32-34, 36, 37) rapidly develop significant insulin resistance, glucose intolerance, and visceral fat growth when increased physical activity or dieting stops. Additionally, the reintroduction to ad libitum feeding followi...

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“…By contrast, higher amounts (20-100 mg/kg) and longer treatments are often reported in the literature. [54][55][56][57] Lack of Bcl-X L increases photoreceptor vulnerability to some stressors, but would not be a direct cause of photoreceptor damage. 58 MFP induced disappearance of Bcl-X L in all retinal cell phenotypes; however, only photoreceptors were damaged after MFP administration.…”

Section: Mfp and Photoreceptor Deathmentioning

confidence: 99%

Mifepristone, a Blocker of Glucocorticoid Receptors, Promotes Photoreceptor Death

Cubilla¹,

Bermúdez²,

Marquioni-Ramella³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Glucocorticoids are best known by their protective effect on retinal photoreceptor damage. However, they could also be involved in photoreceptor homeostasis under basal, nonstressful conditions. Therefore, we aimed to study glucocorticoid-induced changes of survival-related molecules in male mice retinas under standard illumination conditions (12 hours light, 60 lux/12 h dark).METHODS. Male Balb-c mice were injected with dexamethasone (DEX), a selective glucocorticoid receptor a (GRa) agonist, its antagonist mifepristone (MFP), or both drugs (DþM) at noon. A group of mice was subjected to surgical adrenalectomy (AdrX). Retinas were studied by histology, immunohistochemistry, TUNEL procedure, and Western blotting at different periods after pharmacological or surgical intervention (6 hours, 48 hours, or 7 days). RESULTS.The antiapoptotic molecule Bcl-X L significantly increased 6 hours after DEX injection. By contrast, this molecule could no longer be found after MFP injection. At the same time, high levels of cleaved caspase-3 (CC-3) and Bax appeared in retinal extracts, and TUNEL þ nuclei selectively showed in the outer nuclear layer (ONL). After MFP, retinal extracts also contained phosphorylated histone H2AX (p-H2AX), a marker of DNA breakage and repair. Loss of ONL nuclear rows and decrease of rhodopsin levels were evident 7 days after MFP administration. These changes were minimized when DEX was given together with MFP (DþM). In the absence of MFP, DEX increased Bcl-X L in every retinal layer, with a marked intensification in photoreceptor inner segments. Numerous TUNEL þ nuclei rapidly appeared in the ONL after AdrX. CONCLUSIONS.A single dose of MFP induced selective photoreceptor damage in the absence of other environmental stressors. Because damage was prevented by DEX, and was reproduced by AdrX, our findings suggest that glucocorticoids play a critical role in photoreceptor survival. (Invest Ophthalmol Vis Sci. 2013;54:313-322)

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Selective Glucocorticoid Receptor (GR-II) Antagonist Reduces Body Weight Gain in Mice

Cited by 28 publications

References 23 publications

Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator

Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator

Glucocorticoid antagonism limits adiposity rebound and glucose intolerance in young male rats following the cessation of daily exercise and caloric restriction

Mifepristone, a Blocker of Glucocorticoid Receptors, Promotes Photoreceptor Death

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