Chronic UCN2 Treatment Desensitizes CRHR2 and Improves Insulin Sensitivity
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion Lumos
ORGANISM(S): Mus Musculus (ncbitaxon:10090)
SUBMITTER: 
Zhidan Wu
PROVIDER: MSV000092094 | MassIVE | Sun Jun 04 05:29:00 BST 2023
SECONDARY ACCESSION(S): PXD042709
REPOSITORIES: MassIVE
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Project description:Background: Methylphenidate (MPH) a psychostimulant prescribed to manage ADHD symptoms, has been increasingly prescribed to children not meeting the strict criteria for ADHD. It has also been misused as a “cognitive enhancer” and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of methylphenidate in mice at either 1mg/kg or 10mg/kg dosing, affects cell number and gene expression in the basal ganglion. Methodology/Principal findings: Through the use of stereological counting methods, we observed a significant reduction (~20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10mg/kg MPH. This dosage of MPH also induced a significant increase in the number of morphologically-activated SNpc microglia. Additionally, exposure to either 1mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopamine neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced oxidative stress. Unbiased gene screening employing Affymetrix GeneChip® HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1mg/kg and 10mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2 and th in the substantia nigra (SN) was observed with both acute and chronic dosing of 10mg/kg MPH. We also found an increase in mRNA levels of the pro-inflammatory genes il-6 and tnf-α in the striatum; although these were seen only at an acute dose of 10mg/kg and not following chronic dosing. Conclusion: Collectively our results suggest that chronic MPH usage in mice, especially at prolonged higher doses, has long-term neurodegenerative consequences.
2012-08-14 | GSE33619 | GEO
Project description:Tamoxifen, a selective estrogen receptor modulator (SERM), is an effective treatment for breast cancers. In the CD-1 mouse model, neonatal oral dosing with tamoxifen leads to the development of adenomyosis. Both 4-hydroxyestradiol and tamoxifen can form DNA-reactive metabolites and may be involved in carcinogenesis of the uterus. After comparing the uterotrophic response of several SERMs the maximal uterotrophic doses of estradiol (100mg/kg) 4-hydroxyestradiol (385mg/kg) and tamoxifen (250mg/kg) were determined. Maximal uterotrophic doses were given orally to newborn CD-1 mice on days 1 â 4 after birth and gene and pathological changes examined in the uterus at 3 months after dosing. ERKOa knockout mice were dosed orally with tamoxifen (1mg/Kg) on days 1 â 4 after birth and uterine gene expression compared with CD-1 mice. Dosing groups: Estradiol (E2): 100mg/Kg 4-hydroxyestradiol (4OHE2): 385mg/Kg Tamoxifen : 250mg/Kg ERKO mice dosed with tamoxifen (1mg/Kg) 4 dosed animals and 4 controls for each treatment group. Uteri removed at 3 months after dosing and total RNA extracted. Controls were pooled. RNA labelling, hybridisation and analysis of fluorescence was carried out as described by Turton et al (2001). Cy3/Cy5 dye swap labelling was carried out on samples from each animal. Reference: Turton NJ et. al. (Oncogene (2001) 20, 1300-1306
2010-06-30 | E-GEOD-3625 | biostudies-arrayexpress
Project description:Background: Methylphenidate (MPH) a psychostimulant prescribed to manage ADHD symptoms, has been increasingly prescribed to children not meeting the strict criteria for ADHD. It has also been misused as a “cognitive enhancer” and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of methylphenidate in mice at either 1mg/kg or 10mg/kg dosing, affects cell number and gene expression in the basal ganglion. Methodology/Principal findings: Through the use of stereological counting methods, we observed a significant reduction (~20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10mg/kg MPH. This dosage of MPH also induced a significant increase in the number of morphologically-activated SNpc microglia. Additionally, exposure to either 1mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopamine neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced oxidative stress. Unbiased gene screening employing Affymetrix GeneChip® HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1mg/kg and 10mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2 and th in the substantia nigra (SN) was observed with both acute and chronic dosing of 10mg/kg MPH. We also found an increase in mRNA levels of the pro-inflammatory genes il-6 and tnf-α in the striatum; although these were seen only at an acute dose of 10mg/kg and not following chronic dosing. Conclusion: Collectively our results suggest that chronic MPH usage in mice, especially at prolonged higher doses, has long-term neurodegenerative consequences. drug treatment: 3 control, 3 low dose treatment, 3 high dose treatment
2012-08-13 | E-GEOD-33619 | biostudies-arrayexpress
Project description:Tamoxifen, a selective estrogen receptor modulator (SERM), is an effective treatment for breast cancers. In the CD-1 mouse model, neonatal oral dosing with tamoxifen leads to the development of adenomyosis. Both 4-hydroxyestradiol and tamoxifen can form DNA-reactive metabolites and may be involved in carcinogenesis of the uterus. After comparing the uterotrophic response of several SERMs the maximal uterotrophic doses of estradiol (100mg/kg) 4-hydroxyestradiol (385mg/kg) and tamoxifen (250mg/kg) were determined. Maximal uterotrophic doses were given orally to newborn CD-1 mice on days 1 – 4 after birth and gene and pathological changes examined in the uterus at 3 months after dosing. ERKOa knockout mice were dosed orally with tamoxifen (1mg/Kg) on days 1 – 4 after birth and uterine gene expression compared with CD-1 mice. Keywords: Comparison of SERMs at maximal uterotrophic doses
2005-12-02 | GSE3625 | GEO
Project description:Background: The prevalence of type 2 diabetes has increased dramatically in recent decades. Increasing brown adipose tissue (BAT) mass and activity has recently emerged as an interesting approach to not only increase energy expenditure, but also improve glucose homeostasis. BAT can be recruited by prolonged cold exposure in lean, healthy humans. Here, we tested whether cold acclimation could have therapeutic value for patients with type 2 diabetes by improving insulin sensitivity. Methods: Eight type 2 diabetic patients (age 59.3±5.8 years, BMI 29.8±3.2 kg/m2) followed a cold acclimation protocol, consisting of intermittent cold exposure (6 hours/day, 14-14.5 °C) for 12 consecutive days. Before and after cold acclimation, cold-induced BAT activity was assessed by [18F]FDG-PET/CT scanning, insulin sensitivity at thermoneutrality by a hyperinsulinemic-euglycemic clamp, and muscle and WAT biopsies were taken. Results: Cold-induced BAT activity was low, but increased in all patients upon cold acclimation (SUV from 0.40±0.29 to 0.63±0.78, p<0.05). Interestingly, insulin sensitivity showed a very pronounced 40% increase upon cold acclimation (glucose rate of disappearance from 14.9±4.1 to 20.5±6.9 μmol kg-1 min-1, p<0.05). A 40% increase in insulin sensitivity cannot be explained by BAT glucose uptake, in fact basal skeletal muscle GLUT4 content and translocation was markedly increased after cold acclimation, without effects on insulin signaling or AMPk activation. Conclusions: Regular mild cold exposure has marked effects on insulin sensitivity, which are accompanied by small increases in BAT activity and more pronounced effects on skeletal muscle. These data suggest a novel therapeutic option for the treatment of type 2 diabetes. Microarray analysis was performed on abdominal subcutaneous white adipose tissue samples from human type 2 diabetic patients before, and after 10 days of cold acclimation. A total of 14 samples, from 7 subjects, were used for the microarray analysis.
2015-07-05 | E-GEOD-67297 | biostudies-arrayexpress
Project description:Background: The prevalence of type 2 diabetes has increased dramatically in recent decades. Increasing brown adipose tissue (BAT) mass and activity has recently emerged as an interesting approach to not only increase energy expenditure, but also improve glucose homeostasis. BAT can be recruited by prolonged cold exposure in lean, healthy humans. Here, we tested whether cold acclimation could have therapeutic value for patients with type 2 diabetes by improving insulin sensitivity. Methods: Eight type 2 diabetic patients (age 59.3±5.8 years, BMI 29.8±3.2 kg/m2) followed a cold acclimation protocol, consisting of intermittent cold exposure (6 hours/day, 14-14.5 °C) for 12 consecutive days. Before and after cold acclimation, cold-induced BAT activity was assessed by [18F]FDG-PET/CT scanning, insulin sensitivity at thermoneutrality by a hyperinsulinemic-euglycemic clamp, and muscle and WAT biopsies were taken. Results: Cold-induced BAT activity was low, but increased in all patients upon cold acclimation (SUV from 0.40±0.29 to 0.63±0.78, p<0.05). Interestingly, insulin sensitivity showed a very pronounced 40% increase upon cold acclimation (glucose rate of disappearance from 14.9±4.1 to 20.5±6.9 μmol kg-1 min-1, p<0.05). A 40% increase in insulin sensitivity cannot be explained by BAT glucose uptake, in fact basal skeletal muscle GLUT4 content and translocation was markedly increased after cold acclimation, without effects on insulin signaling or AMPk activation. Conclusions: Regular mild cold exposure has marked effects on insulin sensitivity, which are accompanied by small increases in BAT activity and more pronounced effects on skeletal muscle. These data suggest a novel therapeutic option for the treatment of type 2 diabetes.
2015-07-05 | GSE67297 | GEO
Project description:Background and aimsHepatitis C virus (HCV) infection is associated with insulin resistance, which may lead to type 2 diabetes and its complications. Although HCV infects mainly hepatocytes, it may impair insulin sensitivity at the level of uninfected extrahepatic tissues (muscles and adipose tissue). The aim of this study was to assess whether an interferon-free, antiviral therapy may improve HCV-associated hepatic vs. peripheral insulin sensitivity.MethodsIn a single-arm exploratory trial, 17 non-diabetic, lean chronic hepatitis C patients without significant fibrosis were enrolled, and 12 completed the study. Patients were treated with a combination of sofosbuvir/ledipasvir and ribavirin for 12 weeks, and were submitted to a 2-step euglycemic hyperinsulinemic clamp with tracers, together with indirect calorimetry measurement, to measure insulin sensitivity before and after 6 weeks of antivirals. A panel of 27 metabolically active cytokines was analyzed at baseline and after therapy-induced viral suppression.ResultsClamp analysis performed in 12 patients who achieved complete viral suppression after 6 weeks of therapy showed a significant improvement of the peripheral insulin sensitivity (13.1% [4.6-36.7], p = 0.003), whereas no difference was observed neither in the endogenous glucose production, in lipolysis suppression nor in substrate oxidation. A distinct subset of hepatokines, potentially involved in liver-to-periphery crosstalk, was modified by the antiviral therapy.ConclusionPharmacological inhibition of HCV improves peripheral (but not hepatic) insulin sensitivity in non-diabetic, lean individuals with chronic hepatitis C without significant fibrosis.
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Project description:CONTEXT:Sildenafil increases insulin sensitivity in mice. In humans, phosphodiesterase 5 inhibition improves disposition index, but the mechanism of this effect has not been elucidated and may depend on duration. In addition, increasing cyclic GMP without increasing nitric oxide could have beneficial effects on fibrinolytic balance. OBJECTIVE:The objective was to test the hypothesis that chronic phosphodiesterase 5 inhibition with sildenafil improves insulin sensitivity and secretion without diminishing fibrinolytic function. DESIGN:This was a randomized, double-blind, placebo-controlled study. SETTING:This trial was conducted at Vanderbilt Clinical Research Center. PARTICIPANTS:Participants included overweight individuals with prediabetes. INTERVENTIONS:Subjects were randomized to treatment with sildenafil 25 mg three times a day or matching placebo for 3 months. Subjects underwent a hyperglycemic clamp prior to and at the end of treatment. MAIN OUTCOME MEASURES:The primary outcomes of the study were insulin sensitivity and glucose-stimulated insulin secretion. RESULT:Twenty-one subjects completed each treatment arm. After 3 months, the insulin sensitivity index was significantly greater in the sildenafil group compared to the placebo group by 1.84 mg/kg/min per ?U/mL*100 (95% confidence interval, 0.01 to 3.67 mg/kg/min per ?U/mL*100; P = .049), after adjusting for baseline insulin sensitivity index and body mass index. In contrast, there was no effect of 3-month treatment with sildenafil on acute- or late-phase glucose-stimulated insulin secretion (P > .30). Sildenafil decreased plasminogen activator inhibitor-1 (P = .01), without altering tissue-plasminogen activator. In contrast to placebo, sildenafil also decreased the urine albumin-to-creatinine ratio from 12.67 ± 14.67 to 6.84 ± 4.86 ?g/mg Cr. This effect persisted 3 months after sildenafil discontinuation. CONCLUSIONS:Three-month phosphodiesterase 5 inhibition enhances insulin sensitivity and improves markers of endothelial function.
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Project description:BackgroundIncreased tissue cortisol availability has been implicated in abnormal glucose and fat metabolism in patients with obesity, metabolic syndrome, and type 2 diabetes (T2DM). Our objective was to evaluate whether blockade of glucocorticoid receptor (GR) with mifepristone ameliorates insulin resistance (IR) in overweight/obese subjects with glucose intolerance.MethodsWe conducted a randomized, double-blinded, placebo-controlled, crossover study in overweight/obese individuals (n = 16, 44% female) with prediabetes or mild T2DM but not clinical hypercortisolism. Mifepristone (50 mg every 6 h) or placebo was administered for 9 days, followed by crossover to the other treatment arm after a washout period of 6 to 8weeks. At baseline and following each treatment, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIVGTT) were performed. Insulin sensitivity was measured using FSIVGTT [primary outcome: insulin sensitivity index (SI)] and OGTT [Matsuda index (MI) and oral glucose insulin sensitivity index (OGIS)]. Hepatic and adipose insulin resistance were assessed using hepatic insulin resistance index (HIRI), and adipose tissue insulin sensitivity index (Adipo-SI) and adipo-IR, derived from the FSIVGTT.ResultsMifepristone administration did not alter whole-body glucose disposal indices of insulin sensitivity (SI, MI, and OGIS). GR blockade significantly improved Adipo-SI (61.7 ± 32.9 vs 42.8 ± 23.9; P = 0.002) and reduced adipo-IR (49.9 ± 45.9 vs 65.5 ± 43.8; P = 0.004), and HIRI (50.2 ± 38.7 vs 70.0 ± 44.3; P = 0.08). Mifepristone increased insulin clearance but did not affect insulin secretion or β-cell glucose sensitivity.ConclusionShort-term mifepristone administration improves adipose and hepatic insulin sensitivity among obese individuals with hyperglycemia without hypercortisolism.
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