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Pioglitazone treatment of Lethal Yellow mice

ABSTRACT: Goal of the experiment: To examine differential gene expression in the ovaries of heterozygous Lethal Yellow (C57BL/6J Ay/a) mice treated with vehicle or pioglitazone. Brief description of the experiment: The objective of this study was to use whole mouse genome DNA microarrays (Codelink) to examine gene expression the ovaries of heterozygous Lethal Yellow (C57BL/6J Ay/a) mice. Women with polycystic ovary syndrome (PCOS) treated with thiazolidinediones (TZD), such as pioglitazone, show reduced androgen levels and improved ovulatory function. Recent evidence suggests that TZD, acting via peroxisome proliferator-activated receptor gamma (PPAR gamma), alter the expression of ovarian genes involved in insulin/IGF signaling that may account for some of the observed effects. Since TZD can alter the expression of a large variety of genes, there may be other mechanisms involved in the improvement of ovarian function with TZD treatment. Lethal yellow (LY) mice exhibit progressive obesity, reproductive dysfunction, and altered metabolic regulation (e.g. insulin and leptin resistance) similar to women with PCOS. This study was designed to test the hypothesis that prolonged treatment of aging LY mice with pioglitazone would alter the expression of ovarian genes involved in reproduction. Beginning at 120-days and continuing until 180-days of age, female LY mice received daily oral doses of either 0.1 mg pioglitazone (n = 4) or an equal volume of vehicle (0.1 ml 100% DMSO; n = 4). At the end of the treatment regimen, ovaries were removed and RNA extracted. Total RNA extracts were run individually on Codelink Mouse Whole Genome Bioarrays (GE). Relative gene expression was compared between treatments by t-test using GeneSpring software. Keywords: mouse, drug treatment Experimental factors: drug treatment Keywords: drug treatment

ORGANISM(S): Mus musculus

PROVIDER: GSE8806 | GEO | 2008/07/08

SECONDARY ACCESSION(S): PRJNA102117

REPOSITORIES: GEO

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Project description:Mice possessing the lethal yellow (LY) agouti mutation (C57BL/6J Ay/a) exhibit adult-onset obesity, altered metabolic regulation, and early reproductive senescence. The present study was designed to test the hypothesis that aging obese mice possess differences in expression of ovarian genes involved in reproductive function relative to age-matched lean mice. To synchronize ovarian state and exclude gonadotropin-mediated effects, 90- and 180-day old diestrous LY and lean black (C57BL/6J a/a) mice were suppressed with GnRH antagonist (Antide®) for five days, then injected with 5 IU equine chorionic gonadotropin (eCG). Complementary RNA derived from RNA extracts of whole ovarian homogenates collected 36h post eCG were run individually on CodeLink Mouse Whole Genome Bioarrays (Applied Microarrays). Unidentified genes, EST, genes whose expression was below sensitivity limits, and those with less than a 2-fold difference in expression between groups were excluded from analysis. After exclusions, 52 genes had a significant (p<0.05) difference in expression between 180-day-old obese LY and lean black mice. LY exhibited elevated ovarian expression of agouti (350x), leptin (6.5x), and numerous genes involved in cholesterol/lipid transport and metabolism, e.g., lanosterol synthase, CYP51, and steroidogenic acute regulatory protein (StAR). Fewer genes showed lower expression in LY mice, e.g. angiotensinogen. In contrast, none of these genes showed differential expression in 90-day-old LY and black mice, which are of similar body weight. Interestingly, 180-day-old LY mice had a 2-fold greater expression of 11β-hydroxysteroid dehydrogenase (HSD) type 1 and a 2-fold lesser expression of 11β-HSD type 2, differences not seen in 90-day-old mice. Consistent with altered 11β-HSD expression, ovarian concentrations of corticosterone (C) were elevated in aging (180-day) LY mice relative to black mice, but C levels were similar in young (90-day) LY and black mice. The data suggest that reproductive dysfunction in aging obese mice is related to modified intraovarian gene expression that is directly related to acquired obesity, but independent of gonadotropic state.

Project description:Background: Thiazolidinediones (TZDs) activate peroxisome proliferator-activated receptor gamma (PPARgamma) and are used clinically to help restore peripheral insulin sensitivity in Type 2 diabetes (T2DM). Interestingly, long-term treatment of mouse models of Alzheimer’s disease (AD) with TZDs also has been shown to reduce several well-established brain biomarkers of AD including inflammation, oxidative stress and Abeta accumulation. While some of the TZD actions are becoming clear in AD models and may mediate their reported beneficial impact in AD patients, little is known about the functional consequences of TZDs in animal models of normal aging. Because aging is a common risk factor for both AD and T2DM, we investigated whether the TZD, pioglitazone could alter brain aging under non-pathological conditions. Findings: The TZD pioglitazone (PIO) was incorporated into the diet to yield a final dose of approximately 2.3 mg/kg body weight/day. PIO reduced insulin levels irrespective of age. Interestingly, a significant reduction in the Ca2+-dependent afterhyperpolarization was seen in the aged animals with no significant change in LTP maintenance or learning and memory performance. Finally, a combination of microarray analyses on hippocampal tissue and serum-based multiplex cytokine assays revealed that age-dependent inflammatory changes in brain and periphery were not reversed by PIO. Conclusions: While current research efforts continue to address the underlying processes responsible for the progressive decline in cognitive function seen during aging, available medical treatments are still very limited. Our study, therefore, was aimed at elucidating potentially novel actions of TZDs in the aging brain. Using a clinically-relevant dose and delivery method, PIO had no detectable impact on several indices of brain aging and failed to alter both peripheral and central age-related increases in inflammatory signaling. Keywords: hippocampus, rat, young or aged, control or pioglitazone-treated

Project description:Insulin resistance is a common metabolic abnormality in women with PCOS and leads to an elevated risk of type 2 diabetes. Studies have shown that thiazolidinediones (TZD) improve metabolic disturbances in PCOS patients. We hypothesized that the effect of TZD in PCOS is in part mediated by changes in the transcriptional profile of muscle favoring insulin sensitivity. Using Affymetrix microarrays, we examined the effect of pioglitazone (30 mg/day for 16 weeks) on gene expression in skeletal muscle of 10 obese women with PCOS metabolically characterized by a euglycemic-hyperinsulinemic clamp. Moreover, we explored gene expression changes between these PCOS patients before treatment and 13 healthy control women. Treatment with pioglitazone improved insulin-stimulated total, oxidative and non-oxidative glucose metabolism, and reduced fasting serum insulin (all p < 0.05). Global pathway analysis using Gene Map Annotator and Pathway Profiler (GenMAPP 2.1) and Gene Set Enrichment Analysis (GSEA 2.0.1) revealed a significant upregulation of genes involved in mitochondrial oxidative phosphorylation (OXPHOS), ribosomal proteins, mRNA processing reactome, translation factors, and proteasome complexes in PCOS patients after pioglitazone therapy. Quantitative real-time PCR suggested that upregulation of OXPHOS genes was mediated by an increase in PGC-1M-NM-1 expression (p < 0.05). Expression of genes involved in ribosomal proteins and OXPHOS was down-regulated in PCOS patients before treatment compared to matched healthy women using GenMAPP 2.1 and GSEA 2.1. These data indicate that pioglitazone therapy restores insulin sensitivity in part by a coordinated upregulation of genes involved in mitochondrial oxidative metabolism and protein biosynthesis in skeletal muscle of PCOS. These transcriptional effects of pioglitazone therapy may contribute to prevent the onset of type 2 diabetes in these women. Experiment Overall Design: Ten obese women of reproductive age with PCOS participated in the study to test the effect of pioglitazone therapy (data set 1). To test if pioglitazone ameliorate existing defects in PCOS patients, the expression profile of the 10 PCOS patients before treatment were compared to the same cohort of 13 control subjects (data set 2).

Project description:Insulin resistance is a common metabolic abnormality in women with PCOS and leads to an elevated risk of type 2 diabetes. Studies have shown that thiazolidinediones (TZD) improve metabolic disturbances in PCOS patients. We hypothesized that the effect of TZD in PCOS is in part mediated by changes in the transcriptional profile of muscle favoring insulin sensitivity. Using Affymetrix microarrays, we examined the effect of pioglitazone (30 mg/day for 16 weeks) on gene expression in skeletal muscle of 10 obese women with PCOS metabolically characterized by a euglycemic-hyperinsulinemic clamp. Moreover, we explored gene expression changes between these PCOS patients before treatment and 13 healthy control women. Treatment with pioglitazone improved insulin-stimulated total, oxidative and non-oxidative glucose metabolism, and reduced fasting serum insulin (all p < 0.05). Global pathway analysis using Gene Map Annotator and Pathway Profiler (GenMAPP 2.1) and Gene Set Enrichment Analysis (GSEA 2.0.1) revealed a significant upregulation of genes involved in mitochondrial oxidative phosphorylation (OXPHOS), ribosomal proteins, mRNA processing reactome, translation factors, and proteasome complexes in PCOS patients after pioglitazone therapy. Quantitative real-time PCR suggested that upregulation of OXPHOS genes was mediated by an increase in PGC-1α expression (p < 0.05). Expression of genes involved in ribosomal proteins and OXPHOS was down-regulated in PCOS patients before treatment compared to matched healthy women using GenMAPP 2.1 and GSEA 2.1. These data indicate that pioglitazone therapy restores insulin sensitivity in part by a coordinated upregulation of genes involved in mitochondrial oxidative metabolism and protein biosynthesis in skeletal muscle of PCOS. These transcriptional effects of pioglitazone therapy may contribute to prevent the onset of type 2 diabetes in these women. Keywords: PCOS, microarray, global pathway analysis, insulin resistance, pioglitazone, protein metabolism, mitochondrial oxidative metabolism

Project description:Thiazolidinediones (TZDs) are agonists at peroxisome proliferator-activated gamma-type (PPAR-y) receptors and are used clinically for the treatment of type 2 diabetes where they have been shown to reestablish insulin sensitivity, improve lipids profile, and reduce inflammation. Recent work also suggests that TZDs may be beneficial in Alzheimer's disease (AD), ameliorating cognitive decline early in the disease process. However, there have been only a few studies identifying mechanisms through which cognitive benefits may be exerted. Starting at 10 months of age, the triple transgenic mouse model of AD (3xTg-AD) with accelerated amyloid-B (AB) deposition and tau pathology was treated with the TZD pioglitazone (PIO- Actos) at 18 mg/Kg body weight/day. After four months, PIO-treated animals showed multiple beneficial effects, including improved learning on the active avoidance task, reduced serum cholesterol, decreased hippocampal AB deposits, and enhanced short- and long-term plasticity. Baseline electrophysiological membrane properties and blood glucose levels were unchanged by PIO treatment. Gene microarray analyses of hippocampal tissue identified predicted transcriptional responses following TZD treatment as well as potentially novel targets of TZDs, including facilitation of estrogenic processes, and decreases in glutamatergic and ketone metabolic/ cholesterol dependent processes. Taken together, these results confirm prior animal studies showing that TZDs can ameliorate cognitive deficits associated with AD-related pathology, but also extend these findings by pointing to novel molecular targets in the brain. Keywords : Hippocampus; LTP; Microarray analysis; Avoidance learning; Aging; PPAR; Synaptic hyperpolarization; T2DM We used the 3xTg-AD mouse model of Alzheimer's disease and monitored the effects of pioglitazone (PIO-Actos a TZD) on behavioral, electrophysiological, and molecular variables. Emphasis was placed on identifying hippocampal PIO-sensitive genes that were also associated with learning and memory processes. Starting at 10 months of age, female mice were treated for approximately 14 weeks with either a control diet or a PIO-containing diet. PIO was incorporated into the diet to yield a final dose of approximately 18 mg/kg body weight/day.

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Pioglitazone treatment of Lethal Yellow mice

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