Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of human skeletal muscle of women with PCOS reveals reduced expression of mitochondrial oxidative metabolism genes

ABSTRACT: Recently, abnormalities in mitochondrial oxidative phosphorylation (OXPHOS) have been implicated in the pathogenesis of skeletal muscle insulin resistance in type 2 diabetes. In the present study, we hypothesized that decreased expression of OXPHOS genes could be of similar importance for insulin resistance in the polycystic ovary syndrome (PCOS). Using the HG-U133 Plus 2.0 expression array from Affymetrix, we analyzed gene expression in skeletal muscle from obese women with PCOS (n=16) and age- and body mass index-matched control women (n=13) metabolically characterized by euglycemic-hyperinsulinemic clamp and indirect calorimetry. To identify pathways of importance for the pathogenesis of insulin resistance in PCOS, we performed biological pathway analysis using Gene Set Enrichment Analysis (GSEA 1.0) and Gene Microarray Pathway Profiler (GenMAPP 2.0). The expression of 9 genes, selected according to biological relevance, was evaluated by quantitative real time PCR (q-RT-PCR). Women with PCOS were characterized by fasting hyperinsulinemia and impaired insulin-stimulated glucose disposal - caused by reduced glucose oxidation and storage - as well as impaired suppression of lipid oxidation (all P<0.01). GSEA and GenMAPP both revealed the same set of genes involved in OXPHOS, which was also the most downregulated biological pathway (P<0.01). These results were confirmed by q-RT-PCR of six genes from the OXPHOS gene set as well as three transcription factors known to regulate the transcription of these genes. Our results, for the first time, provide evidence for an association between insulin resistance and impaired mitochondrial oxidative metabolism in skeletal muscle in women with PCOS. This may contribute to the increased risk of type 2 diabetes observed in these women Experiment Overall Design: 16 insulin resistant PCOS patients of fertile age were matched to 13 healthy control subjects.

ORGANISM(S): Homo sapiens

SUBMITTER: Vibe Skov

PROVIDER: E-GEOD-6798 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Reduced expression of nuclear-encoded genes involved in mitochondrial oxidative metabolism in skeletal muscle of insulin-resistant women with polycystic ovary syndrome.

Skov Vibe V Glintborg Dorte D Knudsen Steen S Jensen Thomas T Kruse Torben A TA Tan Qihua Q Brusgaard Klaus K Beck-Nielsen Henning H Højlund Kurt K

Diabetes 20070611 9

Insulin resistance in skeletal muscle is a major risk factor for the development of type 2 diabetes in women with polycystic ovary syndrome (PCOS). In patients with type 2 diabetes, insulin resistance in skeletal muscle is associated with abnormalities in insulin signaling, fatty acid metabolism, and mitochondrial oxidative phosphorylation (OXPHOS). In PCOS patients, the molecular mechanisms of insulin resistance are, however, less well characterized. To identify biological pathways of importanc ...[more]

PMID: 17563058

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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

Dataset Information

Transcription profiling of human skeletal muscle of women with PCOS reveals reduced expression of mitochondrial oxidative metabolism genes

Publications

Reduced expression of nuclear-encoded genes involved in mitochondrial oxidative metabolism in skeletal muscle of insulin-resistant women with polycystic ovary syndrome.

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