[Show abstract][Hide abstract] ABSTRACT: Approximately 70% of women with polycystic ovary syndrome (PCOS) have intrinsic insulin resistance (IR), above and beyond that associated with body mass, including dysfunctional glucose metabolism in adipose tissue (AT). In AT, analysis of the IRS/PI3K/AKT pathway signaling components identified only GLUT4 expression to be significantly lower in PCOS patients and in controls with IR. We examined the role of miRNAs, particularly in the regulation of GLUT4, the insulin sensitive glucose transporter, in the AT of PCOS and matched controls. PCOS AT was determined to have a differentially expressed miRNA profile, including upregulated miR-93, -133 and -223. GLUT4 is a highly predicted target for miR-93, while miR-133 and miR-223 have been demonstrated to regulate GLUT4 expression in cardiomyocytes. Expression of miR-93 revealed a strong correlation between the homeostatic model assessment for insulin resistance (HOMA-IR) in vivo values and GLUT4 and miR-93, but not miR-133 and -223, expression in human AT, Overexpression of miR-93 resulted in down-regulation of GLUT4 gene expression in adipocytes through direct targeting of the GLUT4 3'UTR, while inhibition of miR-93 activity led to increased GLUT4 expression. These results point to a novel mechanism for regulating insulin-stimulated glucose uptake via miR-93, and demonstrate upregulated miR-93 expression in all PCOS, and in non-PCOS women with IR, possibly accounting for the IR of the syndrome. In contrast, miR-133 and miR-223 may have a different, although yet to be defined, role in the IR of PCOS.
[Show abstract][Hide abstract] ABSTRACT: Context: Polycystic ovary syndrome (PCOS) is a heterogeneous common genetic disorder characterized by hyperandrogenemia and insulin resistance. Alterations in gene expression profiles of the ovary and adipose tissue identified the candidate gene FBJ murine osteosarcoma viral oncogene homolog (FOS) for further investigation of expression changes in metabolic tissues and genetic studies. Objective: The objective of the study was to confirm the underexpression of the FOS gene in sc adipose and determine whether variants in this gene are risk factors for PCOS. Design: RT-PCR was performed in sc fat from women with and without PCOS. Genotyping of single-nucleotide polymorphisms in the FOS locus was performed to test for association with PCOS. Setting: The study was conducted at a tertiary care academic institution. Participants: Twenty-two PCOS and 13 control subjects were recruited for gene expression studies. We assembled a discovery genotyping cohort of 354 cases and 161 controls and a replication cohort of 476 cases and 315 controls, all of whom were Caucasian. Main Measurements: Gene expression by quantitative real-time RT-PCR, FOS genotype, and PCOS status were measured. Results: FOS expression was confirmed to be reduced in PCOS adipose tissue. Three single-nucleotide polymorphisms were significantly associated with PCOS in the discovery cohort (rs8006998, P = 0.0031; rs8013918, P = 0.0006; rs8013942, P = 0.0087). rs8006998 was also associated with PCOS in the replication cohort (P = 0.013). Conclusions: Differential gene expression in sc fat and genetic association at the FOS locus in PCOS subjects implicates a role for this transcription factor in PCOS. FOS dysfunction may be a common factor between hyperandrogenism and insulin resistance.
The Journal of Clinical Endocrinology and Metabolism 06/2012; 97(9):E1750-7. DOI:10.1210/jc.2011-2153 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women.
Our objective was to compare gene expression pattern in sc abdominal adipose tissue in nonobese PCOS patients vs. body mass index-matched controls.
Eleven PCOS subjects and 12 controls (body mass index 20-28 kg/m(2)) were recruited. Total RNA was isolated, and gene expression profiling was performed using Affymetrix Human Genome U133 arrays. Differentially expressed genes were classified by gene ontology. Microarray results for selected genes were confirmed by quantitative real-time PCR (RT-qPCR). Frequently sampled iv glucose tolerance tests were used to assess dynamic insulin sensitivity.
Ninety-six genes were identified with altered expression of at least 2-fold in nonobese PCOS adipose tissues. Inflammatory response genes were significantly down-regulated. RT-qPCR confirmed decreases in expression of IL6 (12.3-fold), CXCL2 (18.3-fold), and SOCS3 (22.6-fold). Lipid metabolism genes associated with insulin resistance were significantly up-regulated, with confirmed increases in DHRS9 (2.5-fold), UCLH1 (2.6-fold), and FADS1 (2.8-fold) expression. Wnt signaling genes (DKK2, JUN, and FOSB) were differentially expressed. RT-qPCR confirmed significant expression changes in DKK2 (1.9-fold increase), JUN (4.1-fold decrease), and FOSB (60-fold decrease).
Genes involved in inflammation, lipid metabolism, and Wnt signaling are differentially expressed in nonobese PCOS adipose tissue. Because these genes are known to affect adipogenesis and insulin resistance, we hypothesize that their dysregulation may contribute to the metabolic abnormalities observed in women with PCOS.
The Journal of Clinical Endocrinology and Metabolism 02/2012; 97(5):E765-70. DOI:10.1210/jc.2011-2377 · 6.21 Impact Factor