Abstract
Polycystic ovary syndrome (PCOS) is a common metabolic and reproductive disorder with an increasing risk for type 2 diabetes. Insulin resistance is a common feature of women with PCOS, but the underlying molecular mechanism remains unclear. This study aimed to screen critical long non-coding RNAs (lncRNAs) that might play pivotal roles in insulin resistance, which could provide candidate biomarkers and potential therapeutic targets for PCOS. Gene expression profiles of the skeletal muscle in patients with PCOS accompanied by insulin resistance and healthy patients were obtained from the publicly available Gene Expression Omnibus (GEO) database. A global triple network including RNA-binding protein, mRNA, and lncRNAs was constructed based on the data from starBase. Then, we extracted an insulin resistance-associated lncRNA–mRNA network (IRLMN) by integrating the data from starBase and GEO. We also performed a weighted gene co-expression network analysis (WGCNA) on the differentially expressed genes between the women with and without PCOS, to identify hub lncRNAs. Additionally, the findings of key lncRNAs were examined in an independent GEO dataset. The expression level of lncRNA RP11-151A6.4 in ovarian granulosa cells was increased in patients with PCOS compared with that in control women. Levels were also increased in PCOS patients with higher BMI, hyperinsulinemia, and higher HOMA-IR values. As a result, RP11-151A6.4 was identified as a hub lncRNA based on IRLMN and WGCNA and was highly expressed in ovarian granulosa cells, skeletal muscle, and subcutaneous and omental adipose tissues of patients with insulin resistance. This study showed the differences between lncRNA and mRNA profiles from healthy women and women with PCOS and insulin resistance. Here, we demonstrated that RP11-151A6.4 might play a vital role in insulin resistance, androgen excess, and adipose dysfunction in patients with PCOS. Further study concerning RP11-151A6.4 could elucidate the underlying mechanisms of insulin resistance.
Highlights
Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder, defined by a combination of symptoms related to hyperandrogenism and ovarian dysfunction, upon exclusion of other diagnoses
A total of 2,290 transcripts were differentially expressed in the muscle of patients with PCOS and insulin resistance, compared with the control (Figure 1A); and 8,596 transcripts changed after pioglitazone treatment in patients with PCOS (Figure 1B)
After bidirectional hierarchical cluster analysis, we identified an insulin resistance-associated module including six long non-coding RNAs (lncRNAs), three RNA-binding protein (RBP), and 58 mRNAs
Summary
Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder, defined by a combination of symptoms related to hyperandrogenism and ovarian dysfunction, upon exclusion of other diagnoses. PCOS is associated with reproductive co-morbidities (menstrual irregularity, ovulatory dysfunction, infertility, and pregnancy complications), metabolic disorders (metabolic syndrome, type 2 diabetes, and cardiovascular disease), and psychological risk factors (anxiety and depression). A clinical feature of PCOS, is a decreased ability of insulin to mediate metabolic actions on glucose uptake, production, and/or lipolysis. It results in a requirement for increased amounts of insulin to achieve a given metabolic action (Miller et al, 2017). Decreasing insulin resistance through insulin-sensitizing drugs (e.g., metformin, rosiglitazone, pioglitazone, and d-chiroinositol) and/or lifestyle treatments could improve the reproductive and metabolic outcomes for patients with PCOS (Morley et al, 2017; Anithasri et al, 2019). The molecular mechanism of insulin resistance in PCOS remains unknown
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