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Saturated Fat Ingestion Promotes Lipopolysaccharide-Mediated Inflammation and Insulin Resistance in Polycystic Ovary Syndrome.

ABSTRACT: Context:Inflammation and insulin resistance (IR) are often present in polycystic ovary syndrome (PCOS). Objective:We determined the effect of saturated fat ingestion on circulating lipopolysaccharide (LPS) and mononuclear cell (MNC) toll-like receptor-4 (TLR-4) and suppressor of cytokine signaling-3 (SOCS-3) in women with PCOS. Design:Cross-sectional study. Setting:Academic medical center. Patients:Nineteen reproductive-age women with PCOS (10 lean, 9 obese) and 19 ovulatory control subjects (10 lean, 9 obese). Main Outcome Measures:LPS and TNF? levels were measured in plasma. TLR-4 and SOCS-3 mRNA and protein content were quantified in MNC from blood collected after fasting and 2, 3, and 5 hours after saturated fat ingestion. Insulin sensitivity was derived from an oral glucose tolerance test (ISOGTT). Androgen secretion was assessed from blood collected after fasting and 24, 48, and 72 hours after human chorionic gonadotropin (HCG) administration. Results:Regardless of PCOS status, subjects who were obese had lipid-induced increases in circulating LPS and TLR-4 protein content compared with subjects who were lean. Lean and obese women with PCOS had lipid-induced increases in plasma TNF? and SOCS-3 mRNA and protein content compared with lean control subjects. Both PCOS groups had lower ISOGTT and greater HCG-stimulated androgen secretion compared with control subjects. The LPS and SOCS-3 responses were negatively correlated with ISOGTT and positively correlated with HCG-stimulated androgen secretion. Conclusion:In PCOS, lipid-induced LPS-mediated inflammation through TLR-4 is associated with obesity and worsened by PCOS, whereas lipid-induced increases in SOCS-3 may represent an obesity-independent, TNF?-mediated mechanism of IR.

SUBMITTER: Gonzalez F

PROVIDER: S-EPMC6364509 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Project description:Background Polycystic ovary syndrome (PCOS) is a common multifactorial metabolic and endocrine disorder in women of reproductive age. Increasingly, evidence indicates that the microRNA (miRNA)-mRNA axis contributes to the development of PCOS. Methods To investigate the molecular mechanisms through which miRNA-mRNA expression affects hyperandrogenism, ovarian tissue samples from prenatally androgenized (PNA) mice were subjected to miRNA-seq and RNA-seq analysis. Analyses were performed to identify differentially expressed microRNAs (DEmiRs) and differentially expressed genes (DEGs). In combination with our previous data obtained from clinical samples, we have performed an integrated miRNA-mRNA analysis of PNA mice and granulosa cells (GCs) from patients with PCOS. The changes in expression were validated by RT-qPCR in more mouse models and clinical samples. Results In total, 3,432 genes and 16 miRNAs were differentially expressed in PNA mice compared with the control mice. We investigated the regulation pattern of miRNAs-mRNAs and observed a total of 12 miRNA-mRNA pairs involved in negative regulation. Functional analysis concentrated on insulin resistance, the T cell receptor signaling pathway, and other inflammation-related pathways. Verification of these results by RT-qPCR showed that the expression of miR-106-5p and miR-155-5p in clinical GCs was consistent with that in PNA mice. After predicting the target genes of miR-106-5p and miR-155-5p and performing negative regulation analysis, six target genes were obtained in GCs. The integration analysis showed that the network of miR-106-5p/miR-155-5p targets was mostly concentrated in pathway related to insulin resistance and inflammation. In addition, the upregulation of the inflammatory genes Il18/IL18 and Socs3/SOCS3 was validated in the PNA mice and GCs from patients compared with the appropriate control sample. The in vitro experiments showed that the regulatory relationship observed may be related to the direct stimulation of DHT. Conclusions Our results showed that the miRNA-mRNA regulatory network in PCOS was associated with markers of insulin sensitivity and inflammation. Our study provides a new genetic basis and novel insight regarding the pathogenesis of PCOS.

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Saturated Fat Ingestion Promotes Lipopolysaccharide-Mediated Inflammation and Insulin Resistance in Polycystic Ovary Syndrome.

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