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      Sam68 mediates leptin signaling and action in human granulosa cells: possible role in leptin resistance in PCOS


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          Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, obesity, and insulin resistance, that leads to subfertility. Sam68 is an RNA-binding protein with signaling functions that is ubiquitously expressed, including gonads. Sam68 is recruited to leptin signaling, mediating different leptin actions.


          We aimed to investigate the role of Sam68 in leptin signaling, mediating the effect on aromatase expression in granulosa cells and the posible implication of Sam68 in the leptin resistance in PCOS.

          Materials and methods

          Granulosa cells were from healthy donors ( n = 25) and women with PCOS ( n = 25), within the age range of 20 to 40 years, from Valencian Infertility Institute (IVI), Seville, Spain. Sam68 expression was inhibited by siRNA method and overexpressed by expression vector. Expression level was analysed by qPCR and immunoblot. Statistical significance was assessed by ANOVA followed by different post-hoc tests. A P value of <0.05 was considered statistically significant.


          We have found that leptin stimulation increases phosphorylation and expression level of Sam68 and aromatase in granulosa cells from normal donors. Downregulation of Sam68 expression resulted in a lower activation of MAPK and PI3K pathways in response to leptin, whereas overexpression of Sam68 increased leptin stimulation of signaling, enhancing aromatase expression. Granulosa cells from women with PCOS presented lower expression of Sam68 and were resistant to the leptin effect on aromatase expression.


          These results suggest the participation of Sam68 in leptin receptor signaling, mediating the leptin effect on aromatase expression in granulosa cells, and point to a new target in leptin resistance in PCOS.

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          Most cited references43

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          Signal-dependent regulation of splicing via phosphorylation of Sam68.

          Evolution of human organismal complexity from a relatively small number of genes--only approximately twice that of worm or fly--is explained mainly by mechanisms generating multiple proteins from a single gene, the most prevalent of which is alternative pre-messenger-RNA splicing. Appropriate spatial and temporal generation of splice variants demands that alternative splicing be subject to extensive regulation, similar to transcriptional control. Activation by extracellular cues of several cellular signalling pathways can indeed regulate alternative splicing. Here we address the link between signal transduction and splice regulation. We show that the nuclear RNA-binding protein Sam68 is a new extracellular signal-regulated kinase (ERK) target. It binds exonic splice-regulatory elements of an alternatively spliced exon that is physiologically regulated by the Ras signalling pathway, namely exon v5 of CD44. Forced expression of Sam68 enhanced ERK-mediated inclusion of the v5-exon sequence in mRNA. This enhancement was impaired by mutation of ERK-phosphorylation sites in Sam68, whereas ERK phosphorylation of Sam68 stimulated splicing of the v5 exon in vitro. Finally, Ras-pathway-induced alternative splicing of the endogenous CD44-v5 exon was abolished by suppression of Sam68 expression. Our data define Sam68 as a prototype regulator of alternative splicing whose function depends on protein modification in response to extracellular cues.
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            The potential implications of a PCOS diagnosis on a woman's long-term health using data linkage.

            The polycystic ovary syndrome (PCOS) is the commonest endocrine abnormality in women of reproductive age.
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              Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis.

              Polycystic ovary syndrome (PCOS) is a common endocrine disorder with diverse reproductive and metabolic features. It is underpinned by insulin resistance that is exacerbated by obesity. Lifestyle modification is the first line treatment in PCOS, but it is associated with low adherence and sustainability. In small studies, metformin improves outcomes such as hyperinsulinaemia, ovulation and menstrual cyclicity. We conducted a systematic review and meta-analysis to compare the effect of lifestyle modification + metformin with lifestyle modification ± placebo, and of metformin alone with lifestyle modification ± placebo in PCOS on anthropometric, metabolic, reproductive and psychological outcomes.

                Author and article information

                Endocr Connect
                Endocr Connect
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                June 2020
                06 May 2020
                : 9
                : 6
                : 479-488
                [1 ]Department of Medical Biochemistry , Molecular Biology and Immunology. Medical School, Virgen Macarena University Hospital, University of Seville, Seville, Spain
                [2 ]Valencian Infertility Institute (IVI) , Seville, Spain
                Author notes
                Correspondence should be addressed to V Sánchez-Margalet: margalet@ 123456us.es

                *(T Vilariño-García and A Pérez-Pérez contributed equally to this work)

                © 2020 The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                : 19 April 2020
                : 06 May 2020

                sam68,leptin,polycystic ovary syndrome (pcos),aromatase,signalling pathways


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