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FSH stimulates IRS-2 expression in human granulosa cells through cAMP/SP1, an inoperative FSH action in PCOS patients
G Anjali1, Surleen Kaur1, Ruchi Lakra1
1Division of Molecular Endocrinology and Reproduction, Department of Zoology, University of Delhi, Delhi 110007, India.
Abstract:
Follicle stimulating hormone (FSH) plays a central role in growth and differentiation of ovarian follicles. A plethora of information exists on molecular aspects of FSH responses but little is known about the mechanisms involved in its cross-talk with insulin/IGF-1 pathways implicated in the coordination of energy homeostasis in preovulatory granulosa cells (GCs). In this study, we hypothesized that FSH may regulate IRS-2 expression and thereby maintain the energy balance in GCs. We demonstrate here that FSH specifically increases IRS-2 expression in human and rat GCs. FSH-stimulated IRS-2 expression was inhibited by actinomycin D or cycloheximide. Furthermore, FSH decreases IRS-2 mRNA degradation indicating post-transcriptional stabilization. Herein, we demonstrate a role of cAMP pathway in the activation of IRS-2 expression by FSH. Scan and activity analysis of IRS-2 promoter demonstrated that FSH regulates IRS-2 expression through SP1 binding sites. FSH stimulates SP1 translocation into nucleus and its binding to IRS-2 promoter. These results are corroborated by the fact that siRNA mediated knockdown of IRS-2 decreased the FSH-stimulated PI3K activity, p-Akt levels, GLUT4 translocation and glucose uptake. However, FSH was not able to increase IRS-2 expression in GCs from PCOS women undergoing IVF. Interestingly, IRS-2 mRNA expression was downregulated in GCs from the PCOS rat model. Taken together, our findings establish that FSH induces IRS-2 expression and thereby activates PI3K, Akt and glucose uptake. Crucially, our data confirms a molecular defect in FSH action in PCOS GCs which may cause deceleration of metabolism and follicular growth leading to infertility. These results lend support for a therapeutic potential of IRS-2 in the management of PCOS.
Insights
Follicle stimulating hormone (FSH) boosts Insulin Receptor Substrate-2 (IRS-2) expression in granulosa cells, enhancing glucose uptake. This mechanism is impaired in Polycystic Ovary Syndrome (PCOS), suggesting IRS-2 as a therapeutic target.
Area of Science:
- Reproductive Endocrinology
- Molecular Cell Biology
- Metabolic Signaling
Background:
- Follicle stimulating hormone (FSH) is crucial for ovarian follicle development.
- The interplay between FSH and insulin/IGF-1 pathways in granulosa cells (GCs) for energy balance is poorly understood.
- Insulin Receptor Substrate-2 (IRS-2) is a key mediator in insulin/IGF-1 signaling.
Purpose of the Study:
- To investigate if FSH regulates IRS-2 expression in preovulatory GCs.
- To elucidate the molecular mechanisms by which FSH affects IRS-2 expression.
- To examine the role of IRS-2 in FSH-mediated metabolic regulation in GCs and its potential dysfunction in Polycystic Ovary Syndrome (PCOS).
Main Methods:
- Quantitative analysis of IRS-2 expression in human and rat GCs.
- Inhibition studies using actinomycin D and cycloheximide.
- Analysis of mRNA degradation rates.
- Luciferase reporter assays and transcription factor binding site analysis (SP1).
- siRNA-mediated knockdown of IRS-2.
- Assessment of PI3K/Akt pathway activation and glucose uptake.
- Comparison of FSH response in GCs from healthy and PCOS individuals/models.
Main Results:
- FSH significantly increased IRS-2 expression in human and rat GCs via post-transcriptional stabilization, involving the cAMP pathway and SP1 binding to the IRS-2 promoter.
- Knockdown of IRS-2 abolished FSH-stimulated PI3K activity, Akt phosphorylation, GLUT4 translocation, and glucose uptake.
- FSH failed to upregulate IRS-2 in GCs from PCOS women and IRS-2 expression was reduced in a PCOS rat model.
- FSH stimulates IRS-2 expression, activating PI3K, Akt, and glucose uptake, a process defective in PCOS granulosa cells.
Conclusions:
- FSH induces IRS-2 expression in granulosa cells, thereby activating key metabolic pathways essential for follicular function.
- A molecular defect in FSH-induced IRS-2 expression exists in PCOS granulosa cells, potentially contributing to impaired follicular growth and infertility.
- IRS-2 represents a potential therapeutic target for managing PCOS-related infertility.
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