Distress response in granulosa cells of women affected by PCOS with or without insulin resistance

Autores de IIS La Fe

• Mauro Cozzolino

  Autor

• Sonia Herraiz Raya

  Autor

• Antonio Pellicer Martínez

  Autor

Participantes ajenos a IIS La Fe

• Çakiroglu, Y.
• García-Velasco, J.A.
• Tiras, B.
• Pacheco, A.
• Rabadán, S.
• Kohls, G.
• Barrio, A.I.
• Seli, E.

Grupos

• Endocrinología Reproductiva e Infertilidad

• Medicina Fetal y Reproductiva

Abstract

Purpose: In this study, we investigated whether metabolic dysfunction in women with Polycystic ovarian syndrome (PCOS) induces granulosa cell (GC) stress and activates in the endoplamatic reticulum and the mitochondria (UPRer and UPRmt, respectively). Methods: Women who were diagnosed with PCOS (based on the Rotterdam criteria), were divided into two groups, PCOS with insulin resistance (PCOS-IR; n = 20) and PCOS with no insulin resistance (PCOS-nIR; n = 20), and compared to healthy oocyte donors (CONT; n = 20). Insulin resistance (IR) was assessed on the results of homeostasis model assessment (HOMA) that determines IR using the concentration of fasting plasma glucose and fasting insuline. Expression of UPRer genes (i.e., IRE1, ATF4, ATF6, XBP1, BIP, and CHOP), and UPRmt genes (i.e., HSP60, HSP10, CLPP, and HSP40) was assessed in cumulus GCs by qRT-PCR. Results: We found that several genes involved in UPRer and UPRmt were overexpressed in the GCs of PCOS-IR and PCOS-nIR compared to CONT. IRE1, ATF4 and XBP1, that are activated by ER stress, were significantly overexpressed in PCOS-IR compared to CONT. BIP and CHOP were overexpressed in PCOS groups compared to CONT. HSP10 and HSP40 were upregulated in PCOS-IR and PCOS-nIR groups compared to the CONT. HSP60 and CLPP showed no statistical different expression in PCOS-IR and PCOS-nIR compared to CONT group. Conclusion: Our findings suggest that the GCs of women with PCOS (with or without IR) are metabolically distressed and upregulate UPRer and UPRmt genes. Our study contributes to the understanding of the molecular mechanisms underlying the pathological changes that occur in the follicular microenvironment of women with PCOS. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Keywords

• activating transcription factor 4; activating transcription factor 6; chaperonin 60; early pregnancy factor; endopeptidase Clp; endoplasmic reticulum chaperone BiP; glucose; growth arrest and DNA damage inducible protein 153; heat shock protein 40; protein IRE1; X box binding protein 1; adult; Article; ATF4 gene; ATF6 gene; BIP gene; cell activation; cell growth; cell isolation; cell maturation; cell stress; CHOP gene; clinical article; CLPP gene; cohort analysis; concentration (parameter); controlled study; disease assessment; endoplasmic reticulum; fasting; female; gene activation; gene expression; gene overexpression; glucose blood level; granulosa cell; homeostasis model assessment; HSP10 gene; HSP40 gene; HSP60 gene; human; human cell; insulin resistance; IRE1 gene; metabolic disorder; microenvironment; mitochondrion; oocyte donor; oocyte retrieval; ovary polycystic disease; pathophysiology; real time polymerase chain reaction; real time reverse transcription polymerase chain reac