Lipotoxicity Impairs Granulosa Cell Function Through Activated Endoplasmic Reticulum Stress Pathway

Area of Science:

• Reproductive biology
• Endocrinology
• Cellular and molecular biology

Background:

• Obesity is linked to reproductive disorders and infertility.
• Ovarian granulosa cells are crucial for oocyte development and sex steroid production.
• The molecular mechanisms of obesity-induced granulosa cell dysfunction are not well understood.

Purpose of the Study:

• To investigate the molecular mechanisms by which lipotoxicity impairs granulosa cell function.
• To elucidate the role of ER stress and the IRS1 pathway in obesity-related reproductive dysfunction.

Main Methods:

• High-fat diet feeding in mice to induce obesity.
• Treatment of primary mouse granulosa cells with palmitate to mimic lipotoxicity.
• Analysis of ER stress markers, gene expression (Ar, Cyp19a1, Hsd17b1, Irs1), and protein levels.
• Evaluation of testosterone- and insulin-induced estradiol generation.
• Overexpression of IRS1 to assess its protective effects.

Main Results:

• High-fat diet increased GRP78 expression and impaired testosterone-induced estradiol generation in mouse granulosa cells.
• Palmitate treatment induced ER stress and reduced mRNA expression of key granulosa cell function markers.
• Lipotoxicity abolished insulin-promoted aromatase expression and estradiol generation by stimulating ER stress.
• Overexpression of IRS1 ameliorated lipotoxicity-induced impairment of aromatase expression and estradiol generation.

Conclusions:

• Lipotoxicity impairs insulin-stimulated estradiol generation in granulosa cells through ER stress activation.
• Inhibition of the IRS1 pathway by lipotoxicity contributes to granulosa cell dysfunction.
• These findings highlight potential molecular targets for addressing obesity-related infertility.