Reversing endoplasmic reticulum stress restores oocyte mitochondrial activity and embryo development in obese mice. (#77)
Obesity is associated with female infertility and our previous studies in mice have shown that obesity-induced defects in ovulation and oocyte developmental competence are associated with intracellular lipid accumulation and endoplasmic reticulum (ER) stress in cumulus-oocyte complexes (COCs) and altered mitochondrial activity in oocytes. We sought to determine whether ER stress inhibitors can reverse obesity-induced defects in oocytes and embryos. ‘Blobby’ mice which exhibit hyperphagia and extreme obesity even on a chow diet have increased circulating cholesterol (1.6-fold), triglycerides (1.68-fold), free fatty acids (1.74-fold), and insulin (9.67-fold) but not glucose. Female Blobby mice have reduced ovulation, negatively correlated with bodyweight (r=-0.6443; p=0.016). COCs from Blobby mice have increased mRNA expression of ER stress markers (Atf4, Atf6, Xbp1s) and heat shock protein chaperones (Hspa1a, Hspa1b) characteristic of an ER stress response, and reduced production of pentraxin-3, a matrix protein essential for ovulation and fertilisation. Blobby oocytes contain large amounts of neutral lipid and exhibit reduced mitochondrial activity. Treatment of Blobby mice with ER stress inhibitors (one of which is in clinical trials for human use), for just 4 days prior to ovulation, restored oocyte mitochondrial activity and pentraxin-3 protein levels and improved ovulation rate. Ovulated oocytes from Blobby mice exhibited reduced in vitro fertilisation rates and were slower to develop to blastocysts. Blastocysts derived from Blobby oocytes had reduced mtDNA, and after transfer to uteri of pseudopregnant recipients, formed significantly heavier fetuses by e14.5 than blastocysts derived from non-obese oocytes (obese 174±6.49mg, non-obese 130±9.56mg, p=0.01).Treatment of Blobby mice with either ER stress inhibitor prior to ovulation normalised fertilisation rates, blastocyst mtDNA levels and development and fetal weight at e14.5. These results demonstrate that ER stress is a fundamental mechanism involved in obesity-induced female infertility but that it can be reversed in order to normalise ovulation and embryo development.