title: High-fat diet causes lipotoxicity responses in cumulus-oocyte complexes and decreased fertilization rates.
abstract: In obesity, accumulation of lipid in nonadipose tissues, or lipotoxicity, is associated with endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and ultimately apoptosis. We have previously shown that obese women have increased triglycerides in follicular fluid; thus, the present study examined whether high-fat diet-induced obesity causes lipotoxicity in granulosa cells and the cumulus-oocyte complex (COC). Oocytes of mice fed a high-fat diet had dramatically increased lipid content and reduced mitochondrial membrane potential compared to those of mice fed a control diet. COCs from mice fed a high-fat diet had increased expression of ER stress marker genes ATF4 and GRP78. Apoptosis was increased in granulosa and cumulus cells of mice fed a high-fat diet. Mice fed a high-fat diet also exhibited increased anovulation and decreased in vivo fertilization rates. Thus, lipid accumulation, ER stress, mitochondrial dysfunction, and apoptosis are markedly increased in ovarian cells of mice fed a high-fat diet. ER stress markers were also analyzed in granulosa cells and follicular fluid from women with varying body mass indices (BMI). ATF4 was increased in granulosa cells and [Ca(2+)] in follicular fluid from obese women compared to nonobese women. These results indicate that lipotoxicity may be occurring in ovarian cells of obese women and may contribute to the reduced pregnancy rates observed in response to obesity.
authors.affiliation: School of Pediatrics and Reproductive Health, Robinson Institute, University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: Linda Lin-Yan
authors.initials: LL
authors.lastname: Wu
authors.forename: Kylie R
authors.initials: KR
authors.lastname: Dunning
authors.forename: Xing
authors.initials: X
authors.lastname: Yang
authors.forename: Darryl L
authors.initials: DL
authors.lastname: Russell
authors.forename: Michelle
authors.initials: M
authors.lastname: Lane
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Norman
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Robker
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis; D054885:Cumulus Cells / Q000378:metabolism*; D004032:Diet; D004041:Dietary Fats / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D005306:Fertilization / Q000502:physiology*; D015571:Follicular Fluid / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D008055:Lipids / Q000032:analysis*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D009865:Oocytes / Q000737:chemistry / Q000378:metabolism*; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004041:Dietary Fats; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D008055:Lipids