Genome wide effects of oleic acid on cultured bovine granulosa cells: evidence for the activation of pathways favoring folliculo-luteal transition

Abstract

Background Metabolic stress, as negative energy balance on one hand or obesity on the other hand can lead to increased levels of free fatty acids in the plasma and follicular fluid of animals and humans. In an earlier study, we showed that increased oleic acid (OA) concentrations affected the function of cultured bovine granulosa cells (GCs). Here, we focus on genome wide effects of increased OA concentrations. Results Our data showed that 413 genes were affected, of which 197 were down- and 216 up-regulated. Specifically, the expression of FSH-regulated functional key genes, CCND2, LHCGR, INHA and CYP19A1 and 17-β-estradiol (E2) production were reduced by OA treatment, whereas the expression of the fatty acid transporter CD36 was increased and the morphology of the cells was changed due to lipid droplet accumulation. Bioinformatic analysis revealed that associated pathways of the putative upstream regulators “FSH” and “Cg (choriogonadotropin)” were inhibited and activated, respectively. Down-regulated genes are over-represented in GO terms “reproductive structure/system development”, “ovulation cycle process”, and “(positive) regulation of gonadotropin secretion”, whereas up-regulated genes are involved in “circulatory system development”, “vasculature development”, “angiogenesis” or “extracellular matrix/structure organization”. Conclusions From these data we conclude that besides inhibiting GC functionality, increased OA levels seemingly promote angiogenesis and tissue remodelling, thus suggestively initiating a premature fulliculo-luteal transition. In vivo this may lead to impeded folliculogenesis and ovulation, and cause sub-fertility.

High-Fat Diet and Female Fertility across Lifespan: A Comparative Lesson from Mammal Models

“…Moreover, studies in mice [ 151 , 153 , 154 , 155 , 156 , 157 ], humans [ 158 ], bovines [ 150 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 ], pigs [ 85 , 169 , 170 , 171 ], and sheep [ 172 ] demonstrated that the lipid profile alteration resulted in lipotoxicity in the follicular cells and oocyte. Follicular cell biological functions were affected in their viability, proliferation, ROS production, lipid storage, and ER stress response which ultimately resulted in apoptosis.…”

Estradiol production of granulosa cells is unaffected by the physiological mix of nonesterified fatty acids in follicular fluid

“…1 E ). Stearate is a direct substrate for oleate biosynthesis by the enzyme stearoyl CoA desaturase, which is abundantly expressed in GCs ( 34 , 35 ). Therefore, the decrease of estradiol at higher stearate concentrations than its lower concentrations might be because of the increased biosynthesis of oleic acid from the exogenous stearate.…”

“…We have recently reported a genome-wide transcriptome analysis of GCs treated with OA (GEO reference: GSE152307) ( 35 ). In the present study, we have reanalyzed the datasets and identified significantly regulated genes using false discovery rate (FDR) (q) <0.05 without considering the fold change cutoff value, which was previously used as a stringent selection criterion for identifying differentially regulated genes.…”

Cocultured porcine granulosa cells respond to excess non-esterified fatty acids during in vitro maturation

“…Prediction of their downregulation in this study implies that the EMT from GCs to luteal cells was possibly inhibited in vitro in the presence of COCs and NEFAs. A recent study suggested that increased concentrations of oleic acid (OA) may promote the EMT process in bovine GCs [26]. Oleic acid was Fig.…”