Abstract
BackgroundMetabolic 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.ResultsOur 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”.ConclusionsFrom 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.
Highlights
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
We showed in a bovine Granulosa Cell (GC) culture model that oleic acid (OA) affects the cell morphology and reduces expression of genes that are involved in 17-β-estradiol (E2) production and gonadotropin signalling as CYP19A1, FSHR and luteinizing hormone/ choriogonadotropin receptor (LHCGR) [17, 18]
To elucidate the pathways and upstream molecules that are involved in GC dysfunction under OA treatment we studied effects of OA on global gene expression and analyzed effects on signaling pathways, upstream regulators and biological processes
Summary
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. We showed that increased oleic acid (OA) concentrations affected the function of cultured bovine granulosa cells (GCs). Dairy cows frequently suffer from negative energy balance (NEB) after parturition Under these metabolic conditions, the serum levels of non-esterified fatty acids (NEFAs) become elevated and can negatively affect the reproductive performance [1,2,3]. Levels of free fatty acids (FFAs) like palmitic acid (PA, 16:0), stearic acid (SA, 18: 0), oleic acid (OA, 18:1) and of β-hydroxybutyric acid, increase in the plasma and follicular fluid [3, 7] and can negatively affect milk production and cause increased vulnerability to infections, various metabolic diseases and reduced fertility [8,9,10]. During the present genome-wide approach we selected to study OA effects because it was found at highest concentration in animals after fasting as compared to PA and SA [11] and it was shown to elicit strong and reproducible effects on cultured E2 producing GCs [17, 18]
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