Abstract
BackgroundIncreasing evidence supports a relationship between obesity and either infertility or subfertility in women. Most previous omics studies were focused on determining if the serum and follicular fluid expression profiles of subjects afflicted with both obesity-related infertility and polycystic ovary syndrome (PCOS) are different than those in normal healthy controls. As granulosa cells (GCs) are essential for oocyte development and fertility, we determined here if the protein expression profiles in the GCs from obese subjects are different than those in their normal-weight counterpart.MethodsGC samples were collected from obese female subjects (n = 14) and normal-weight female subjects (n = 12) who were infertile and underwent in vitro fertilization (IVF) treatment due to tubal pathology. A quantitative approach including tandem mass tag labeling and liquid chromatography tandem mass spectrometry (TMT) was employed to identify differentially expressed proteins. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were then conducted to interrogate the functions and pathways of identified proteins. Clinical, hormonal, and biochemical parameters were also analyzed in both groups.ResultsA total of 228 differentially expressed proteins were noted, including 138 that were upregulated whereas 90 others were downregulated. Significant pathways and GO terms associated with protein expression changes were also identified, especially within the mitochondrial electron transport chain. The levels of free fatty acids in both the serum and follicular fluid of obese subjects were significantly higher than those in matched normal-weight subjects.ConclusionsIn GCs obtained from obese subjects, their mitochondria were damaged and the endoplasmic reticulum stress response was accompanied by dysregulated hormonal synthesis whereas none of these changes occurred in normal-weight subjects. These alterations may be related to the high FFA and TG levels detected in human follicular fluid.
Highlights
Increasing evidence supports a relationship between obesity and either infertility or subfertility in women
The exposure of ovarian cells to high levels of fatty acids could result in an inflammatory response within ovarian follicles [32], excessive ovarian androgen production through ineffective free fatty acid (FFA) β-oxidation in mitochondria [33], insulin resistance [34], and oxidative DNA damage caused by reactive oxygen species (ROS) reacting with DNA within the cell, including mitochondrial DNA [35]
The concentration of FFA and triglycerides in the follicular fluid of obese subjects was higher than that in control group. This was consistent with the results of our previous study, in which we found that FFA and triglycerides, as important biomedical indicators of abnormal lipid metabolism, were elevated in the serum and follicular fluid of obese subjects with polycystic ovary syndrome (PCOS) and associated with lower embryo quality [36]
Summary
Increasing evidence supports a relationship between obesity and either infertility or subfertility in women. As granulosa cells (GCs) are essential for oocyte development and fertility, we determined here if the protein expression profiles in the GCs from obese subjects are different than those in their normal-weight counterpart. Compared to age-matched normal-weight women, obese women have an increased risk of ovulatory subfertility and anovulatory infertility [2,3,4]. Multiple studies reported no significant association between BMI and assisted reproductive outcomes [10,11,12] This controversy indicates that the effect of obesity on oocyte quality and fertility outcome is somewhat complex, and underlying mechanisms remain to be elucidated [13]
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