TMT-based proteomic and bioinformatic analyses of human granulosa cells from obese and normal-weight female subjects

Si, Chenchen; Wang, Nan; Wang, Mingjie; Liu, Yue; Niu, Zhihong; Ding, Zhide

doi:10.1186/s12958-021-00760-x

Cited by 14 publications

(21 citation statements)

References 70 publications

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“…There is evidence that obesity induced changes can be the result of disordered insulin signaling in the ovary and pituitary gland metabolic activity [19,20]. Other studies suggest that disrupted normal reproductive behavior may instead stem from abnormal adipogenesis [21] and mitochondrial dysfunction in the ovarian follicular cells [22][23][24]. Recently, it has become apparent throughout the world that a chronic low-grade inflammatory status accompanies obesity in both humans and experimental animal models [13,25,26].…”

Section: Introductionmentioning

confidence: 99%

Obesity induces morphological and functional changes in female reproductive system through increases in NF-κB and MAPK signaling in mice

Gao

et al. 2021

Reprod Biol Endocrinol

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Background Recently, human infertility incidence is increasing in obese women causing it to become an emerging global health challenge requiring improved treatment. There is extensive evidence that obesity caused female reproductive dysfunction is accompanied by an endocrinological influence. Besides, systemic and tissue-specific chronic inflammatory status are common characteristics of obesity. However, the underlying molecular mechanism is unclear linking obesity to infertility or subfertility. Methods To deal with this question, we created an obese mouse model through providing a high fat diet (HFD) and determined the fertility of the obese mice. The morphological alterations were evaluated in both the reproductive glands and tracts, such as uterus, ovary and oviduct. Furthermore, to explore the underlying mechanism of these functional changes, the expressions of pro-inflammatory cytokines as well as the activations of MAPK signaling and NF-κB signaling were detected in these reproductive tissues. Results The obese females were successful construction and displayed subfertility. They accumulated lipid droplets and developed morphological alterations in each of their reproductive organs including uterus, ovary and oviduct. These pathological changes accompanied increases in pro-inflammatory cytokine expression levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in all of these sites. Such effects also accompanied increases in nuclear factor kappa B (NF-kB) expression and mitogen-activated protein kinase (MAPK) signaling pathway stimulation based on uniform time dependent increases in the NF-κB (p-NF-κB), JNK (p-JNK), ERK1/2 (p-ERK) and p38 (p-p38) phosphorylation status. Conclusions These HFD-induced increases in pro-inflammatory cytokine expression levels and NF-κB and MAPKs signaling pathway activation in reproductive organs support the notion that increases of adipocytes resident and inflammatory status are symptomatic of female fertility impairment in obese mice.

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Section: Introductionmentioning

confidence: 99%

Obesity induces morphological and functional changes in female reproductive system through increases in NF-κB and MAPK signaling in mice

Gao

et al. 2021

Reprod Biol Endocrinol

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“…SUMO3 is involved in the posttranslation modification of target proteins known as sumoylation [ 53 ]. SUMO3 has been found to be involved in disorders like obesity and neurodegenerative disorders like Parkinson disease and amyotrophic lateral sclerosis [ 53 - 55 ]. In a study that looked at obese and normal weight participants, proteomic analysis identified SUMO3 to be one of the top 10 differentially expressed genes between the 2 groups [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Prediction of Weight Loss to Decrease the Risk for Type 2 Diabetes Using Multidimensional Data in Filipino Americans: Secondary Analysis

Chang¹,

Fukuoka²,

Aouizerat³

et al. 2023

JMIR Diabetes

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Background Type 2 diabetes (T2D) has an immense disease burden, affecting millions of people worldwide and costing billions of dollars in treatment. As T2D is a multifactorial disease with both genetic and nongenetic influences, accurate risk assessments for patients are difficult to perform. Machine learning has served as a useful tool in T2D risk prediction, as it can analyze and detect patterns in large and complex data sets like that of RNA sequencing. However, before machine learning can be implemented, feature selection is a necessary step to reduce the dimensionality in high-dimensional data and optimize modeling results. Different combinations of feature selection methods and machine learning models have been used in studies reporting disease predictions and classifications with high accuracy. Objective The purpose of this study was to assess the use of feature selection and classification approaches that integrate different data types to predict weight loss for the prevention of T2D. Methods The data of 56 participants (ie, demographic and clinical factors, dietary scores, step counts, and transcriptomics) were obtained from a previously completed randomized clinical trial adaptation of the Diabetes Prevention Program study. Feature selection methods were used to select for subsets of transcripts to be used in the selected classification approaches: support vector machine, logistic regression, decision trees, random forest, and extremely randomized decision trees (extra-trees). Data types were included in different classification approaches in an additive manner to assess model performance for the prediction of weight loss. Results Average waist and hip circumference were found to be different between those who exhibited weight loss and those who did not exhibit weight loss (P=.02 and P=.04, respectively). The incorporation of dietary and step count data did not improve modeling performance compared to classifiers that included only demographic and clinical data. Optimal subsets of transcripts identified through feature selection yielded higher prediction accuracy than when all available transcripts were included. After comparison of different feature selection methods and classifiers, DESeq2 as a feature selection method and an extra-trees classifier with and without ensemble learning provided the most optimal results, as defined by differences in training and testing accuracy, cross-validated area under the curve, and other factors. We identified 5 genes in two or more of the feature selection subsets (ie, CDP-diacylglycerol-inositol 3-phosphatidyltransferase [CDIPT], mannose receptor C type 2 [MRC2], PAT1 homolog 2 [PATL2], regulatory factor X-associated ankyrin containing protein [RFXANK], and small ubiquitin like modifier 3 [SUMO3]). Conclusions Our results suggest that the inclusion of transcriptomic data in classification approaches for prediction has the potential to improve weight loss prediction models. Identification of which individuals are likely to respond to interventions for weight loss may help to prevent incident T2D. Out of the 5 genes identified as optimal predictors, 3 (ie, CDIPT, MRC2, and SUMO3) have been previously shown to be associated with T2D or obesity. Trial Registration ClinicalTrials.gov NCT02278939; https://clinicaltrials.gov/ct2/show/NCT02278939

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“…A proteomic screen of GCs from obese subjects identi ed more DEPs associated with the response to impaired mitochondrial electron transport chain and endoplasmic reticulum stress, alterations that may be related to the high levels of free fatty acids detected in FF [24]. DEPs identi ed by proteomic analysis of serum from normal-weight adolescent women with PCOS were also shown to be enriched in GO-BP categories, such as in ammatory immune response, metabolism, and insulin-like growth factor receptor signaling [25].…”

Section: Discussionmentioning

confidence: 99%

Fetuin B alleviates testosterone propionate-induced oxidative stress and mitochondrial dysfunction in KGN cells by upregulating the TGFR2/SMAD3 pathway

Gao

Zheng

et al. 2022

Preprint

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Background Polycystic ovary syndrome (PCOS) is one of the most common reproduction and endocrine disorders. Patients with abnormal follicle growth develop ovulation disorders and amenorrhea, and eventually infertility. The role of Fetuin-B (FETUB), one of the differentially expressed proteins (DEPs) in follicular fluid (FF) of PCOS patients, in pathogenesis of PCOS was not clearly clarified. Methods In this study, we performed iTRAQ-based quantitative proteomic analysis on FF collected from non-PCOS healthy controls and PCOS patients to identify DEPs. In addition, KGN cells treated with testosterone propionate (TP) were used as a model of hyperandrogenism in vitro to investigate the regulatory effects of the selected DEP, FETUB, on cellular processes in KGN cells and its molecular mechanism by detecting steroid hormone secretion, measuring indicators of oxidative stress (OS), mitochondria functions and apoptosis and characterizing the FETUB-altered downstream signaling. Results We found that supplementation with recombinant FETUB could significantly restore the total antioxidant capacity and activity of antioxidant enzymes, which were reduced by treatment with TP. Additionally, FETUB restored the secretory and mitochondrial functions in TP-impaired KGN cells and reduced their apoptosis. Furthermore, our study revealed that FETUB could bind with transforming growth factor beta receptor 2 (TGFR2) on the cell membrane of KGN cells and promote phosphorylation of SMAD3, which had a therapeutic effect against tissue injury and inflammation. And the protective effect of FETUB on TP-treated KGN cells was inhibited by pre-treatment with SB431542 and SIS3, selective inhibitors of TGFR2 and SMAD3, respectively. Conclusions These results indicate that FETUB may protect TP-treated KGN by alleviating OS and mitochondrial dysfunction via the TGFR2-mediated SMAD pathway. Data are available via ProteomeXchange with identifier PXD036531

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TMT-based proteomic and bioinformatic analyses of human granulosa cells from obese and normal-weight female subjects

Cited by 14 publications

References 70 publications

Obesity induces morphological and functional changes in female reproductive system through increases in NF-κB and MAPK signaling in mice

Obesity induces morphological and functional changes in female reproductive system through increases in NF-κB and MAPK signaling in mice

Prediction of Weight Loss to Decrease the Risk for Type 2 Diabetes Using Multidimensional Data in Filipino Americans: Secondary Analysis

Fetuin B alleviates testosterone propionate-induced oxidative stress and mitochondrial dysfunction in KGN cells by upregulating the TGFR2/SMAD3 pathway

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