A Systematic Review of Proteomics in Obesity: Unpacking the Molecular Puzzle.

PURPOSE OF REVIEW: The present study aims to review the existing literature to identify pathophysiological proteins in obesity by conducting a systematic review of proteomics studies. Proteomics may reveal the mechanisms of obesity development and clarify the links between obesity and related diseases, improving our comprehension of obesity and its clinical implications. RECENT FINDINGS: Most of the molecular events implicated in obesity development remain incomplete. Proteomics stands as a powerful tool for elucidating the intricate interactions among proteins in the context of obesity. This methodology has the potential to identify proteins involved in pathological processes and to evaluate changes in protein abundance during obesity development, contributing to the identification of early disease predisposition, monitoring the effectiveness of interventions and improving disease management overall. Despite many non-targeted proteomic studies exploring obesity, a comprehensive and up-to-date systematic review of the molecular events implicated in obesity development is lacking. The lack of such a review presents a significant challenge for researchers trying to interpret the existing literature. This systematic review was conducted following the PRISMA guidelines and included sixteen human proteomic studies, each of which delineated proteins exhibiting significant alterations in obesity. A total of 41 proteins were reported to be altered in obesity by at least two or more studies. These proteins were involved in metabolic pathways, oxidative stress responses, inflammatory processes, protein folding, coagulation, as well as structure/cytoskeleton. Many of the identified proteomic biomarkers of obesity have also been reported to be dysregulated in obesity-related disease. Among them, seven proteins, which belong to metabolic pathways (aldehyde dehydrogenase and apolipoprotein A1), the chaperone family (albumin, heat shock protein beta 1, protein disulfide-isomerase A3) and oxidative stress and inflammation proteins (catalase and complement C3), could potentially serve as biomarkers for the progression of obesity and the development of comorbidities, contributing to personalized medicine in the field of obesity. Our systematic review in proteomics represents a substantial step forward in unravelling the complexities of protein alterations associated with obesity. It provides valuable insights into the pathophysiological mechanisms underlying obesity, thereby opening avenues for the discovery of potential biomarkers and the development of personalized medicine in obesity.

Stem Cell Protein PIWIL2 Promotes EMT Process and Stem Cell-Like Properties in MCF7 Breast Cancer Cell Line.

Background: Piwi-like RNA-mediated gene silencing 2 (PIWIL2) is a member of AGO/PIWI gene family, which is enriched in cancer stem cells (CSCs). The purpose of this research was to investigate the overexpression of PIWIL2 and its role in the induction of EMT and CSC properties in MCF7 breast cancer cell line. Materials and Methods: MCF7 cells were transfected with the human gene PIWIL2 (Hili) under the control of CMV promoter utilizing the neon electroporation method. Subsequently, the selection was conducted using G418, and doubling time was calculated in the transformed and control cells. RT and real-time PCR were also performed to analyze the expression of epithelial and mesenchymal genes and those related to CSCs. Results: According to the observations from this study, transfecting MCF7 cells with PIWIL2 triggered the conversion of epithelial cells to mesenchymal cells and induced the genes specific for breast CSCs, which was coincident with 9-h reduction in the doubling time of the transfected cells. Furthermore, the molecular analyses revealed a significant reduction in the expression of epithelial markers, while a significant increase was detected in the expression of mesenchymal genes and many CSC biomarkers. Conclusion: PIWIL2 protein acts as a master regulatory protein that is able to manipulate the transcription through specific signaling pathways, which allow the cells to gain stem cell-like properties.

Characterization of altered microRNAs related to different phenotypes of polycystic ovarian syndrome (PCOS) in serum, follicular fluid, and cumulus cells.

OBJECTIVE: Polycystic ovarian syndrome (PCOS) is a metabolic syndrome in which steroidogenesis, folliculogenesis, and cellular adhesion play crucial roles in its prognosis. These pathways are controlled and regulated by some small non-coding RNAs called microRNAs (miRs). Several miRs have differential expression in PCOS compared to healthy women, and their dysregulation suggests important roles of miRs in PCOS pathophysiology. However, the role of miRs is still unclear, especially in various phenotypes of PCOS. MATERIALS AND METHODS: This study was conducted to evaluate the diagnostic potential of miR-212-3p, miR-490-5p, miR-647, and miR-4643 in different subtypes of PCOS. Accordingly, nineteen PCOS patients with different subtypes based on Rotterdam criteria (A: 8, B: not detected in this study, C: 5, and D: 6 patients) and six control age and BMI matched women under ICSI treatment were selected. The relative expression of miRs was then measured in blood serum before hormonal treatment (S1) and before ovum pickup (S2), follicular fluid (FF), and cumulus cells (CC) in all subjects. Also, the expression of miRs predicted target genes (AMH, AR, CYP11A1, CYP17A1, CYP19A1, GDF9, and HSD17B12) were done in the CC of understudy groups. RESULTS: In general, the results indicated that PCOS significantly increased the expression of miR-212-3p, miR-490-5p, and miR-4643 in FF and CCs compared to control. Although these miRs tend to increase in serum 1 of the PCOS patients, the differences were insignificant. However, there was a significant reduction in the expression of miR-647 in FF and CCs between PCOS vs. control. In addition, the miRs had significantly different expressions in various phenotypes of PCOS. For example, high levels of miR-647 in S2 and low levels of miR-490 in FF and miR-212 in CC can differentiate phenotype A from the other. Also, upregulation of miR-212 in FF and miR-4643 in S1 and low levels of this miR in FF can specifically differentiate subtype A from D. On the other hand, high levels of miR-4643 in FF and miR-490 in CC and lower titter of miR-647 can distinguish subtype C from the other. On the other hand, high levels of AMH, AR, CYP11, CYP17, and HSD17 in the hyperandrogenic PCOS and upregulation of CYP19A1 in the hypoandrogenic group can validate the role of selected miRs in the prognosis of PCOS. CONCLUSION: Characterization of altered microRNAs in serum, FF, and CCs and their targets in CC showed that the miRs might play critical roles in steroidogenesis and folliculogenesis. These miRs may be used for molecular classification of PCOS subtypes and as biomarkers for PCOS diagnosis.

Evaluation of Adipose Tissue Zinc-Alpha 2-Glycoprotein Gene Expression and Its Relationship with Metabolic Status and Bariatric Surgery Outcomes in Patients with Class III Obesity.

Zinc-α2 glycoprotein (ZAG) is an adipokine involved in adipocyte metabolism with potential implications in the pathogenesis of metabolic disorders. Our aim was to evaluate the relationship between visceral (VAT) and subcutaneous adipose tissue (SAT) ZAG expression and metabolic parameters in patients with class III obesity, along with the impact of basal ZAG expression on short- and medium-term outcomes related to bariatric surgery. 41 patients with class III obesity who underwent bariatric surgery were included in this study. ZAG gene expression was quantified in SAT and VAT. Patients were classified into two groups according to SAT and VAT ZAG percentile. Anthropometric and biochemical variables were obtained before and 15 days, 45 days, and 1 year after surgery. The lower basal SAT ZAG expression percentile was associated with higher weight and waist circumference, while the lower basal VAT ZAG expression percentile was associated with higher weight, waist circumference, insulin, insulin resistance, and the presence of metabolic syndrome. Basal SAT ZAG expression was inversely related to weight loss at 45 days after surgery, whereas no associations were found between basal VAT ZAG expression and weight loss after surgery. Additionally, a negative association was observed between basal SAT and VAT ZAG expression and the decrease of gamma-glutamyl transferase after bariatric surgery. Therefore, lower SAT and VAT ZAG expression levels were associated with an adverse metabolic profile. However, this fact did not seem to confer worse bariatric surgery-related outcomes. Further research is needed to assess the clinical significance of the role of ZAG expression levels in the dynamics of hepatic enzymes after bariatric surgery.

The Effect of Sex and Obesity on the Gene Expression of Lipid Flippases in Adipose Tissue.

Molecular mechanisms behind obesity and sex-related effects in adipose tissue remain elusive. During adipocyte expansion, adipocytes undergo drastic remodelling of lipid membrane compositions. Lipid flippases catalyse phospholipid translocation from exoplasmic to the cytoplasmic leaflet of membranes. The present study aimed to analyse the effect of sex, obesity, and their interactions on the gene expression of two lipid flippases-ATP8A1 and ATP8B1-and their possible microRNA (miR) modulators in visceral adipose tissue (VAT). In total, 12 normal-weight subjects (5 premenopausal women and 7 men) and 13 morbidly obese patients (7 premenopausal women and 6 men) were submitted to surgery, and VAT samples were obtained. Gene expression levels of ATP8A1, ATP8B1, miR-548b-5p, and miR-4643 were measured in VAT. Our results showed a marked influence of obesity on VAT ATP8A1 and ATP8B1, although the effects of obesity were stronger in men for ATP8A1. Both genes positively correlated with obesity and metabolic markers. Furthermore, ATP8B1 was positively associated with miR-548b-5p and negatively associated with miR-4643. Both miRs were also affected by sex. Thus, lipid flippases are altered by obesity in VAT in a sex-specific manner. Our study provides a better understanding of the sex-specific molecular mechanisms underlying obesity, which may contribute to the development of sex-based precision medicine.

Mitochondrial Homeostasis in Obesity-related Hypertriglyceridemia.

CONTEXT: The prevalence of obesity and hypertriglyceridemia is an alarming worldwide health issue. Mitochondria play a central role in these disorders as they control cell metabolism. OBJECTIVE: The aim of the present study was to characterize mitochondrial homeostasis in subcutaneous and visceral adipose tissue (SAT and VAT) in grade III obese patients with and without hypertriglyceridemia. Moreover, this study presents the evaluation of mitochondrial fitness as a marker for hypertriglyceridemia improvement. PATIENTS: Eight control and 12 hypertriglyceridemic (HTG) grade III obese subjects undergoing bariatric surgery were included. MAIN OUTCOME MEASURES: Anthropometric and biochemical data were obtained before and 3 months after surgery. Mitochondrial homeostasis was evaluated by mitochondrial DNA (mtDNA), gene expression and protein abundance in SAT and VAT. RESULTS: Mitophagy-related gene expression was increased in HTG SAT and VAT, while mitochondrial marker gene expression and mtDNA were decreased, indicating an altered mitochondrial homeostasis in HTG. Mitophagy protein abundance was increased in VAT of those subjects that did not improve their levels of triglycerides after bariatric surgery, whereas mitochondrial protein was decreased in the same tissue. Indeed, triglyceride levels positively correlated with mitophagy-related genes and negatively with mitochondrial content markers. Moreover, mitochondria content and mitophagy markers seem to be significant predictors of hypertriglyceridemia and hypertriglyceridemia remission. CONCLUSIONS: Mitochondrial homeostasis of adipose tissue is altered in hypertriglyceridemic patients. At the protein level, mitochondria content and mitophagy are potential markers of hypertriglyceridemia remission in obese patients after bariatric surgery. These results may contribute to the implementation of a clinical approach for personalized medicine.