Obesity and the reproductive system disorders: epigenetics as a potential bridge

BACKGROUND: Obesity and overweight are significantly involved in several reproductive pathologies contributing to infertility in men and women. In addition, several cancers of the reproductive system, such as endometrial, ovarian, breast, testicular and prostate cancers, are strongly influenced by obesity. However, the molecular mechanisms involved in the association between obesity and reproductive disorders remain unclear. Our proposal is to review the current scientific evidence regarding the effect of obesity-related factors as the core of the collective mechanisms directly and indirectly involved in the relationship between obesity and reproductive disorders, with a special and original focus on the effect of the obesity state microenvironment on the epigenetic profile as a reversible mechanistic link between obesity and the reproductive disorders. METHODS: A PubMed search was performed using keywords related to obesity and adipose-related factors and epigenetics and associated with keywords related to reproduction. Full-text articles and abstracts in the English language published prior to 31 December 2013 were reviewed. RESULTS: The obesity state notably contributes to a reproductive dysfunction in both men and women, ranging from infertility to oncological outcomes. Several epidemiological and experimental studies demonstrate that factors secreted by the adipose tissue and gut in an obesity state can directly induce reproductive disturbances. Relevantly, these same factors are able to alter the epigenetic regulation of genes, a dynamic and reversible mechanism by which the organism responds to environmental pressures critical to the reproductive function. CONCLUSION: This review outlines the evidence showing that the association between the reproductive pathologies and obesity is not inevitable but is potentially preventable and reversible. The epigenetic marks related to obesity could constitute a therapeutic target for the reproductive disorders associated with obesity.Instituto de Salud Carlos III/CIBERobnInstituto de Salud Carlos III/INTRASALUDXunta de GaliciaFundación Lill

Pituitary tumor centers of excellence for Cushing’s disease

Open Access funding provided thanks to the CRUE-CSIC agreement with Springer NatureS

Leptin, Obesity, and Leptin Resistance: Where Are We 25 Years Later?

Leptin, a hormone that is capable of effectively reducing food intake and body weight, was initially considered for use in the treatment of obesity. However, obese subjects have since been found to have high levels of circulating leptin and to be insensitive to the exogenous administration of leptin. The inability of leptin to exert its anorexigenic effects in obese individuals, and therefore, the lack of clinical utility of leptin in obesity, is defined as leptin resistance. This phenomenon has not yet been adequately characterized. Elucidation of the molecular mechanisms underlying leptin resistance is of vital importance for the application of leptin as an effective treatment for obesity. Leptin must cross the blood–brain barrier (BBB) to reach the hypothalamus and exert its anorexigenic functions. The mechanisms involved in leptin transportation across the blood–brain barrier continue to be unclear, thereby preventing the clinical application of leptin in the treatment of obesity. In recent years, new strategies have been developed to recover the response to leptin in obesity. We have summarized these strategies in this review.This work was supported by Centro de Investigacion Biomedicaen Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn) and grants from the Instituto de Salud Carlos III (PI17/01287) cofinanced by the European Regional Development Fund (FEDER). Andrea G. Izquierdo and Marcos C Carreira are funded by CIBERobn and Ana B. Crujeiras is funded by a research contract “Miguel Servet” (CP17/00088) from the Instituto de Salud Carlos III, cofinanced by the European Regional Development Fund (FEDER)S

Drug development strategies for the treatment of obesity: how to ensure efficacy, safety, and sustainable weight loss

The prevalence of obesity has increased worldwide, and approximately 25%-35% of the adult population is obese in some countries. The excess of body fat is associated with adverse health consequences. Considering the limited efficacy of diet and exercise in the current obese population and the use of bariatric surgery only for morbid obesity, it appears that drug therapy is the only available method to address the problem on a large scale. Currently, pharmacological obesity treatment options are limited. However, new antiobesity drugs acting through central nervous system pathways or the peripheral adiposity signals and gastrointestinal tract are under clinical development. One of the most promising approaches is the use of peptides that influence the peripheral satiety signals and brain-gut axis such as GLP-1 analogs. However, considering that any antiobesity drug may affect one or several of the systems that control food intake and energy expenditure, it is unlikely that a single pharmacological agent will be effective as a striking obesity treatment. Thus, future strategies to treat obesity will need to be directed at sustainable weight loss to ensure maximal safety. This strategy will probably require the coadministration of medications that act through different mechanisms.Instituto de Salud Carlos IIIXunta de GaliciaFundación Mutua Madrileñ

Comparative secretome analysis of rat stomach under different nutritional status

The fact that gastric surgery is at the moment the most effective treatment to fight against obesity highlights the relevance of gastric derived proteins as potential targets to treat this pathology. Taking advantage of a previously established gastric explant model for endocrine studies, the proteomic analysis of gastric secretome was performed. To validate this gastric explant system for proteomic analysis, the identification of ghrelin, a classical gastric derived peptide, was performed by MS. In addition, the differential analysis of gastric secretomes under differential nutritional status (control feeding vs fasting vs re-feeding) was performed. The MS identified proteins are showed in the present manuscript. The data supplied in this article is related to the research article entitled "Comparative secretome analysis of rat stomach under different nutritional status" (L.L. Senin, A. Roca-Rivada, C. Castelao, J. Alonso, C. Folgueira, F.F. Casanueva, M. Pardo, L.M. Seoane Comparative secretome analysis of rat stomach under different nutritional status J. Proteomics (2015))

Analysis of platelets from a diet-induced obesity rat model: elucidating platelet dysfunction in obesity

Obesity is one of the main health problems in industrialized countries. The contribution of multiple factors developed in obesity can hardly be modeled in vitro. In this context, the development of animal models mimicking human obesity could be essential. The aim of the present study was to compare platelets from a diet-induced obesity (DIO) rat model with their lean control group in order to elucidate platelet dysfunction mechanisms in obesity and correlate the results with previous data from morbid obese patients. In parallel, we also established a blood collection and platelet isolation methodology to study the DIO rat model at biochemical and functional level. Optimal blood collection was obtained from vena cava and platelet isolation was based on a serial of centrifugations avoiding platelet activation. Our results show that the DIO rat model simulate obesity pathologically since weight gain, fasting glucose and platelet counts are increased in obese rats. Interestingly, platelet levels of the active form of Src (pTyr(419)) showed a tendency to increase in DIO rats pointing towards a potential dysfunction in Src family kinases-related signalling pathways in obesity. Moreover, platelets from DIO rats adhere more to collagen compared with the control group, pointing towards Glycoprotein VI (GPVI) as one of the dysregulated receptors in obesity, in agreement with our recent studies in humans. These results confirm that obesity, in line with human studies, present a platelet dysregulation, and highlight the relevance of considering novel antithrombotic drug targets in these patients, such as GPVI

Plasma irisin depletion under energy restriction is associated with improvements in lipid profile in metabolic syndrome patients

OBJECTIVE: A recently discovered myokine, irisin, may have an important role in energy metabolism. This study aimed to evaluate the relationship between this hormone and the lipid profile of patients with metabolic syndrome (MetS) following a hypocaloric diet. DESIGN: Ninety-three Caucasian adults (52 men/41 women) diagnosed with MetS followed an 8-week-long energy-restricted programme (-30% of the energy requirements). Anthropometric measurements, biochemical markers and plasma irisin levels were analysed before and after the nutritional intervention. RESULTS: Global plasma irisin levels were significantly reduced at the end of the study (-72.0 +/- 100.9 ng/ml, P < 0.001) accompanying the weight loss (-6.9%). The depletion of irisin significantly correlated with changes in some atherogenic-related variables: total cholesterol (B = 0.106, P = 0.018), total cholesterol/high-density lipoprotein cholesterol ratio (B = 0.002, P = 0.036), low-density lipoprotein cholesterol (B = 0.085, P = 0.037) and apolipoprotein B (B = 0.052, P = 0.002), independently of changes in body weight. CONCLUSIONS: An association between the reduction in plasma irisin levels and the depletion of important lipid metabolism biomarkers was observed in patients with MetS undergoing an energy-restricted programme

Effect of excess body adiposity on the expression of genes involved in early steps of mammary carcinogenesis on diet-induced obese female rats

Introduction: Obesity is increasing worldwide and is associated with higher risk for some cancers. However, the mechanisms underlying this association are unclear. Because the obesity microenvironment could promote the onset of carcinogenesis, the aim of this study was to evaluate the association between excess body adiposity and the expression of genes related to the activation of early steps of tumor promotion on the mammary gland. Methods: Three weeks-old female Sprague-Dawley rats were fed a high fat diet (DIO: 60% Kcal/g fat, n = 14) or standard chow (LEAN: 3% Kcal/g fat, n = 15) for 10 weeks. Body weight and food intake were measured weekly. After sacrifice, retroperitoneal fat tissue was weighed and mammary tissue was extracted for qRT-PCR analysis. Genes associated with cell proliferation (Survivin/BIRC5 and MYC), DNA repair (TP53), and antioxidant protection (GSTM2, ALDH3A1) were quantified. Results: The DIO group showed a body weight 14.1% higher than LEAN group (p < 0.001). These differences were reflected on higher retroperitoneal fat content on DIO (3.22 ± 0.89g) vs. LEAN group (2.33 ± 0.52g; p = 0.012). Interestingly, DIO rats showed a higher gene expression for Survivin (∆68.2%), MYC (∆50.1%), TP53 (∆40.5%), ALDH3A1 (∆74.1%), and GSTM2 (∆25.7%) with respect to LEAN group. Conclusion: These data show that obesity is associated with changes potentially involved in early steps of tumor promotion, as shown by an increase in cellular proliferation and DNA damage related genes, even before detecting histological changes on the mammary tissue of obese female individuals. Further studies are needed to elucidate weather reducing body weight might be a therapeutic strategy to prevent this process

Higher baseline irisin concentrations are associated with greater reductions in glycemia and insulinemia after weight loss in obese subjects

Irisin is assumed to be a relevant link between muscle and weight maintenance as well as to mediate exercise benefits on health. The aim of this study was to assess the possible associations between irisin levels and glucose homeostasis in obese subjects with metabolic syndrome (MetS) following an energy-restricted treatment. Ninety-six adults with excessive body weight and MetS features underwent a hypocaloric dietary pattern for 8 weeks, within the RESMENA randomized controlled trial (www.clinicaltrials.gov; NCT01087086). After the intervention, dietary restriction significantly reduced body weight and evidenced a dietary-induced decrease in circulating levels of irisin in parallel with improvements on glucose homeostasis markers. Interestingly, participants with higher irisin values at baseline (above the median) showed a greater reduction on glucose (P=0.022) and insulin (P=0.021) concentrations as well as on the homeostasis model assessment index (P=0.008) and triglycerides (P=0.006) after the dietary intervention, compared with those presenting low-irisin baseline values (below the median). Interestingly, a positive correlation between irisin and carbohydrate intake was found at the end of the experimental period. In conclusion, irisin appears to be involved in glucose metabolism regulation after a dietary-induced weight loss

Vesicles Shed by Pathological Murine Adipocytes Spread Pathology: Characterization and Functional Role of Insulin Resistant/Hypertrophied Adiposomes

Extracellular vesicles (EVs) have recently emerged as a relevant way of cell to cell communication, and its analysis has become an indirect approach to assess the cell/tissue of origin status. However, the knowledge about their nature and role on metabolic diseases is still very scarce. We have established an insulin resistant (IR) and two lipid (palmitic/oleic) hypertrophied adipocyte cell models to isolate EVs to perform a protein cargo qualitative and quantitative Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH) analysis by mass spectrometry. Our results show a high proportion of obesity and IR-related proteins in pathological EVs; thus, we propose a panel of potential obese adipose tissue EV-biomarkers. Among those, lipid hypertrophied vesicles are characterized by ceruloplasmin, mimecan, and perilipin 1 adipokines, and those from the IR by the striking presence of the adiposity and IR related transforming growth factor-beta-induced protein ig-h3 (TFGBI). Interestingly, functional assays show that IR and hypertrophied adipocytes induce differentiation/hypertrophy and IR in healthy adipocytes through secreted EVs. Finally, we demonstrate that lipid atrophied adipocytes shed EVs promote macrophage inflammation by stimulating IL-6 and TNFα expression. Thus, we conclude that pathological adipocytes release vesicles containing representative protein cargo of the cell of origin that are able to induce metabolic alterations on healthy cells probably exacerbating the disease once establishedThis research was funded by Instituto de Salud Carlos III-FEDER, grant number PI16/01212S