Changes in UCP mRNA expression levels in brown adipose tissue and skeletal muscle after feeding a high-energy diet and relationships with leptin, glucose and PPARgamma

Brown adipose tissue and skeletal muscle are known to be important sites for nonshivering thermogenesis. In this context, it is accepted that uncoupling proteins (UCPs) are involved in such process, but little is known about the physiological regulation of these proteins as affected by the intake of a high-energy (cafeteria) diet inducing fat deposition. In this study, the UCP messenger RNA (mRNA) expression in interscapular brown adipose tissue (iBAT) and skeletal muscle was assessed to evaluate the influence of a dietary manipulation on energy homeostasis regulation. We report a statistically significant increase in mRNA levels of iBAT UCP1 and UCP3 and a statistical marginal rise in skeletal muscle UCP3 mRNA expression after feeding a high-energy diet, whereas no changes in UCP2 expression were found in either tissue. Furthermore, significant positive associations between iBAT UCP1 and UCP3 mRNA levels with serum leptin were found. Although the expression of the b3 adrenoceptor (b3AR) was about 50% in the lean controls compared with the obese group in iBAT, no statistically significant changes were observed concerning peroxisome proliferator-activated receptor g2 (PPARg2) mRNA levels in muscle or iBAT. We conclude that feeding a diet inducing weight and fat gain produces different outcomes on iBAT and skeletal muscle UCP mRNA expression, revealing a tissue-dependent response for the three UCPs. Results suggest that the regulation of UCP expression in both tissues under these specific dietary conditions may be related to leptin circulating levels

Up-regulation of a thermogenesis-related gene (UCP1) and down-regulation of PPARgamma and aP2 genes in adipose tissue: possible features of the antiobesity effects of a beta3-adrenergic agonist.

A number of experiments have demonstrated the antiobesity effects of beta(3)-adrenergic receptor stimulation by promoting thermogenesis and/or lipolysis. While many studies have been performed in order to develop beta(3)-adrenergic agonists as a novel strategy in the management of obesity, more information is needed about the mechanisms involved in thermogenesis and the actions of these drugs on adipocyte differentiation. To address this, the possible thermogenic and antiadipogenic properties of Tertatolol, a beta(3)-adrenergic agonist, in a diet-induced obesity model has been tested. Animals fed on a high-fat diet gained more weight and fat mass as compared with control and high-fat fed animals treated with Tertatolol. A RT-PCR was carried out in white adipose tissue specific genes involved in thermogenesis such as uncoupling proteins (UCPs) and adipogenesis such as peroxisome proliferator-activated receptor (PPARgamma2), retinoid receptors (RXRalpha/RARalpha), and fatty acid binding protein (aP2). Levels of UCP1 mRNA were augmented in the Tertatolol-treated group as compared to non-treated high-fat fed animals, while the beta(3)-adrenergic agonist treatment significantly decreased the expression levels of aP2 and transcription factors such as PPARgamma2 and the ratio RXRalpha/RARalpha as compared to obese rats. Altogether these data suggest that the antiobesity effects of beta(3)-adrenergic agonists are not limited to the promotion of thermogenesis and/or lipolysis and support the implication that these beta(3)-adrenergic agonists also affect fat deposition by impairing adipogenesis in white adipose tissue (WAT)

Circulating miRNAs as Biomarkers of Obesity and Obesity-Associated Comorbidities in Children and Adolescents: A Systematic Review

Early detection of obesity and its associated comorbidities in children needs priority for the development of effective therapeutic intervention. Circulating miRNAs (microRNAs) have been proposed as biomarkers for obesity and its comorbidities; therefore, we conducted a systematic review to summarize results of studies that have quantified the profile of miRNAs in children and adolescents with obesity and/or associated disorders. Nine studies aiming to examine differences in miRNA expression levels between children with normal weight and obesity or between obese children with or without cardiometabolic diseases were included in this review. We identified four miRNAs overexpressed in obesity (miR-222, miR-142–3, miR-140-5p, and miR-143) and two miRNAs (miR-122 and miR-34a) overexpressed in children with obesity and nonalcoholic fatty liver disease (NAFLD) and/or insulin resistance. In conclusion, circulating miRNAs are promising diagnostic biomarkers of obesity-associated diseases such as NAFLD and type 2 diabetes already in childhood. However, more studies in children, using massive search technology and with larger sample sizes, are required to draw any firm conclusions.This research was funded by the Spanish Ministry of Industry and Competitiveness (DEP2016-78377-R) and by the European Regional Development Fund (ERDF), M.O. is supported by a grant from the Spanish Ministry of Economy and Competitiveness, grant number; BES-2017-080770 and the APC was funded by additional support from the University of Granada, UGR Research and Knowledge Transfer Fund (PPIT) 2016, Excellence Actions Programme, and Excellence Actions Programe. C.M.A. and I.L.G. are part of the “URG Plan propio de Investigación 2016” and the “Excellence actions: Unit of Excellence on Exercise and Health (UCEES), University of Granada

Prevention of diabetes in overweight/obese children through a family based intervention program including supervised exercise (PREDIKID project): study protocol for a randomized controlled trial

Background: The global pandemic of obesity has led to an increased risk for prediabetes and type-2 diabetes (T2D). The aims of the current project are: (1) to evaluate the effect of a 22-week family based intervention program, including supervised exercise, on insulin resistance syndrome (IRS) risk in children with a high risk of developing T2D and (2) to identify the profile of microRNA in circulating exosomes and in peripheral blood mononuclear cells in children with a high risk of developing T2D and its response to a multidisciplinary intervention program including exercise. Methods: A total of 84 children, aged 8-12 years, with a high risk of T2D will be included and randomly assigned to control (N = 42) or intervention (N = 42) groups. The control group will receive a family based lifestyle education and psycho-educational program (2 days/month), while the intervention group will attend the same lifestyle education and psycho-educational program plus the exercise program (3 days/week, 90 min per session including warm-up, moderate to vigorous aerobic activities, and strength exercises). The following measurements will be evaluated at baseline prior to randomization and after the intervention: fasting insulin, glucose and hemoglobin A1c; body composition (dual-energy X-ray absorptiometry); ectopic fat (magnetic resonance imaging); microRNA expression in circulating exosomes and in peripheral blood mononuclear cells (MiSeq; Illumina); cardiorespiratory fitness (cardiopulmonary exercise testing); dietary habits and physical activity (accelerometry). Discussion: Prevention and identification of children with a high risk of developing T2D could help to improve their cardiovascular health and to reduce the comorbidities associated with obesity.The Spanish Ministry of Industry and Competitiveness (DEP2016-78377-R), by “Fondos Estructurales de la Unión Europea (FEDER), Una manera de hacer Europa.” and by the University of the Basque Country (GIU14/21). This work was also supported by grants from Spanish Ministry of Economy and Competitiveness (RYC-2010-05957; RYC- 2011-09011), Spanish Ministry of Education, Culture and Sports (FPU14/ 03329) and by the Education, Linguistic Policy and Culture Department of the Government of the Basque Country (PRE_2016_1_0057)

Differential expression of oxidative stress and inflammation related genes in peripheral blood mononuclear cells in response to a low-calorie diet: a nutrigenomics study

Nutrigenomics is a new application of omics technologies in nutritional science. Nutrigenomics aims to identify molecular markers of diet-related diseases and mechanisms of interindividual variability in response to food. The aim of this study was to evaluate peripheral blood mononuclear cells (PBMC) as a model system and readily available source of RNA to discern gene expression signatures in relation to personalized therapy of obesity. PBMC were collected from obese men before and after an 8-week low-calorie diet (LCD) to lose weight. Changes in gene expression before and after the LCD were initially screened using a DNA-microarray platform and validated by qRT-PCR. Global gene expression analysis identified 385 differentially expressed transcripts after the LCD. Further analyses showed a decrease in some specific oxidative stress and inflammation genes. Interestingly, expression of these genes was directly related to body weight, while a lower IL8 gene expression was associated with higher fat mass decrease. Collectively, these observations suggest that PBMCs are a suitable RNA source and model system to perform nutrigenomics studies related to obesity and development of personalized dietary treatments. IL8 gene expression warrant further research as a putative novel biomarker of changes in body fat percentage in response to an LCD

Computational and Experimental Evaluation of the Immune Response of Neoantigens for Personalized Vaccine Design

In the last few years, the importance of neoantigens in the development of personalized antitumor vaccines has increased remarkably. In order to study whether bioinformatic tools are effective in detecting neoantigens that generate an immune response, DNA samples from patients with cutaneous melanoma in different stages were obtained, resulting in a total of 6048 potential neoantigens gathered. Thereafter, the immunological responses generated by some of those neoantigens ex vivo were tested, using a vaccine designed by a new optimization approach and encapsulated in nanoparticles. Our bioinformatic analysis indicated that no differences were found between the number of neoantigens and that of non-mutated sequences detected as potential binders by IEDB tools. However, those tools were able to highlight neoantigens over non-mutated peptides in HLA-II recognition (p-value 0.03). However, neither HLA-I binding affinity (p-value 0.08) nor Class I immunogenicity values (p-value 0.96) indicated significant differences for the latter parameters. Subsequently, the new vaccine, using aggregative functions and combinatorial optimization, was designed. The six best neoantigens were selected and formulated into two nanoparticles, with which the immune response ex vivo was evaluated, demonstrating a specific activation of the immune response. This study reinforces the use of bioinformatic tools in vaccine development, as their usefulness is proven both in silico and ex vivo.This work was supported by Basque Government funding (IT456-22; IT1448-22, IT693-22 and IT1524-22; ONKOVAC 2021111042), as well as by the UPV/EHU (GIU20/035; US21/27; US18/21; PIF18/295) and Basque Center of Applied Mathematics (US21/27 and US18/21)