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Objectives To evaluate whether there is an association between the serum levels of the novel insulin-like adipokine isthmin- 1 (ISM1) and obesity-related phenotypes in a population of Spanish children and to investigate the plausible molecular alterations behind the alteration of the serum levels of this protein in children with obesity. Methods The study population is a sub-cohort of the PUBMEP research project, consisting of a cross-sectional population of 119 pubertal children with overweight (17 boys, 19 girls), obesity (20 boys, 25 girls), and normal weight (17 boys, 21 girls). All subjects were classified into experimental groups according to their sex, obesity, and insulin resistance (IR) status. They were counted anthropometry, glucose and lipid metabolism, inflammation and cardiovascular biomarkers as well as isthmin-1 (ISM1) serum levels. This population was intended as a discovery population to elucidate the relationship between obesity and ISM1 levels in children. Furthermore, the study population had blood whole-genome DNA methylation examined, allowing deepening into the obesity–ISM1 molecular relationship. Results Higher serum ISM1 levels were observed in boys with obesity than in normal weight (P = 0.004) and overweight (P = 0.007) boys. ISM1 serum levels were positively associated with body mass index (BMI) Z-score (P = 0.005) and fat mass (P = 0.058) and negatively associated with myeloperoxidase (MPO) (P = 0.043) in boys. Although we did not find associations between ISM1 serum levels and metabolic outcomes in girls, which may indicate a putative sexual dimorphism, fat mass was positively associated in all children, including boys and girls (P = 0.011). DNA methylation levels in two-enhancer-related CpG sites of ISM1 (cg03304641 and cg14269097) were associated with serum levels of ISM1 in children. Conclusions ISM1 is associated with obesity in boys at the pubertal stage, elucidating how this protein might be of special relevance as a new biomarker of obesity in children. Further studies including a longitudinal design during puberty are needed., Universidad de Granada/CBUA, Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica (I + D + I), Instituto de Salud Carlos III-Health Research Funding (FONDOS FEDER) PI051968 PI1102042 PI1600871, Redes tematicas de Investigacion cooperativa RETIC Red SAMID RD12/0026/0015, Mapfre Foundation

Protein-energy malnutrition is a state of disordered catabolism resulting from metabolic derangements or starvation. It is associated with chronic disease, hypoglycemia, hypothermia, serious infections, and even an increased prevalence of morbidity and mortality in countries with poor socioeconomic or environmental factors. Adequate food administration is essential to satisfy the main caloric and nutritional demands of humans. The most significant factors seen in the development of protein-energy malnutrition in areas of high incidence, such as underdeveloped countries, are inadequate food and nutrient supplies. It has been well established that one of the strategies to alleviate undernourishment is the biofortification of staple crops. This is because vegetables and plants are significant sources of crucial nutrients for human growth and development. To enhance plant nutrition, recent tactics aim to formulated balanced and diverse diets with acceptable levels of vitamins and minerals that benefit human health. New advances in plant biotechnology and animal productivity could control key enzymes in several metabolic pathways, enriching important nutrients such as iron and vitamins and decreasing the content of disadvantageous compounds such as acrylamide-forming amino acids and phytic acids. Numerous biofortified crops such as rice, maize, and wheat have been created to resolve the problem of nutrition deficiencies. Some examples of these methodologies are genome editing engineered nucleases, transcriptional activator-like effector nucleases, zinc finger nucleases, and clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease which have been created and widely studied for their application, efficiency, and specificity.

BackgroundBreastmilk is the most appropriate food for infants and exclusive breastfeeding is highly recommended for the first six months of life to promote adequate growth and development and lower infant morbidity and mortality. Among the best-documented benefits of breastfeeding is the reduced risk of disease and infections such as pneumonia, diarrhea and acute otitis media. Nonetheless, there are situations in which the infant cannot be breastfed; therefore, it is essential to use an appropriately designed infant formula. As current infant formulas incorporate novel ingredients to partly mimic the composition of human milk, the safety and suitability of each specific infant formula should be tested by clinical evaluation in the target population. Here, we report the results of a multicenter, randomized, blinded, controlled clinical trial that aimed to evaluate a novel starting formula on weight gain and body composition of infants up to 6 and 12 months (INNOVA 2020 study), as well as safety and tolerability. The complete protocol of this study has been previously issued.Study design210 infants (70/group) were enrolled in the study, and completed the intervention until 12 months of age. For the intervention period, infants were divided into three groups: group 1 received the formula 1 (Nutribén® Innova1 or INN), with a lower amount of protein, and enriched in α-lactalbumin protein, and with a double amount of docosahexaenoic acid (DHA)/ arachidonic acid (ARA) than the standard formula; it also contained a thermally inactivated postbiotic (Bifidobacterium animalissubsp.lactis, BPL1™ HT). Group 2 received the standard formula or formula 2 (Nutriben® Natal or STD) and the third group was exclusively breastfed for exploratory analysis and used as a reference (BFD group). During the study, visits were made at 21 days, 2, 4, 6, and 12 months of age, with ± 3 days for the visit at 21 days of age, ± 1 week for the visit at 2 months, and ± 2 weeks for the others. During the first 6 months of the study, the infants were only supplied with the starting formula or natural breastfeeding.ResultsThe primary outcome, weight gain, was higher in both formula groups than in the BFD group at 6 and 12 months, whereas no differences were found between STD and INN groups neither at 6 nor at 12 months. Likewise, BMI was higher in infants fed the two formulas compared with the BFD group. Regarding body composition, length, head circumference and tricipital/subscapular skinfolds were alike between groups. The INN formula was considered safe as weight gain and body composition were within the normal limits, according to WHO standards. The BFD group exhibited more liquid consistency in the stools compared to both formula groups. All groups showed similar digestive tolerance and infant behavior. However, a higher frequency of gastrointestinal (GI) symptoms was reported by the STD formula group (291), followed by the INN formula (282) and the BFD groups (227). There were fewer respiratory, thoracic, and mediastinal disorders among BFD children. Additionally, infants receiving the INN formula experienced significantly fewer general disorders and disturbances than those receiving the STD formula. Indeed, atopic dermatitis, bronchitis, and bronchiolitis were significantly more prevalent among infants who were fed the STD formula compared to those fed INN formula or breastfed. To evaluate whether there are significant differences between formula treatments, beyond growth parameters, it would seem necessary to examine more precise health biomarkers and to carry out long-term longitudinal studies.Clinical Trial RegistrationThe trial was registered withClinicaltrial.gov(NCT05303077) on March 31, 2022, and lastly updated on April 7, 2022.

BackgroundBreastmilk is the ideal food for infants and exclusive breastfeeding is recommended. In the clinical trial aimed to evaluate a new starting formula on weight gain of infants up to 6 and 12 months. The novel formula was compared with a standard formula and breastfeeding, the latter being used as the reference method.Methods210 infants (70/group) were enrolled in the study, and completed the intervention until 12 months of age. For the intervention period, infants were divided into three groups: group 1 received the formula 1 (Nutribén Innova®1 or INN), with a lower amount of protein, and enriched in α-lactalbumin protein, and with double amount of docosahexaenoic acid (DHA)/ arachidonic acid (ARA) than the standard formula; it also contained a thermally inactivated postbiotic (Bifidobacterium animalissubsp.lactis, BPL1™ HT). Group 2 received the standard formula or formula 2 (Nutriben® or STD) and the third group was exclusively breastfed for exploratory analysis. During the study, visits were made at 21 days, 2, 4, 6, and 12 months of age, with ± 3 days for the visit at 21 days of age, ± 1 week for the visit at 2 months, and ± 2 weeks for the others.DiscussionThe findings of this study will provide evidence regarding the beneficial health effects of having a novel starting infant formula with reduced levels of protein, enriched in α-lactalbumin, and increased levels of DHA and ARA, and containing a postbiotic, compared with infants fed standard formula.Trial registrationThe trial was registered withClinicaltrial.gov(NCT05303077) on March 31, 2022, and lastly updated on April 7, 2022.

PurposeThe aims of this study were; 1) to evaluate if there is an association between the serum levels of the novel insulin-like adipokine isthmin-1 (ISM1) and obesity-related phenotypes in a population of Spanish children, 2) to investigate the plausible molecular alterations behind the alteration of the serum levels of this protein in children with obesity.MethodsThe study population is a sub-cohort of the PUBMEP research project, consisting of a cross-sectional population of 119 pubertal children with overweight (17 boys, 19 girls), obesity (20 boys, 25 girls) and normal weight (17 boys, 21 girls). All subjects were classified into experimental groups according to their sex, obesity and insulin resistance (IR) status. They counted on anthropometry, glucose, and lipid metabolism, inflammation and cardiovascular biomarkers as well as ISM1 serum levels measured. This population was intended as a discovery population in which to elucidate the relationship between obesity and ISM1 levels in children. Furthermore, the study population had blood whole-genome DNA methylation allowing deepening into the obesity-ISM1 molecular relationship.ResultsHigher serum levels of ISM1 were observed in boys with obesity when compared with normal-weight (P=0.004), and overweight (P=0.007). ISM1 serum levels were positively associated with BMI Z-score (P=0.005), and negatively with myeloperoxidase (MPO) (p=0.043) in boys. Nevertheless, we did not find associations between ISM1 serum levels and metabolic outcomes in girls, indicating a putative sexual dimorphism. DNA methylation levels in two-enhancer-related CpG sites of ISM1 (cg03304641 and cg14269097) were associated with serum levels of ISM1 in children.DiscussionWe report an unprecedented study that provides a major step forward showing that ISM1 is robustly associated with obesity in pubertal boys, elucidating how this protein might be of special relevance as a new biomarker of obesity in children.

Julio Plaza-Diaz is part of the “UGR Plan Propio de Investigación 2016” and the “Excellence actions: Unit of Excellence on Exercise and Health (UCEES), University of Granada”. Patricio Solis-Urra was supported by a fellowship from the National Agency for Research and Development (ANID) BECAS Chile/72180543. Julio Plaza-Diaz is supported by a fellowship awarded to postdoctoral researchers at foreign universities and research centers from the “Fundación Ramón Areces”, Madrid, Spain. Jerónimo Aragón-Vela was funded by a Postdoctoral fellowship from the ‘Fundación Alfonso Martín Escudero’ (Spain). Francisco Javier Ruiz-Ojeda is supported by a fellowship from Spanish Government “Agencia Estatal de Investigación-Juan de la Cierva-Incorporación” program (IJC2020-042739-I). We are grateful to Belén Vázquez-González for her assistance with the illustration service., Physical activity, exercise, or physical fitness are being studied as helpful nonpharmacological therapies to reduce signaling pathways related to inflammation. Studies describing changes in intestinal microbiota have stated that physical activity could increase the microbial variance and enhance the ratio of Firmicutes/Bacteroidetes, and both actions could neutralize the obesity progression and diminish body weight. The aim of this review is to provide an overview of the literature describing the relationship between physical activity profiles and gut microbiota and in obesity and some associated comorbidities. Promoting physical activity could support as a treatment to maintain the gut microbiota composition or to restore the balance toward an improvement of dysbiosis in obesity; however, these mechanisms need to be studied in more detail. The opportunity to control the microbiota by physical activity to improve health results and decrease obesity and related comorbidities is very attractive. Nevertheless, several incompletely answered questions need to be addressed before this strategy can be implemented., ANID BECAS Chile/72180543, Agencia Estatal de Investigación-Juan de la Cierva-Incorporación, National Agency for Research and Development, University of Granada, Fundación Alfonso Martín Escudero, Fundación Ramón Areces, Agencia Estatal de Investigación IJC2020-042739-I

The main objective of this work was to investigate whether mitochondrial fusion occurs in the skeletal muscle of well-trained athletes in response to high-intensity exercise. Well-trained swimmers (n = 9) performed a duration-matched sprint interval training (SIT) and high-intensity high-volume training (HIHVT) session on separate days. Muscle samples from triceps brachii were taken before, immediately after, and 3 h after the training sessions. Transmission electron microscopy (TEM) was applied to assess mitochondrial morphology. Moreover, expression of genes coding for regulators of mitochondrial fusion and fission were assessed by real-time quantitative PCR. In addition, mitofusin (MFN)2 and optic atrophy 1 (OPA1) were quantified by Western blot analysis. TEM analyses showed that mitochondrial morphology remained altered for 3 h after HIHVT, whereas SIT-induced changes were only evident immediately after exercise. Only SIT increased MFN1 and MFN2 mRNA expression, whereas SIT and HIHVT both increased MFN2 protein content 3 h after exercise. Notably, only HIHVT increased OPA1 protein content. Mitochondrial morphologic changes that suggest fusion occurs in well-adapted athletes during exercise. However, HIHVT appears as a more robust inducer of mitochondrial fusion events than SIT. Indeed, SIT induces a rapid and transient change in mitochondrial morphology.-Huertas, J. R., Ruiz-Ojeda, F. J., Plaza-Díaz, J., Nordsborg, N. B., Martín-Albo, J., Rueda-Robles, A., Casuso, R. A. Human muscular mitochondrial fusion in athletes during exercise.

Summary Pathologies of the micro- and macrovascular systems are a hallmark of the metabolic syndrome, which can lead to chronically elevated blood pressure. However, the underlying pathomechanisms involved still need to be clarified. Here, we report that an obesity-associated increase in serum leptin triggers the select expansion of the micro-angioarchitecture in pre-autonomic brain centers that regulate hemodynamic homeostasis. By using a series of cell- and region-specific loss- and gain-of-function models, we show that this pathophysiological process depends on hypothalamic astroglial hypoxia-inducible factor 1α-vascular endothelial growth factor (HIF1α-VEGF) signaling downstream of leptin signaling. Importantly, several distinct models of HIF1α-VEGF pathway disruption in astrocytes are protected not only from obesity-induced hypothalamic angiopathy but also from sympathetic hyperactivity or arterial hypertension. These results suggest that hyperleptinemia promotes obesity-induced hypertension via a HIF1α-VEGF signaling cascade in hypothalamic astrocytes while establishing a novel mechanistic link that connects hypothalamic micro-angioarchitecture with control over systemic blood pressure., Graphical abstract, Highlights • The hypothalamic gliovascular interface is dynamically remodeled during obesity • Circulating leptin couples hypercaloric states with hypothalamic microangiopathy • Leptin-induced astroglial HIF1α-VEGF drives angiogenesis in the hypothalamus • VEGF in astrocytes promotes the development of arterial hypertension during obesity, Here, Gruber et al. show that during diet-induced obesity in mice there is a profound remodeling of the gliovascular interface in the hypothalamus, resulting in arterial hypertension. This process is driven by elevated leptin levels and upregulation of a HIF1α-VEGF signaling axis in local astrocytes.

Bisphenol F (BPF) and bisphenol S (BPS) are increasingly used as substitutes for bisphenol A (BPA), an endocrine disrupting chemical (EDC) with obesogenic activity. We investigated the in vitro effects of BPS and BPF on the adipogenesis of human adipose-derived stem cells (hASCs) exposed to different doses (0.01, 0.1, 1, 10 and 25 μM), stopping the adipogenic process at 7 or 14 days. Intracellular lipid accumulation was quantified by the Oil Red O assay, gene expression of peroxisome proliferator-activated receptor gamma (PPARγ), CCAT/enhancer-binding protein (C/EBPα), lipoprotein-lipase (LPL) and fatty acid binding protein 4 (FABP4), by quantitative real-time polymerase chain reaction (qRT-PCR) and protein levels by Western Blot. hASCs with BPF or BPS produced a linear dose-response increase in intracellular lipid accumulation and in gene expression of the adipogenic markers, confirmed by protein levels. Co-treatment ICI 182,780 significantly inhibited BPF- but not BPS-induced lipid accumulation. Given the affinity of bisphenols for diverse nuclear receptors, their obesogenic effects may result from a combination of pathways rather than a single mechanism. Further research is warranted on the manner in which chemicals interfere with adipogenic differentiation. To our best knowledge, this report shows for the first time the obesogenic potential of BPF in hASCs.

Objective Reorganization of the extracellular matrix is a prerequisite for healthy adipose tissue expansion, whereas fibrosis is a key feature of adipose dysfunction and inflammation. However, very little is known about the direct effects of impaired cell–matrix interaction in adipocyte function and insulin sensitivity. The objective of this study was to determine whether integrin activity can regulate insulin sensitivity in adipocytes and thereby systemic metabolism. Methods We characterized integrin activity in adipose tissue and its consequences on whole-body metabolism using adipose-selective deletion of β1 integrin (Itgb1adipo-cre) and Kindlin-2 (Kind2adipo-cre) in mice. Results We demonstrate that integrin signaling regulates white adipocyte insulin action and systemic metabolism. Consequently, loss of adipose integrin activity, similar to loss of adipose insulin receptors, results in a lipodystrophy-like phenotype and systemic insulin resistance. However, brown adipose tissue of Kind2adipo-cre and Itgb1adipo-cre mice is chronically hyperactivated and has increased substrate delivery, reduced endothelial basement membrane thickness, and increased endothelial vesicular transport. Conclusions Thus, we establish integrin-extracellular matrix interactions as key regulators of white and brown adipose tissue function and whole-body metabolism., Highlights • β1 and β3 integrins interact with insulin signaling to regulate white adipocyte insulin sensitivity and systemic metabolism. • Impaired integrin activity results in lipodystrophy in the absence of hepatosteatosis. • β1 integrin activity regulates energy expenditure and vascular permeability in brown adipose tissue.

Reorganization of the extracellular matrix is a prerequisite for healthy adipose tissue expansion, whereas fibrosis is a key feature of adipose dysfunction and inflammation. However, very little is known about the direct effects of impaired cell-matrix interaction in adipocyte function and insulin sensitivity. Using adipose selective deletion of β1 integrin (Itgb1adipo-cre) and Kindlin-2 (Kind2adipo-cre), we demonstrate here that active β1 and β3 integrins directly interact with the insulin receptor to regulate white adipocyte insulin action and systemic metabolism. Consequently, loss of adipose integrin activity, similar to loss of adipose insulin receptors, results in lipodystrophy and systemic insulin resistance. Conversely, we find that brown adipose tissue of Kind2adipo-cre and Itgb1adipo-cre mice is chronically hyperactivated, and has increased substrate delivery, reduced endothelial basement membrane thickness, and increased endothelial vesicular transport. Thus, we establish integrin-extracellular matrix interactions as key regulators of white and brown adipose tissue function and whole body metabolism.

Julio Plaza-Díaz is part of the “UGR Plan Propio de Investigación 2016” and the “Excellence actions: Unit of Excellence on Exercise and Health (UCEES), University of Granada”. Francisco J. Ruiz-Ojeda and Belén Pastor-Villaescusa are supported by a grant to postdoctoral researchers at foreign universities and research centers from the “Fundación Alfonso Martín-Escudero”, Madrid, Spain. We are grateful to Belen Vazquez-Gonzalez for assistance with the illustration service., Sweeteners that are a hundred thousand times sweeter than sucrose are being consumed as sugar substitutes. The effects of sweeteners on gut microbiota composition have not been completely elucidated yet, and numerous gaps related to the effects of nonnutritive sweeteners (NNS) on health still remain. The NNS aspartame and acesulfame-K do not interact with the colonic microbiota, and, as a result, potentially expected shifts in the gut microbiota are relatively limited, although acesulfame-K intake increases Firmicutes and depletes Akkermansia muciniphila populations. On the other hand, saccharin and sucralose provoke changes in the gut microbiota populations, while no health effects, either positive or negative, have been described; hence, further studies are needed to clarify these observations. Steviol glycosides might directly interact with the intestinal microbiota and need bacteria for their metabolization, thus they could potentially alter the bacterial population. Finally, the effects of polyols, which are sugar alcohols that can reach the colonic microbiota, are not completely understood; polyols have some prebiotics properties, with laxative effects, especially in patients with inflammatory bowel syndrome. In this review, we aimed to update the current evidence about sweeteners’ effects on and their plausible biological interactions with the gut microbiota.

Training induces a number of healthy effects including a rise in skeletal muscle (SKM) glucose uptake. These adaptations are at least in part due to the reactive oxygen species produced within SKM, which is in agreement with the notion that antioxidant supplementation blunts some training-induced adaptations. Here, we tested whether hydroxytyrosol (HT), the main polyphenol of olive oil, would modify the molecular regulators of glucose uptake when HT is supplemented during exercise. Rats were included into sedentary and exercised (EXE) groups. EXE group was further divided into a group consuming a low HT dose (0.31 mg·kg·d; EXElow), a moderate HT dose (4.61 mg·kg·d; EXEmid), and a control group (EXE). EXE raised glucose transporter type 4 (GLUT4) protein content, Ras-related C3 botulinum toxin substrate 1 (Rac1) activity, and protein kinase b (AKT) phosphorylation in SKM. Furthermore, EXElow blunted GLUT4 protein content and AKT phosphorylation while EXEmid showed a downregulation of the GLUT4/AKT/Rac1 axis. Hence, a low-to-moderate dose of HT, when it is supplemented as an isolated compound, might alter the beneficial effect of training on basal AKT phosphorylation and Rac1 activity in rats.

This is the peer-reviewed but unedited manuscript version of the following article: [Ann Nutr Metab 2018;73:89–99 (DOI: 10.1159/000490669)]. The final, published version is available at http://www.karger.com/?doi=[10.1159/000490669]., Vitamin D (vitD) deficiency is associated with a wide range of chronic diseases and conditions, including obesity, and with an increasing severity of metabolic dysregulation, such as insulin resistance, hyperlipidemia, liver disease, and hypertension, both in children and adults. However, the nature of the association between low vitD status and obesity remains unclear. This fact has motivated the scientific community to conduct genetic association analyses between 25-hydroxyvitamin D (25[OH]D)-related genes and obesity traits. In this line, the variation in the vitD receptor (VDR) gene represents the bulk of the findings. Specifically, polymorphisms in the VDR gene have been associated with obesity traits in some but not all, studies. Thus, results regarding this matter remain inconclusive. Other genes aside from VDR have also been investigated in relation to obesity-related traits. However, again, findings have been inconsistent. In general, results point to the fact that the DBP/GC gene could be an important protein-linking obesity and vitD status. On the other hand, several studies have attempted to determine the molecular mechanism of the relationship between 25(OH)-D levels and obesity. Some of these studies suggest that vitD, due to its fat-soluble characteristic, is retained by the adipose tissue and has the capacity to metabolize 25(OH)-D locally, and this can be altered during obesity. Additionally, vitD is capable of regulating the gene expression related to adipogenesis process, inflammation, oxidative stress, and metabolism in mature adipocytes. Therefore, the aim of the present review was to evaluate the association between obesity and vitD deficiency describing the main molecular mechanism of the relationship and the link with genetic factors, This work was supported by Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D+I), Instituto de Salud Carlos III-Fondo de Investigación Sanitaria (PI1600871 and IFI17/00048) and Fondo Europeo De Desarrollo Regional (FEDER).

X chromosome genetic variation has been proposed as a potential source of missing heritability for many complex diseases, including obesity. Currently, there is a lack of public available genetic datasets incorporating X chromosome genotype data. Although several X chromosome-specific statistics have been developed, there is also a lack of readily available implementations for routine analysis. Here, we aimed: (1) to make public and describe a dataset incorporating phenotype and X chromosome genotype data from a cohort of 915 normal-weight, overweight and obese children, and (2) to deeply describe a whole implementation of the special X chromosome analytic process in genetics. Datasets and pipelines like this are crucial to get familiar with the steps in which X chromosome requires special attention and may raise awareness of the importance of this genomic region., This paper will be part of Augusto Anguita-Ruiz’s doctorate, which is being completed as part of the “Nutrition and Food Sciences Program” at the University of Granada, Spain. The authors would like to thank the children and parents who participated in the study. This work was supported by the Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D+I), Instituto de Salud Carlos III-Fondo de Investigación Sanitaria (FONDOS FEDER) Projects numbers PI051968, PI1102042 and PI1600871, Redes temáticas de investigación cooperativa RETIC (Red SAMID RD12/0026/0015) and the Mapfre Foundation. The authors also acknowledge the Institute of Health Carlos III for personal funding: “Contratos i-PFIS: doctorados IIS-empresa en ciencias y tecnologías de la salud de la convocatoria 2017 de la Acción Estratégica en Salud 2013–2016, Project number: IFI17/00048”.

VIII Congreso Iberoamericano de Nutrición. ¿Nutrición basada en la videncia o en la evidencia?

The consumption of sugar-free foods is growing because of their low-calorie content and the health concerns about products with high sugar content. Sweeteners that are frequently several hundred thousand times sweeter than sucrose are being consumed as sugar substitutes. Although nonnutritive sweeteners (NNSs) are considered safe and well tolerated, their effects on glucose intolerance, the activation of sweet taste receptors, and alterations to the composition of the intestinal microbiota are controversial. This review critically discusses the evidence supporting the effects of NNSs, both synthetic sweeteners (acesulfame K, aspartame, cyclamate, saccharin, neotame, advantame, and sucralose) and natural sweeteners (NSs; thaumatin, steviol glucosides, monellin, neohesperidin dihydrochalcone, and glycyrrhizin) and nutritive sweeteners (polyols or sugar alcohols) on the composition of microbiota in the human gut. So far, only saccharin and sucralose (NNSs) and stevia (NS) change the composition of the gut microbiota. By definition, a prebiotic is a nondigestible food ingredient, but some polyols can be absorbed, at least partially, in the small intestine by passive diffusion: however, a number of them, such as isomaltose, maltitol, lactitol, and xylitol, can reach the large bowel and increase the numbers of bifidobacteria in humans. Further research on the effects of sweeteners on the composition of the human gut microbiome is necessary.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This paper will be part of Augusto Anguita-Ruiz’s doctorate, which is being performed under the “Nutrition and Food Sciences Program” at the University of Granada., Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-019-40482-0., Tenomodulin (TNMD) is a type II transmembrane glycoprotein that has been recently linked to obesity, and it is highly expressed in obese adipose tissue. Several sex-dependent associations have been observed between single-nucleotide polymorphisms (SNPs) of the TNMD gene, which is located in the X-chromosome, and obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome in adults. On the other hand, results are lacking for children. We aimed (i) to study the association between TNMD genetic variants and metabolic complications related to childhood obesity and (ii) to investigate the function of TNMD in human adipocytes. We conducted a case-control, multicenter study in 915 Spanish children and demonstrated significant positive associations between TNMD genetic variants and BMI z-score, waist circumference, fasting glucose, and insulin resistance in boys, highlighting the SNP rs4828038. Additionally, we showed a BMI-adjusted inverse association with waist circumference in girls. Second, in vitro experiments revealed that TNMD is involved in adipogenesis, along with glucose and lipid metabolism in differentiated adipocytes, and these effects may be mediated through AMPK activation. Hence, these results suggest that TNMD genetic variants could be potentially useful as early life risk indicators for obesity and T2DM. In addition, we support the fact that TNMD exhibits significant metabolic functions in adipocytes., This work was supported by Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I + D + I), Instituto de Salud Carlos III-Fondo de Investigación Sanitaria (Projects numbers PI020826, PI051968, PI1102042, PI1600871), RETIC (Red SAMID RD12/0026/0015), Fondo Europeo De Desarrollo Regional (FEDER) and the Junta de Andalucía (project number CTS-6770); Secretaría General de Universidades, Investigación y Tecnología. Consejería de Economía, Innovación y Ciencia).

Probiotics are living microorganisms that confer health benefits to the host when administered in adequate amounts; however, dead bacteria and their components can also exhibit probiotic properties. Bifidobacterium and strains of lactic acid bacteria are the most widely used bacteria that exhibit probiotic properties and are included in many functional foods and dietary supplements. Probiotics have been shown to prevent and ameliorate the course of digestive disorders such as acute, nosocomial, and antibiotic-associated diarrhea; allergic disorders such as atopic dermatitis (eczema) and allergic rhinitis in infants; and Clostridium difficile-associated diarrhea and some inflammatory bowel disorders in adults. In addition, probiotics may be of interest as coadjuvants in the treatment of metabolic disorders, including obesity, metabolic syndrome, nonalcoholic fatty liver disease, and type 2 diabetes. However, the mechanisms of action of probiotics, which are diverse, heterogeneous, and strain specific, have received little attention. Thus, the aim of the present work was to review the main mechanisms of action of probiotics, including colonization and normalization of perturbed intestinal microbial communities in children and adults; competitive exclusion of pathogens and bacteriocin production; modulation of fecal enzymatic activities associated with the metabolization of biliary salts and inactivation of carcinogens and other xenobiotics; production of short-chain and branched-chain fatty acids, which, in turn, have wide effects not only in the intestine but also in peripheral tissues via interactions with short-chain fatty acid receptors, modulating mainly tissue insulin sensitivity; cell adhesion and mucin production; modulation of the immune system, which results mainly in the differentiation of T-regulatory cells and upregulation of anti-inflammatory cytokines and growth factors, i.e., interleukin-10 and transforming growth factor; and interaction with the brain-gut axis by regulation of endocrine and neurologic functions. Further research to elucidate the precise molecular mechanisms of action of probiotics is warranted.

The pediatric population is continually at risk of developing infectious and inflammatory diseases. The treatment for infections, particularly gastrointestinal conditions, focuses on oral or intravenous rehydration, nutritional support and, in certain case, antibiotics. Over the past decade, the probiotics and synbiotics administration for the prevention and treatment of different acute and chronic infectious diseases has dramatically increased. Probiotic microorganisms are primarily used as treatments because they can stimulate changes in the intestinal microbial ecosystem and improve the immunological status of the host. The beneficial impact of probiotics is mediated by different mechanisms. These mechanisms include the probiotics’ capacity to increase the intestinal barrier function, to prevent bacterial transferation and to modulate inflammation through immune receptor cascade signaling, as well as their ability to regulate the expression of selected host intestinal genes. Nevertheless, with respect to pediatric intestinal diseases, information pertaining to these key mechanisms of action is scarce, particularly for immune-mediated mechanisms of action. In the present work, we review the biochemical and molecular mechanisms of action of probiotics and synbiotics that affect the immune system., Julio Plaza-Diaz, Francisco Javier Ruiz-Ojeda and Angel Gil are part of University of Granada, Plan Propio de Investigación 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES).

Obesity is a worldwide public health problem that has been increasing in the last decades. It is characterized by excessive fat accumulation, and accompanied by low-grade chronic inflammation and increased oxidative stress. A growing body of evidence supports that both chronic inflammation and oxidative stress play a key role in the development of obesity-associated comorbidities such as insulin resistance (IR), which probably is the first step of a dysfunctional metabolic system. Subsequent to central obesity, IR, hyperglycemia, hypertriglyceridemia, hypoalphalipoproteinemia, hypertension, and fatty liver are grouped in the so-called metabolic syndrome (MetS). The purpose of this chapter is to review the clinical correlates of systemic oxidative stress and inflammation markers in patients with obesity or MetS.

To study the antioxidant activity of melatonin in diabetes in relation to the regulation and levels of plasma copper (Cu), zinc (Zn), iron (Fe), manganese (Mn), and selenium (Se) in Zucker diabetic fatty (ZDF) and lean (ZL) rats.At 6 wk of age, both ZDF (n = 30) and ZL (n = 30) animals were subdivided into three groups: control (C) (n = 10), vehicle (V) (n = 10), and melatonin-treated (M) (10 mg/kg/d; n = 10) rats for a 6-wk period. At the end of treatment period, plasma mineral levels were measured by flame (Cu, Zn, and Fe), electrothermal (Mn), and hydride generation (Se) atomic absorption spectrometry.ZDF rats had significantly higher Cu, Fe, and Mn plasma levels than did ZL rats (P 0.05). No significant differences were found between control and vehicle groups (P 0.05). Melatonin treatment did not influence plasma levels of these antioxidant minerals (Cu, Zn, Fe, and Mn) in ZDF groups (M-ZDF versus C-ZDF group) and ZL (M-ZL versus C-ZL group) rats with the exception of Zn, whose mean plasma level was lower in the M-ZL versus C-ZL group. However, plasma Se levels increased significantly (P 0.05) after melatonin supplementation in both groups (M-ZDF and M-ZL).The higher mean plasma Cu, Fe, and Mn levels in the ZDF group are related to the enhanced oxidative stress in diabetes and obesity. Melatonin administration significantly enhanced plasma Se levels in both groups (M-ZDF and M-ZL). This is the first study to report that melatonin treatment increases plasma Se levels.