Prenatal nutrition and the risk of adult obesity: Long-term effects of nutrition on epigenetic mechanisms regulating gene expression.

Solid epidemiological evidence indicates that part of the risk of obesity in adulthood could be programmed during prenatal development by the quality of maternal nutrition. Nevertheless, the molecular mechanisms involved are mostly unknown, which hinders our capacity to develop effective intervention policies. Here, we discuss the hypothesis that mechanisms underlying prenatal programming of adult risk are epigenetic and sensitive to environmental cues such as nutrition. While the information encoded in DNA is essentially stable, regulatory epigenetic mechanisms include reversible, covalent modifications of DNA and chromatin, such as methylation, acetylation etc. It is known that dietary availability of methyl donors has an impact on the patterns of gene expression by affecting DNA methylation at regulatory regions, a likely basis for reprogramming developmental plasticity. The Agouti and Axin-fused genes, as well as the embryonic growth factor IGF2/H19 locus are examples of diet-induced modulation of phenotypic traits by affecting methylation of gene-regulatory regions. Recent work has evidenced an unsuspected role for chromatin as metabolic sensor. Chromatin is susceptible to a number of post-translational modifications that modulate gene expression, among them the GlcNAcylation of histone proteins and other epigenetic regulators. Intracellular levels of the precursor molecule UDP-GlcNAc, and hence the degree of global chromatin GlcNAcylation, depend on the energetic state of the cell, making GlcNAcylation a functional link between nutrition and regulation of gene expression. Dietary interference with these regulatory mechanisms could effectively counteract the early-life programming of adult risk.

Impact of diet on cardiometabolic health in children and adolescents.

The manifestation of cardiovascular risk factors, such as hypertension, diabetes, and particularly obesity begins in children and adolescents, with deleterious effects for cardiometabolic health at adulthood. Although the impact of diet on cardiovascular risk factors has been studied extensively in adults, showing that their cardiometabolic health is strongly lifestyle-dependent, less is known about this impact in children and adolescents. In particular, little is known about the relationship between their dietary patterns, especially when derived a posteriori, and cardiovascular risk. An adverse association of cardiovascular health and increased intake of sodium, saturated fat, meat, fast food and soft drinks has been reported in this population. In contrast, vitamin D, fiber, mono-and poly-unsaturated fatty acids, dairy, fruits and vegetables were positively linked to cardiovascular health.The aim of this review was to summarize current epidemiological and experimental evidence on the impact of nutrients, foods, and dietary pattern on cardiometabolic health in children and adolescents. A comprehensive review of the literature available in English and related to diet and cardiometabolic health in this population was undertaken via the electronic databases PubMed, Cochrane Library, and Medline.

Can metabolically healthy obesity be explained by diet, genetics, and inflammation?

A substantial proportion of obese individuals do not present cardiometabolic complications such as diabetes, hypertension, or dyslipidemia. Some, but not all, prospective studies observe similar risk of cardiovascular events and all-cause mortality among individuals with this so-called "metabolically healthy obese" (MHO) phenotype, compared to the metabolically healthy normal weight or metabolically healthy non-obese phenotypes. Compared to the metabolically unhealthy obese (MUO) phenotype, MHO is often characterized by a more favorable inflammatory profile, less visceral fat, less infiltration of macrophages into adipose tissue, and smaller adipocyte cell size. Tipping the inflammation balance in adipose tissue might be particularly important for metabolic health in the obese. While the potential role of genetic predisposition or lifestyle factors such as diet in the MHO phenotype is yet to be clarified, it is well known that diet affects inflammation profile and contributes to the functionality of adipose tissue. This review will discuss genetic predisposition and the molecular mechanisms underlying the potential effect of food on the development of the metabolic phenotype characteristic of obesity.

Measuring activity of endocytosis-regulating factors in T-lymphocytes by flow cytometry.

Elucidation of the mechanisms regulating membrane traffic of lymphocyte receptors is of great interest to manipulate the immune response, as well as for accurately delivering drugs and nanoprobes to cells. Aiming to detect and characterize regulators of endocytosis and intracellular traffic, we have modified the FACS-based endocytosis assay to measure and quantify the activity of putative endocytic regulators as EGFP chimeras. To study the activity of putative endocytosis regulators, we transfected Jurkat T-lymphocytes with EGFP-tagged constructs of the regulators to be tested. Cells were then incubated with a αCD3(APC) antibody, and were allowed to internalize the label. After acid-washing the cells, APC fluorescence was measured by flow cytometry in cells gated for EGFP(+), as well as in their EGFP(-) (transfection-resistant) counterparts that were taken as internal controls. This approach facilitated intra- and inter-assay normalization of endocytic rates/loads by comparison with the internal control. We have used this assay to test the regulatory activity of polarity kinase EMK1, and here we substantiate a role for EMK1 in the control of receptor internalization in T-lymphocytes. The method here presented gives quantitative measures of internalization, and will facilitate the development of tools to modulate endocytic rates or the intracellular fate of internalized materials.

Pretransplant low CD3+CD25high cell counts or a low CD3+CD25high/CD3+HLA-DR+ ratio are associated with an increased risk to acute renal allograft rejection.

BACKGROUND: Detection of markers predicting allograft rejection is important for risk assessment before kidney transplantation, as well as to minimize posttransplantation immunosuppression. METHODS: We studied the expression of CD25, HLA-DR, CD134, CD62L, and CD44 by flow cytometry in CD4, CD8, and CD3 cells, from pretransplant blood samples from 91 transplanted patients accounting for 16 episodes of acute renal rejection in the first month after transplantation. RESULTS: None of the activation markers showed a significant association to acute rejection. Early rejectors showed less pretransplant CD3CD25 cells than nonrejectors (0.79%±0.50% vs. 1.51%±0.79% of CD3 cells; P=0.001) and a lower CD3CD25/CD3HLA-DR ratio (0.043±0.034 vs. 0.111±0.079; P<0.00001). When levels of CD25 cells fell below 0.7% of CD3 cells, the odds ratio of suffering an episode of acute rejection was 105 fold (95% confidence interval: 11.41-966.43, P<0.0001), with a sensitivity (true-positive results) of 0.63 and a specificity (true-negative results) of 0.98 for predicting the risk of acute rejection. Furthermore, when the CD3CD25/CD3HLA-DR ratio fell below 0.04, the odds ratio of suffering an episode of acute rejection was 7.71 fold (95% confidence interval: 2.29-25.97, P=0.001), with a sensitivity of 0.56 and a specificity of 0.86 for predicting risk of acute rejection. CONCLUSIONS: Our results suggest that low pretransplant levels of CD3CD25 cells or a low CD3CD25/CD3HLA-DR ratio could identify those patients with an increased risk of early acute allograft rejection. If these data can be independently confirmed, pretransplant CD3CD25 cells and the CD3CD25/CD3HLA-DR ratio might provide additional information for risk assessment before kidney transplantation.