[Show abstract][Hide abstract] ABSTRACT: Optimal health is maintained by interaction of multiple intrinsic and environmental factors at different levels of complexity—from molecular, to physiological, to social. Understanding and quantification of these interactions will aid design of successful health interventions. We introduce the reference network concept as a platform for multi-level exploration of biological relations relevant for metabolic health, by integration and mining of biological interactions derived from public resources and context-specific experimental data. A White Adipose Tissue Health Reference Network (WATRefNet) was constructed as a resource for discovery and prioritization of mechanism-based biomarkers for white adipose tissue (WAT) health status and the effect of food and drug compounds on WAT health status. The WATRefNet (6,797 nodes and 32,171 edges) is based on (1) experimental data obtained from 10 studies addressing different adiposity states, (2) seven public knowledge bases of molecular interactions, (3) expert’s definitions of five physiologically relevant processes key to WAT health, namely WAT expandability, Oxidative capacity, Metabolic state, Oxidative stress and Tissue inflammation, and (4) a collection of relevant biomarkers of these processes identified by BIOCLAIMS (http://bioclaims.uib.es). The WATRefNet comprehends multiple layers of biological complexity as it contains various types of nodes and edges that represent different biological levels and interactions. We have validated the reference network by showing overrepresentation with anti-obesity drug targets, pathology-associated genes and differentially expressed genes from an external disease model dataset. The resulting network has been used to extract subnetworks specific to the above-mentioned expert-defined physiological processes. Each of these process-specific signatures represents a mechanistically supported composite biomarker for assessing and quantifying the effect of interventions on a physiological aspect that determines WAT health status. Following this principle, five anti-diabetic drug interventions and one diet intervention were scored for the match of their expression signature to the five biomarker signatures derived from the WATRefNet. This confirmed previous observations of successful intervention by dietary lifestyle and revealed WAT-specific effects of drug interventions. The WATRefNet represents a sustainable knowledge resource for extraction of relevant relationships such as mechanisms of action, nutrient intervention targets and biomarkers and for assessment of health effects for support of health claims made on food products.
[Show abstract][Hide abstract] ABSTRACT: Objective
We analysed the effects of a short exposure to a cafeteria diet during early infancy in rats on their metabolic response to fed/fasting conditions in key tissues involved in energy homeostasis.Methods10-day-old male pups were fed a control or a cafeteria diet for 12 days and then sacrificed under ad libitum feeding conditions or 12 h fasting. The expression of key genes related to energy metabolism in liver, retroperitoneal white adipose tissue (WAT) and hypothalamus were analysed.ResultsDespite no differences in body weight, cafeteria fed animals had almost double the fat mass of control rats. They also showed higher food intake, higher leptinemia and altered hypothalamic expression of Npy, suggesting a dysfunction in the control of food intake. Unlike controls, cafeteria fed animals did not decrease WAT expression of Pparg, Srebf1 or Cidea under fasting conditions, and displayed lower Pnpla2 expression than controls. In liver, compared to controls, cafeteria animals presented: i) lower expression of genes related with fatty acid uptake and lipogenesis under ad libitum fed conditions; ii) higher expression of fatty acid oxidation related genes and glucokinase under fasting conditions; iii) greater expression of leptin and insulin receptors, and higher protein levels of insulin receptor and the pAMPK/AMPK ratio.ConclusionA short period of exposure to a cafeteria diet in early infancy in rat pups is enough to disturb the metabolic response to fed/fasting conditions in key tissues involved in energy homeostasis, particularly in WAT, and hence induces an exacerbated body fat accumulation and increased metabolic risk, with no apparent effects on body weight.International Journal of Obesity accepted article preview online, 21 July 2014; doi:10.1038/ijo.2014.125.
International journal of obesity (2005) 07/2014; · 5.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:Maternal calorie restriction during pregnancy programs offspring for later overweight and metabolic disturbances. Brown adipose tissue (BAT) is responsible for nonshivering thermogenesis and has recently emerged as a very likely target for human obesity therapy.Objective:Here we aimed to assess whether the detrimental effects of undernutrition during gestation could be related to impaired thermogenic capacity in BAT and to investigate the potential mechanisms involved.Methods:Offspring of control and 20% calorie-restricted rats (days 1-12 of pregnancy) (CR) were studied at the age of 25-days. Protein levels of uncoupling protein 1 (UCP1) and tyrosine hydroxylase (TyrOH); mRNA levels of lipoprotein lipase (LPL), carnitine palmitoyltransferase 1 (CPT1) and deiodinase iodothyronine type II (DIO2) in BAT; and blood parameters including thyroid hormones, were determined. The response to 24-h cold-exposure was also studied by measuring body temperature changes over time, and final BAT UCP1 levels.Results:Compared to controls, CR animals displayed in BAT lower UCP1 and TyrOH protein levels and lower LPL and CPT1 mRNA levels; they also showed lower triiodothyronine (T3) plasma levels. CR males, but not females, revealed lower DIO2 mRNA levels than controls. When exposed to cold, CR rats experienced a transient decline in body temperature, but the values were reestablished after 24-h, despite having lower UCP1 levels than controls.Conclusions:These results suggest that BAT thermogenic capacity is diminished in CR animals, involving impaired BAT sympathetic innervation and thyroid hormone signaling. These alterations make animals more sensitive to cold and may contribute to long-term outcomes of gestational calorie restriction in promoting obesity and related metabolic alterations.International Journal of Obesity accepted article peview online, 03 April 2014; doi:10.1038/ijo.2014.56.
International journal of obesity (2005) 04/2014; 39(2). · 5.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Moderate maternal calorie restriction during lactation protects rat offspring against obesity development in adulthood, due to an improved ability to handle and store excess dietary fuel. We used this model to identify early transcriptome-based biomarkers of metabolic health using peripheral blood mononuclear cells (PBMCs), an easily accessible surrogate tissue, by focusing on molecular markers of lipid handling. Male and female offspring of control and 20 % calorie-restricted lactating dams (CR) were studied. At weaning, a set of pups was killed, and PBMCs were isolated for whole-genome microarray analysis. The remaining pups were killed at 6 months of age. CR gave lower body weight, food intake and fat accumulation, and improved levels of insulin and leptin throughout life, particularly in females. Microarray analysis of weaned rat PBMCs identified 278 genes significantly differentially expressed between control and CR. Among lipid metabolism-related genes, expression of Cpt1a, Lipe and Star was increased and Fasn, Lrp1 and Rxrb decreased in CR versus control, with changes fully confirmed by qPCR. Among them, Cpt1a, Fasn and Star emerged as particularly interesting. Transcript levels of Cpt1a in PBMCs correlated with their levels in WAT and liver at both ages examined; Fasn expression levels in PBMCs at an early age correlated with their expression levels in WAT; and early changes in Star expression levels in PBMCs correlated with their expression levels in liver and were sustained in adulthood. These findings reveal the possibility of using transcript levels of lipid metabolism-related genes in PBMCs as early biomarkers of metabolic health status.
[Show abstract][Hide abstract] ABSTRACT: The health benefits of daily consumption of at least 5 portions of a variety of fruit and
vegetables are well documented. The World Health Organization (WHO) public health goal,
established in 600 grams per person/day, is not achieved in Spain, so it is important to
improve access to these foods, maintain their potential nutritive value and overcome barriers
for their consumption. The objectives of this paper are: facilitate responsible decision-making
regarding health; maximize the nutritional value of fruit and vegetables, help overcome
barriers for fruit and vegetables consumption and report on how their storage at home, their
handling and cooking affect to nutritional value of fruit and vegetables.
In order to minimize nutrients loss and improve their bioavailability during fruit and
vegetables handling, the Association for the promotion of fruit and vegetables “5 a day”
(Spain) recommends: avoid prolonged storage of fruit and vegetables in the fridge; use layers
and outer leaves; peel and/or cut them just before consumption; wash the whole pieces and
then chop them; controlling the soaking time of cut pieces; prefer cooking techniques that do
not require direct contact with water; a shorter cooking time, less loss of nutrients; the correct
frying retains nutrients very well, although it is a technique of which should not be abused;
add a few drops of vinegar or lemon juice to the cooking water if it does not change the taste
and dish acceptance; use the water of cooking to elaborate other foods (e.g. sauces, soups,
purees, etc.) except those coming from chard, spinach or beets. The “5 a day” Association
(Spain) recommends increasing consumption of fruit and vegetables, and state that the
loss of nutrients during their home handling should not be understood as a barrier for their
Revista Española de Nutrición Humana y Dietética - Spanish Journal of Human Nutrition and Dietetics. 01/2014; 18(2):100-115.
[Show abstract][Hide abstract] ABSTRACT: What is already known about this subject The expression of specific genes in peripheral blood cells (PBCs) may be used as biomarkers of the metabolic status. High levels of expression of CPT1A, SLC27A2, INSR, LEPR, FASN and PPARα in PBCs are indicative of a lower risk for the insulin resistant or dyslipidaemic state associated with obesity in children. Breastfeeding seems to confer protective effects against obesity and its related metabolic problems. What this study adds Children who had been breastfed showed higher expression levels of SLC27A2, FASN, PPARα and INSR in PBCs compared with formula-fed subjects. The relationship of the PBC transcript levels of SLC27A2, INSR, FASN and PPARα with insulin resistance and dyslipidaemia may be dependent on the type of infant feeding (breast vs. formula). The transcript levels of the mentioned biomarkers could be useful to distinguish the formula-fed children who are at higher risk of metabolic alterations.
Blood-cell transcripts have showed to be good biomarkers of metabolic alterations and their use in early detection and prevention of future disorders is promising.
This study aimed to examine the relation between previously proposed transcriptional biomarkers of metabolic health (SLC27A2, CPT1A, FASN, PPARα, INSR, LEPR) in peripheral blood cells and the type of infant feeding in a subset of children from the IDEFICS (Identification and Prevention of Dietary- and Lifestyle-Induced Health Effects in Children and Infants) cohort.
A total of 237 children aged 2-9 years from eight European countries were studied.
Breastfed children showed higher expression levels of SLC27A2, FASN, PPARα and INSR, and lower risk of being overweight and of having high plasma triglyceride levels vs. formula-fed children. Besides, overweight formula-fed children presented higher HOMA-index than overweight breastfed children (1.90 vs. 1.62); however, this negative effect was absent in formula-fed children with high expression of SLC27A2. Moreover, formula-fed children with low expression of SLC27A2, FASN, PPARα and INSR presented higher triglyceride levels than subjects with high expression of these genes (77.7 mg dL(-1) vs. 44.8 mg dL(-1) ). This difference was absent in breastfed children.
Protective effects of breastfeeding are reflected in higher expression levels of SLC27A2, FASN, PPARα and INSR in blood cells. These biomarkers may also serve to discriminate the formula-fed children that are at higher risk of metabolic alterations.
[Show abstract][Hide abstract] ABSTRACT: Objective:To assess the influence of supplementation with a moderate dose of vitamin A in early life on adipose tissue development and the response to an obesogenic diet later in life.Methods:During the suckling period, rat pups received a daily oral dose of retinyl palmitate corresponding to three times the vitamin A ingested daily from maternal milk. Control rats received the vehicle (olive oil). Short-term effects of treatment on gene expression and morphology of white adipose tissue (WAT) were analyzed in animals on the day after weaning (day 21). To study long-term effects, control and vitamin A-treated rats were fed, after weaning, a normal fat or a high-fat (HF) diet for 16 weeks.Results:WAT of vitamin A-treated young rats (day 21) was enriched in small adipocytes with a reduced expression of adipogenic markers (peroxisome proliferator-activated receptor γ and lipoprotein lipase) and an increased cell proliferation potential as indicated by increased expression of proliferating cell nuclear antigen. Increased retinoic acid (RA)-induced transcriptional responses were present in the tissues of vitamin A-treated young rats (day 21) including WAT. Vitamin A-treated rats developed higher adiposity than control rats on a HF diet as indicated by body composition analysis and increased WAT depot mass, adipocyte diameter, WAT DNA content, leptinemia and adipose leptin gene expression. Excess adiposity gain in vitamin A-treated rats developed in the absence of changes in body weight and was attributable to excess adipocyte hyperplasia. No differences in adiposity were observed between vitamin A-treated rats and control rats on a normal fat diet. Total retinol levels in WAT of vitamin A-treated rats were elevated at weaning (day 21) and normalized by day 135 of age.Conclusion:Vitamin A intake in the early stages of postnatal life favors subsequent HF diet-induced adiposity gain through mechanisms that may relate to changes in adipose tissue development, likely mediated by RA.International Journal of Obesity advance online publication, 4 December 2012; doi:10.1038/ijo.2012.190.
International journal of obesity (2005) 12/2012; · 5.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IDEFICS (Identification and Prevention of Dietary- and Lifestyle-Induced Health Effects in Children and Infants Project) is a European multicenter study on childhood obesity. One of its goals is to define early biomarkers of risk associated with obesity and its comorbid conditions.
We considered blood cells as a new potential source of transcriptional biomarkers for these metabolic disorders and examined whether blood cell mRNA levels of some selected genes (LEPR, INSR, CPT1A, SLC27A2, UCP2, FASN, and PPARα) were altered in overweight children and whether their expression levels could be defined as markers of the insulin-resistant or dyslipidemic state associated with overweight.
Blood samples were obtained from 306 normal-weight and overweight children, aged 2-9 yr, from eight different European countries. Whole-blood mRNA levels were assessed by quantitative RT-PCR.
LEPR, INSR, and CPT1A mRNA levels were higher in overweight compared with normal-weight children (the two latter only in males), whereas SLC27A2 mRNA levels were lower in overweight children. Significant associations were also found between expression levels of LEPR, INSR, CPT1A, SLC27A2, FASN, PPARα, and different parameters, including body mass index, homeostasis model assessment index, and plasma triglycerides and cholesterol levels. These associations showed that high expression levels of CPT1A, SLC27A2, INSR, FASN, or PPARα may be indicative of a lower risk for the insulin-resistant or dyslipidemic state associated with obesity, whereas low LEPR mRNA levels appear as a marker of high low-density lipoprotein cholesterol, independently of body mass index.
These findings point toward the possibility of using the expression levels of these genes in blood cells as markers of metabolic status and can potentially provide an early warning of a future disorder.
The Journal of Clinical Endocrinology and Metabolism 01/2012; 97(4):E648-52. · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adiponutrin/PNPLA3 and adipose triglyceride lipase (ATGL) are proteins highly expressed in adipose tissue which have apparently different roles (lipogenic/lipolytic). Gene expression of both proteins and their nutritional regulation have been described to be altered in genetically obese animals.
We studied adiponutrin and ATGL expression in 6-month-old rats made obese by cafeteria diet feeding, submitted to different feeding conditions (feeding/fasting/re-feeding), compared with normoweight animals. Adiponutrin and ATGL mRNA levels were determined in white adipose tissue depots (subcutaneous and visceral) and in interscapular brown adipose tissue, and ATGL protein levels in selected depots. In addition, basal adiponutrin and ATGL expression levels were compared between 6- and 3-month-old animals.
Obesity decreased adiponutrin and ATGL expression in different adipose depots. For adiponutrin, a tendency to lower mRNA levels was observed in the white adipose depots studied in obese animals, although the decrease was only significant in the subcutaneous depot. For ATGL, a generalized and significant lower expression was found in white and brown adipose tissue of cafeteria-obese rats. When considering nutritional regulation, according to a lipogenic role, adiponutrin mRNA expression decreased with fasting and was recovered by re-feeding in normoweight animals; this regulation was lost in obese rats. Expression of the lipolytic ATGL (mRNA and protein levels) was increased by fasting in normoweight animals in the mesenteric adipose depot, while no change was evident in obese rats. Moreover, adiponutrin and ATGL nutritional regulation was affected by age, and we report a downregulation of adiponutrin mRNA basal levels with age in internal adipose depots.
Cafeteria diet-induced obesity and age alter adiponutrin and ATGL expression and their regulation by feeding conditions. These results reinforce the importance of a proper expression and regulation of both proteins for body weight maintenance and their role in energy metabolism.
International journal of obesity (2005) 05/2011; 36(2):225-32. · 5.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Leptin supplementation of neonatal rats during the suckling period protects against being overweight in adulthood and ameliorates the control of food intake. This was associated with changes in the expression of hypothalamic genes involved in the central action of leptin: pro-opiomelanocortin (Pomc), leptin receptor (Lepr) and suppressor of cytokine signalling (Socs3). The purpose of the present study was to determine the methylation status within the promoter regions of these genes and to assess whether the observed changes in the expression levels of these genes could be explained by changes in their methylation status. Male rats were treated daily with an oral physiological dose of leptin or vehicle during the suckling period. After weaning, animals were fed with a normal-fat or a high-fat (HF) diet until aged 6 months. DNA was extracted from the hypothalamus and methylation within the promoter regions of the gene panel was measured by pyrosequencing. Pomc promoter methylation increased in control animals fed the HF diet but decreased in leptin-treated animals. In addition, there was a weak negative correlation between DNA methylation and POMC mRNA levels (P = 0·075). There were no changes in the methylation status of the CpG sites studied within the promoter regions of Lepr and Socs3 in response to leptin or HF treatments. This is the first demonstration that leptin treatment during lactation may programme methylation of an appetite-related gene in the hypothalamus of animals fed HF diets, with possible implications for gene expression and protection against the development of obesity.
The British journal of nutrition 05/2011; 106(5):769-78. · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Experts in the field of carotenoids met at the Hohenheim consensus conference in July 2009 to elucidate the current status of β-carotene research and to summarize the current knowledge with respect to the chemical properties, physiological function, and intake of β-carotene. The experts discussed 17 questions and reached an agreement formulated in a consensus answer in each case. These consensus answers are based on published valid data, which were carefully reviewed by the individual experts and are justified here by background statements. Ascertaining the impact of β-carotene on the total dietary intake of vitamin A is complicated, because the efficiency of conversion of β-carotene to retinol is not a single ratio and different conversion factors have been used in various surveys and following governmental recommendations within different countries. However, a role of β-carotene in fulfilling the recommended intake for vitamin A is apparent from a variety of studies. Thus, besides elucidating the various functions, distribution, and uptake of β-carotene, the consensus conference placed special emphasis on the provitamin A function of β-carotene and the role of β-carotene in the realization of the required/recommended total vitamin A intake in both developed and developing countries. There was consensus that β-carotene is a safe source of vitamin A and that the provitamin A function of β-carotene contributes to vitamin A intake.
Journal of Nutrition 10/2010; 140(12):2268S-2285S. · 4.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We aimed to characterize the developmental programming effects of moderate caloric restriction during early pregnancy on factors involved in hypothalamic control of energy balance.
Twenty-five-days-old offspring Wistar rats from 20% caloric restricted dams (from 1 to 12 days of pregnancy) (CR) and from control dams were studied under fed and 12 h fasting conditions. Morphometric studies on arcuate nucleus (ARC) and determinations of circulating parameters and hypothalamic levels of neuropeptide Y (NPY), proopiomelanocortin (POMC), long-form leptin receptor (ObRb), insulin receptor (InsR) and suppressor of cytokine signalling-3 (SOCS-3) mRNA were performed.
CR animals did not show different body weight with respect to their controls, but presented higher food intake. They exhibited lower neuropeptide Y- and alpha-melanocyte-stimulating hormone-neurons (decreases of 18 and 13% in males, and 10 and 18% in females respectively) and lower total cells (decrease of 3% in males and 18% in females) in ARC. Under fed conditions, CR animals presented lower circulating leptin and ghrelin levels (decreases of 37 and 43% in males, and 15 and 34% in females respectively); furthermore, hypothalamic POMC, NPY (only in females), ObRb and InsR mRNA levels were reduced (39, 16 and 26% in males, and 112, 33, 61 and 56% in females), and those of SOCS-3 were increased (86% in males and 74% in females). Unlike control animals, under fasting conditions, ObRb, InsR and POMC mRNA levels did not decrease in CR females, and NPY mRNA decreased instead of increase in CR males.
Moderate caloric restriction during gestation affects offspring hypothalamic structure and function, impairing its response to fed/fasting conditions, which suggests a predisposition to insulin and leptin resistance.
Diabetes Obesity and Metabolism 05/2010; 12(5):403-13. · 5.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to assess the effects of dietary leucine supplementation in lactating dams, particularly on energy homeostasis through signaling mechanisms in the central nervous system. Dams were fed ad libitum with standard diet during pregnancy (control dams) or supplemented with 2% leucine (leucine-supplemented dams) from delivery onwards. Food intake, body weight and composition were periodically recorded. Hypothalamus was collected at the end of lactation, and the expression of neuropeptide Y (NPY), agouti-related protein (AgRP) pro-opiomelanocortin (POMC), cocaine and amphetamine regulated transcript (CART), insulin receptor (InsR), ghrelin receptor (GSHR), melanocortin receptor (MCR4), leptin receptor (Ob-Rb) and suppressor of cytokine signaling 3 (SOCS3) were analyzed. Dietary leucine supplementation to lactating rats increased plasma leucine by 56%, modulated body composition and contributed to a tendency of higher ratio of lean/fat mass content of dams during lactation, without affecting food intake, thermogenesis capacity or body or tissue/organs weights. No differences in body weight of offspring from control and leucine-supplemented dams were found. The expression of orexigenic peptides (NPY and AgRP) decreased in leucine-dams, whereas the expression of anorexigenic peptides (POMC and CART), the hypothalamic receptors of insulin, ghrelin, melanocortin and leptin and SOCS3 did not change by leucine supplementation. In conclusion, increased leucine intake during lactation may contribute to a healthier profile of body composition in dams, without compromising the growth and development of the progeny by a mechanism associated with lower expression of orexigenic neuropeptides in hypothalamus.