Could GLUT12 be a Potential Therapeutic Target in Cancer Treatment? A Preliminary Report.

BACKGROUND: Recent studies proposed GLUT12 to be a major glucose transporter involved in the glycolytic metabolism of cancer cells. METHODS: GLUT12 expression was determined by immunohistochemistry in a selection of cancer cell lines and a tumour spheroid model. RESULTS: GLUT12 expression was high in A549 and RH-36; low in HT29; and absent in NB-EB cancer cell lines. GLUT12 expression was located in the necrotic centre of HT29 spheroids, which is characterised by anaerobic metabolism. CONCLUSION: The data supports the involvement of GLUT12 in the glycolytic metabolism of cancer cells and therefore, its potential as a novel therapeutic target for cancer treatment.

Socioeconomic factors are associated with folate and vitamin B12 intakes and related biomarkers concentrations in European adolescents: the Healthy Lifestyle in Europe by Nutrition in Adolescence study.

Because socioeconomic factors (SEFs) may influence dietary quality and vitamin intakes, this study aimed to examine associations between socioeconomic factors and folate and vitamin B12 intakes as well as their related biomarkers in the Healthy Lifestyle in Europe by Nutrition in Adolescence study. Vitamin intakes were obtained from two 24-hour recalls in 2253 participants (47% males). Vitamin B biomarkers were assessed in a subsample of 977 participants (46% males). Socioeconomic factors were assessed by questionnaire, and 1-way analysis of covariance and linear regression analysis were applied. For males and females, mean intakes of folate were 211.19 and 177.18 µg/d, and for vitamin B12, 5.98 and 4.54 µg/d, respectively. Levels of plasma folate, red blood cell folate, serum B12, and holotranscobalamin were 18.74, 807.19, 330.64, and 63.04 nmol/L in males, respectively, and 19.13, 770.16, 377.9, and 65.63 nmol/L in females, respectively. Lower folate intakes were associated with several SEFs, including maternal and paternal education in both sexes. Regarding folate biomarkers, lower plasma folate intakes were associated with single/shared care in males and with lower paternal occupation in females. Lower vitamin B12 intakes were associated with almost all the studied SEFs, except paternal occupation in both sexes. In females, when considering vitamin B12 biomarkers, lower plasma vitamin B12 was associated with lower maternal education and occupation, and lower holotranscobalamin was associated with lower maternal education and lower paternal occupation. In conclusion, from the set of socioeconomic determinants studied in a sample of European adolescents, maternal education and paternal occupation were more consistently associated with folate and vitamin B12 intakes and biomarkers concentrations.

Obesity, inflammation and the immune system.

Obesity shares with most chronic diseases the presence of an inflammatory component, which accounts for the development of metabolic disease and other associated health alterations. This inflammatory state is reflected in increased circulating levels of pro-inflammatory proteins, and it occurs not only in adults but also in adolescents and children. The chronic inflammatory response has its origin in the links existing between the adipose tissue and the immune system. Obesity, like other states of malnutrition, is known to impair the immune function, altering leucocyte counts as well as cell-mediated immune responses. In addition, evidence has arisen that an altered immune function contributes to the pathogenesis of obesity. This review attempts to briefly comment on the various plausible explanations that have been proposed for the phenomenon: (1) the obesity-associated increase in the production of leptin (pro-inflammatory) and the reduction in adiponectin (anti-inflammatory) seem to affect the activation of immune cells; (2) NEFA can induce inflammation through various mechanisms (such as modulation of adipokine production or activation of Toll-like receptors); (3) nutrient excess and adipocyte expansion trigger endoplasmic reticulum stress; and (4) hypoxia occurring in hypertrophied adipose tissue stimulates the expression of inflammatory genes and activates immune cells. Interestingly, data suggest a greater impact of visceral adipose tissue and central obesity, rather than total body fat, on the inflammatory process. In summary, there is a positive feedback loop between local inflammation in adipose tissue and altered immune response in obesity, both contributing to the development of related metabolic complications.

Dietary fatty acid intake, its food sources and determinants in European adolescents: the HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) Study.

Dietary fatty acids (FA) play a role in several (patho)physiological processes at any age, and different FA have different effects on lipid status and health outcome. The present study aims to describe the FA intake and its main food sources in a population of healthy European adolescents and to assess the variation in intake as a function of non-dietary factors. FA intake was assessed with 24 h recall interviews in 1804 adolescents aged 12·5-17·5 years. Usual intakes were calculated using the multiple source method. Multilevel analyses, adjusting for study centre, were used to investigate the influence of non-dietary factors. The mean total fat intake was 33·3 (sd 1·2) % of total energy intake (%E). The mean SFA intake was 13·8 (sd 1·2) %E, with 99·8 % of the population exceeding the recommendations. SFA was mainly delivered by meat and cake, pies and biscuits. In most adolescents, the PUFA intake was too low, and 35·5 % of the population did not achieve the minimum recommended intake for α-linolenic acid (ALA). The main determinants of FA intake in the present study population were age and sex, as well as physical activity in the male subgroup. No contributions of body composition, socio-economic status or sexual maturation to the variance in FA intake were observed. In conclusion, the most important public health concerns regarding FA intake in this adolescent population were the low intake of ALA and the high intake of SFA, mainly seen in the younger-aged boys. In this group the major contributor to SFA was meat.

Cellular hypoxia and adipose tissue dysfunction in obesity.

Expansion of adipose tissue mass, the distinctive feature of obesity, is associated with low-grade inflammation. White adipose tissue secretes a diverse range of adipokines, a number of which are inflammatory mediators (such as TNFalpha, IL-1beta, IL-6, monocyte chemoattractant protein 1). The production of inflammatory adipokines is increased with obesity and these adipokines have been implicated in the development of insulin resistance and the metabolic syndrome. However, the basis for the link between increased adiposity and inflammation is unclear. It has been proposed previously that hypoxia may occur in areas within adipose tissue in obesity as a result of adipocyte hypertrophy compromising effective O2 supply from the vasculature, thereby instigating an inflammatory response through recruitment of the transcription factor, hypoxic inducible factor-1. Studies in animal models (mutant mice, diet-induced obesity) and cell-culture systems (mouse and human adipocytes) have provided strong support for a role for hypoxia in modulating the production of several inflammation-related adipokines, including increased IL-6, leptin and macrophage migratory inhibition factor production together with reduced adiponectin synthesis. Increased glucose transport into adipocytes is also observed with low O2 tension, largely as a result of the up-regulation of GLUT-1 expression, indicating changes in cellular glucose metabolism. Hypoxia also induces inflammatory responses in macrophages and inhibits the differentiation of preadipocytes (while inducing the expression of leptin). Collectively, there is strong evidence to suggest that cellular hypoxia may be a key factor in adipocyte physiology and the underlying cause of adipose tissue dysfunction contributing to the adverse metabolic milieu associated with obesity.

Dehydroepiandrosterone modifies rat fatty acid composition of serum and different adipose tissue depots and lowers serum insulin levels.

Dehydroepiandrosterone (DHEA) is reported to exert beneficial effects, such as protection from cardiovascular risk and lowering serum insulin levels. Adipose tissue (AT) is a target for DHEA actions, and the hormone can also affect hepatic fatty acid (FA) metabolism. FAs are involved in the development of insulin resistance; thus, there might be a relationship between DHEA, FA, and insulin. However, few data are available regarding DHEA and FA composition, especially concerning AT. Seventeen-month old female Sprague-Dawley rats (n=11; controls: n=10) were treated with DHEA (0.5% w/w in the diet) for 13 weeks, after which serum, periovarian, mesenteric, s.c., and brown AT were analyzed for FA composition. DHEA treatment resulted in significant changes in FA profiles in serum and adipose depots, like reduced 16:1n-7 (s.c. and brown AT; P<0.01), elevated n-9 monounsaturated FA (serum and s.c. AT; P<0.05), diminished n-6 polyunsaturated FA (PUFA; general; P<0.05) and increased n-3 PUFA (brown AT; P<0.01), along with lower n-6/n-3 ratios (s.c. and brown AT; P<0.05, P<0.01 respectively). DHEA modified estimates of desaturase activities, decreasing stearoyl-CoA-desaturase markers in s.c., and brown AT (P<0.05) and increasing those of delta-6-desaturase in serum and AT (P<0.05). In addition, DHEA-treated rats showed lower serum insulin levels (P<0.05). We have demonstrated for the first time that DHEA induces significant modifications in AT fatty acid composition in vivo, mainly concerning unsaturated FAs, and changes occurred in a tissue-dependent manner. We propose that these changes may be related to the capacity of DHEA to lower serum insulin levels.

Age-related changes in fatty acids from different adipose depots in rat and their association with adiposity and insulin.

OBJECTIVE: We studied age-related changes in fatty acids (FAs) from serum and adipose tissue in rats by comparing different adipose regions and analyzed their relations to adiposity and insulin function. METHODS: Female weaned rats were fed on a high-fat diet until 6, 14, and 20 mo of age (n = 12, n = 6, n = 10, respectively). Body weight, adiposity, serum insulin, serum glucose, and homeostatic model assessment index were measured. FA compositions from serum and interscapular brown, periovarian, mesenteric, and subcutaneous tissues were determined by gas chromatography. RESULTS: Body weight and adiposity increased with age; visceral depots grew by hypertrophy, whereas subcutaneous depots grew by hyperplasia and in a higher ratio. Initially, the mesenteric tissue showed greater saturated and trans-FA contents, whereas brown tissue had higher polyunsaturated FA (PUFA) proportions. Aging resulted in a lower saturation degree in adipose tissue, attenuating earlier differences among depots. There was an elevation in omega-6 PUFAs with age, mainly because of C18:2omega-6, whereas omega-3 long-chain PUFAs, C20:5omega-3 and C22:6omega-3, tended to decrease in serum and adipose tissue. Adiposity was associated positively with monounsaturated FAs and inversely with PUFAs; insulin-related variables correlated negatively with serum omega-6 PUFA but positively with serum monounsaturated FAs and subcutaneous depot trans-FAs. CONCLUSION: The mesenteric tissue showed the least favorable FA profile compared with the other depots, but differences among adipose regions diminished with age. In rats fed a high-fat diet, aging resulted in a lower saturation degree, with increased values in the cardiometabolic risk factor omega-6/omega-3 ratio in serum and adipose tissue.

Adiponectin, the controversial hormone.

OBJECTIVE: To discuss present knowledge about adiponectin hormone. DESIGN: Review of existing literature. SETTING AND RESULTS: Adiponectin is one of the most interesting cytokines associated with obesity, although its physiological role remains to be fully clarified. Adiponectin is a 247-amino acid protein that contains four differentiable domains. Contrary to most adipose-related cytokines, adiponectin levels are surprisingly lower in obese than in lean humans. Women have been found to have significantly higher adiponectin plasma concentrations than men. Further research is needed in order to identify new polymorphisms which contribute to explain the potential role of adiponectin in obesity and related pathologies. Considering the anti-inflammatory properties of adiponectin and the fact that it is negatively associated with adiposity, this cytokine could be one of the links between obesity and inflammation. The main mechanisms of action of adiponectin are directed to a protective role against atherogenic and insulin resistance processes. Research has revealed interesting new functions far beyond metabolism, such as immunity, cancer and bone formation. Contrary to all adipose-related proteins, adiponectin decreases with obesity. Most of the contradictory data surrounding adiponectin are related to plasma values and their relationship with body fat, gender differences and insulin resistance. There are important confounding results regarding the mechanisms of action and functions of adiponectin, especially in relation to insulin resistance and inflammation.

Effect of dehydroepiandrosterone on protein and fat digestibility, body protein and muscular composition in high-fat-diet-fed old rats.

The main objective of the present study was to examine the effects of dehydroepiandrosterone (DHEA) on the digestive efficiency of dietary protein and fat. Second, we analysed the specific changes in muscle composition induced by the hormone. DHEA was given in the diet (0 x 5 %, w/w) to 75-week-old, high-fat-fed Sprague-Dawley rats (n 11) for 13 weeks; age- and weight-matched rats fed on the same diet without DHEA supplementation were used as controls (n 10). To determine dietary protein and fat apparent digestibility coefficients, 1-week 24 h faecal depositions were collected. In parallel, urine N was assessed. These assays were performed twice, in the short term (2-week treatment) and in the long term (13-week treatment). Body and gastrocnemius muscle compositions were also analysed. The present results show that DHEA decreased energy intake, body weight, body fat, adipocyte size and number (P<0 x 001). The feed efficiency ratio indicates that DHEA-treated rats were less efficient in transforming nutrients fed into their own biomass. Also, a short-term reduction in protein digestibility (P<0 x 05) and in body-protein degradation (P<0 x 01) was found in DHEA-treated rats, resulting in an increased content of body protein (P<0 x 05). Gastrocnemius muscles were smaller, as a result of fat (P<0 x 05) but not protein reduction. In conclusion, we confirm the slimming effect of DHEA and, for the first time, we demonstrate that DHEA has an effect at the digestive level. The anti-obesity properties of DHEA could be related to a reduction in protein digestibility in the short term and a protective effect on body protein with a selective mass loss from body fat.