The pons as reference region for intensity normalization in semi-quantitative analysis of brain 18FDG PET: application to metabolic changes related to ageing in conventional and digital control databases.

BACKGROUND: The objective of the study is to define the most appropriate region for intensity normalization in brain 18FDG PET semi-quantitative analysis. The best option could be based on previous absolute quantification studies, which showed that the metabolic changes related to ageing affect the quasi-totality of brain regions in healthy subjects. Consequently, brain metabolic changes related to ageing were evaluated in two populations of healthy controls who underwent conventional (n = 56) or digital (n = 78) 18FDG PET/CT. The median correlation coefficients between age and the metabolism of each 120 atlas brain region were reported for 120 distinct intensity normalizations (according to the 120 regions). SPM linear regression analyses with age were performed on most significant normalizations (FWE, p < 0.05). RESULTS: The cerebellum and pons were the two sole regions showing median coefficients of correlation with age less than - 0.5. With SPM, the intensity normalization by the pons provided at least 1.7- and 2.5-fold more significant cluster volumes than other normalizations for conventional and digital PET, respectively. CONCLUSIONS: The pons is the most appropriate area for brain 18FDG PET intensity normalization for examining the metabolic changes through ageing.

18F-FDG brain PET hypometabolism in patients with long COVID.

PURPOSE: In the context of the worldwide outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), some patients report functional complaints after apparent recovery from COVID-19. This clinical presentation has been referred as "long COVID." We here present a retrospective analysis of 18F-FDG brain PET of long COVID patients from the same center with a biologically confirmed diagnosis of SARS-CoV-2 infection and persistent functional complaints at least 3 weeks after the initial infection. METHODS: PET scans of 35 patients with long COVID were compared using whole-brain voxel-based analysis to a local database of 44 healthy subjects controlled for age and sex to characterize cerebral hypometabolism. The individual relevance of this metabolic profile was evaluated to classify patients and healthy subjects. Finally, the PET abnormalities were exploratory compared with the patients' characteristics and functional complaints. RESULTS: In comparison to healthy subjects, patients with long COVID exhibited bilateral hypometabolism in the bilateral rectal/orbital gyrus, including the olfactory gyrus; the right temporal lobe, including the amygdala and the hippocampus, extending to the right thalamus; the bilateral pons/medulla brainstem; the bilateral cerebellum (p-voxel < 0.001 uncorrected, p-cluster < 0.05 FWE-corrected). These metabolic clusters were highly discriminant to distinguish patients and healthy subjects (100% correct classification). These clusters of hypometabolism were significantly associated with more numerous functional complaints (brainstem and cerebellar clusters), and all associated with the occurrence of certain symptoms (hyposmia/anosmia, memory/cognitive impairment, pain and insomnia) (p < 0.05). In a more preliminary analysis, the metabolism of the frontal cluster which included the olfactory gyrus was worse in the 7 patients treated by ACE drugs for high blood pressure (p = 0.032), and better in the 3 patients that had used nasal decongestant spray at the infectious stage (p < 0.001). CONCLUSION: This study demonstrates a profile of brain PET hypometabolism in long COVID patients with biologically confirmed SARS-CoV-2 and persistent functional complaints more than 3 weeks after the initial infection symptoms, involving the olfactory gyrus and connected limbic/paralimbic regions, extended to the brainstem and the cerebellum. These hypometabolisms are associated with patients' symptoms, with a biomarker value to identify and potentially follow these patients. The hypometabolism of the frontal cluster, which included the olfactory gyrus, seems to be linked to ACE drugs in patients with high blood pressure, with also a better metabolism of this olfactory region in patients using nasal decongestant spray, suggesting a possible role of ACE receptors as an olfactory gateway for this neurotropism.

Ecodesign of cosmetic formulae: methodology and application.

OBJECTIVE: This article describes an easy-to-use ecodesign methodology developed and applied since 2014 by the L'Oréal Group to improve the sustainable performance of its new products without any compromise on their cosmetic efficacy. METHODS: Cosmetic products, after being used, are often discharged into the sewers and the aquatic compartment. This discharge is considered as dispersive and continuous. A consistent progress in reducing the environmental impact of cosmetic products can be achieved through focusing upon three strategic indicators: biodegradability, grey water footprint adapted for ecodesign (GWFE) and a global indicator, complementary to these two endpoints. Biodegradability represents the key process in the removal of organic ingredients from the environment. GWFE is defined herein as the theoretical volume of natural freshwater required to dilute a cosmetic formula after being used by the consumer, down to a concentration without any foreseeable toxic effects upon aquatic species. Finally, the complementary indicator highlights a possible alert on formula ingredients due to an unfavourable environmental profile based on hazard properties: for example Global Harmonization System/Classification, Labelling and Packaging (GHS/CLP) H410 classification or potential very persistent and very bioaccumulative (vPvB) classification. RESULTS: The ecodesign of a new cosmetic product can be a challenge as the cosmetic properties and quality of this new product should at least match the benchmark reference. As shown in the case studies described herein, new methodologies have been developed to maximize the biodegradability of cosmetic formulae, to minimize their GWFE and to limit the use of ingredients that present an unfavourable environmental profile, while reaching the highest standards in terms of cosmetic efficacy. CONCLUSION: By applying these methodologies, highly biodegradable products (≥ 95% based on ingredient composition) have been developed and marketed, with a low GWFE. This new ecodesign approach shows that embedding sustainability in developing new cosmetic products can also open up new innovative opportunities.

Perinatal maternal feeding with an energy dense diet and/or micronutrient mixture drives offspring fat distribution depending on the sex and growth stage.

Maternal nutrition during pregnancy and lactation influences offspring development and health. Novel studies have described the effects on next generation obesity-related features depending on maternal macro- and micro-nutrient perinatal feeding. We hypothesized that the maternal obesogenic diet during pregnancy and lactation programs an obese phenotype, while maternal micronutrient supplementation at these stages could partially prevent these features. Thus, the aim was to assess the influence of a perinatal maternal feeding with an obesogenic diet enriched in fat and sucrose and a micronutrient supplementation during pregnancy and lactation on offspring growth and obese phenotypical features during life course. Female Wistar rats were assigned to four dietary groups during pregnancy and lactation: control, control supplemented with micronutrients (choline, betaine, folic acid and vitamin B12 ), high-fat sucrose (HFS) and HFS supplemented. At weaning, the offspring were transferred to a chow diet, and weight and fat mass were measured at weeks 3, 12 and 20. At birth, both male and female offspring from mothers fed the obesogenic diet showed lower body weight (-5 and -6%, respectively), while only female offspring weight decreased by maternal micronutrient supplementation (-5%). During lactation, maternal HFS diet was associated with increased body weight, while micronutrient supplementation protected against body weight gain. Whole body fat mass content increased at weeks 3, 12 and 20 (from 16 to 65%) due to maternal HFS diet. Maternal micronutrient supplementation decreased offspring fat mass content at week 3 (-8%). Male offspring showed higher adiposity than females at weeks 12 and 20. In conclusion, maternal HFS feeding during pregnancy and lactation was associated with a low offspring weight at birth and obese phenotypical features during adult life in a sex- and time-dependent manner. Furthermore, maternal methyl donor supplementation protected against body weight gain in male offspring during lactation and in female offspring also during juvenile period.

Supplementation with methyl donors during lactation to high-fat-sucrose-fed dams protects offspring against liver fat accumulation when consuming an obesogenic diet.

Methyl donor supplementation has been reported to prevent obesity-induced liver fat accumulation in adult rats. We hypothesized that this protection could be mediated by perinatal nutrition. For this purpose, we assessed the response to an obesogenic diet (high-fat-sucrose, HFS) during adulthood depending on maternal diet during lactation. Female Wistar rats fed control diet during pregnancy were assigned to four postpartum dietary groups: control, control supplemented with methyl donors (choline, betaine, folic acid, vitamin B12), HFS and HFS supplemented with methyl donors. At weaning, the male offspring was transferred to a chow diet and at week 12th assigned to a control or a HFS diet during 8 weeks. The offspring whose mothers were fed HFS during lactation showed increased adiposity (19%, P<0.001). When fed the HFS diet as adults, offspring whose mothers were HFS supplemented had more body fat (23%, P<0.001) than those from HFS non-supplemented. However, they showed lower liver fat accumulation (-18%, P<0.001). Srebf1, Dnmt1 and Lepr liver mRNA levels increased after adulthood HFS feeding. In those animals HFS fed during adulthood, previous maternal HFS decreased Lepr and Dnmt1 expression levels when compared with c-HFS offspring, while the supplementation of control and HFS-fed dams, respectively, induced higher hepatic Mme and Lepr mRNA levels after adult HFS intake compared with hfs-HFS offspring. In conclusion, maternal HFS diet during lactation influenced the response to an obesogenic diet in the adult progeny. Interestingly, dietary methyl donor supplementation in lactating mothers fed an obesogenic diet reduced liver fat accumulation, but increased adipose tissue storage in adult HFS-fed offspring.

Epigenetic patterns of two gene promoters (TNF-α and PON) in stroke considering obesity condition and dietary intake.

Some causal bases of stroke remain unclear, but the nutritional effects on the epigenetic regulation of different genes may be involved. The aim was to assess the impact of epigenetic processes of human tumor necrosis factor (TNF-α) and paraoxonase (PON) promoters in the susceptibility to stroke when considering body composition and dietary intake. Twenty-four patients (12 non-stroke/12 stroke) were matched by sex (12 male/12 female), age (mean 70 ± 12 years old), and BMI (12 normal-weight/12 obese; mean 28.1 ± 6.7 kg/m(2)). Blood cell DNA was isolated and DNA methylation levels of TNF-α (-186 to +349 bp) and PON (-231 to +250 bp) promoters were analyzed by the Sequenom EpiTYPER approach. Histone modifications (H3K9ac and H3K4me3) were analyzed also by chromatin immunoprecipitation in a region of TNF-α (-297 to -185). Total TNF-α promoter methylation was lower in stroke patients (p < 0.001) and showed no interaction with body composition (p = 0.807). TNF-α and PON total methylation levels correlated each other (r = 0.44; p = 0.031), especially in stroke patients (r = 0.72; p = 0.008). The +309 CpG methylation site from TNF-α promoter was related to body weight (p = 0.027) and the region containing three CpGs (from -170 to -162 bp) to the percentage of lipid intake and dietary indexes (p < 0.05) in non-stroke patients. The methylation of PON +15 and +241 CpGs was related to body weight (p = 0.021), waist circumference (p = 0.020), and energy intake (p = 0.018), whereas +214 was associated to the quality of the diet (p < 0.05) in non-stroke patients. When comparing stroke vs non-stroke patients regarding the histone modifications analyzed at TNF-α promoter, no changes were found, although a significant association was identified between circulating TNF-α level and H3K9ac with H3K4me3. TNF-α and PON promoter methylation levels could be involved in the susceptibility to stroke and obesity outcome, respectively. The dietary intake and body composition may influence this epigenetic regulation in non-stroke patients.

TNF-alpha promoter methylation in peripheral white blood cells: relationship with circulating TNFα, truncal fat and n-6 PUFA intake in young women.

The aim of this article is to assess the potential relationships between TNFα gene promoter methylation in peripheral white blood cells and central adiposity (truncal fat), metabolic features and dietary fat intake. A group of 40 normal-weight young women (21 ± 3y; BMI 21.0 ± 1.7 kg/m(2)) was included in this cross-sectional study. Anthropometric, biochemical and dietary data were assessed using validated procedures. DNA from white blood cells was isolated and 5-methylcytosine levels of the CpGs sites present in TNFα gene promoter (from -170 to +359 pb) were analyzed by Sequenom EpiTyper. Those women with high truncal fat (≥52.3%) showed lower 5-methylcytosine levels (P<0.05) in the site CpG13 (at position +207) and CpG19 (+317 pb) of the TNFα gene promoter when were compared to women with lower truncal adiposity. The methylation levels of CpG13 were also correlated with circulating TNFα levels, which were higher in those women with greater truncal adiposity. In a linear regression model, truncal fat, HDL-cholesterol, insulin, plasma TNFα, and daily n-6 PUFA intake explained the methylation levels of CpG13 site +207 by 48% and the average of CpG13 and CpG19 by 43% (P<0.001). In conclusion, women with higher truncal fat showed lower methylation levels of TNFα promoter in peripheral white blood cells and higher plasma TNFα concentrations. DNA methylation levels of TNFα promoter were associated with some metabolic features and with n-6 PUFA intake, suggesting a complex nutriepigenomic network in the regulation of this recognized pro-inflammatory marker.

Shifting to a control diet after a high-fat, high-sucrose diet intake induces epigenetic changes in retroperitoneal adipocytes of Wistar rats.

The aim of the study was to analyze the phenotypic and epigenetic changes induced by the shift to a chow diet after an obesogenic environment. Animals were randomized to fed chow (control group) or high-fat-sucrose diet (HFS). After 10 weeks, half of the rats fed with HFS diet were reassigned to a chow diet (rest group) while the other half continued with the obesogenic diet (HFS group) until week 20. Changes in fat content, biochemical profile, and DNA methylation levels of several gene promoters from retroperitoneal adipocytes were analyzed. HFS diet intake for 10 weeks induced obese phenotype in the animals, increasing body weight and fat content. These effects were maintained until the end of the trial in HFS group, where an increase in liver fat content, a modification of lipid profile, and retroperitoneal adipose tissue hypertrophy were also observed. Changing the dietary pattern reversed these parameters. Epigenetic analysis showed that HFS diet intake for 20 weeks hypermethylated several CpG sites (6.7 and 29.30) and hypomethylated CpG site 15 from leptin gene promoter. Moreover, the obesogenic diet also hypomethylated CpG site 1 from Fasn (fatty acid synthase) gene promoter, without changes on Ppargc1a (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), Srebf1 (sterol regulatory element-binding transcription factor 1), and aquaporin 7. Shifting to a chow diet reverted HFS-induced DNA methylation levels of some CpG sites of leptin promoter. Changing the dietary pattern hypomethylated a CpG site of Srebf1 and hypermethylated other CpGs on Ppargc1a and Fasn promoter. This study shed light on the reversibility of phenotypical and epigenetic changes induced by a HFS diet intake.

Dietary supplementation with methyl donors reduces fatty liver and modifies the fatty acid synthase DNA methylation profile in rats fed an obesogenic diet.

Non-alcoholic fatty liver disease (NAFLD) is one of the first hepatic manifestations of metabolic syndrome, whose progression can lead to cirrhosis and hepatic carcinoma. Interestingly, methyl donor supplementation could improve obesogenic diet-induced hepatic triglyceride accumulation. The aim of this research is to describe methyl donor effects on a high-fat-sucrose (HFS) diet in both sexes and epigenetic changes induced on fatty acid synthase (FASN) promoter methylation pattern as well as gene expression of NAFLD key metabolic genes. Twenty-four male and 28 female Wistar rats were assigned to three dietary groups: control, HFS, and HFS supplemented with methyl donors (choline, betaine, vitamin B12, and folic acid). After 8 weeks of treatment, somatic, biochemical, mRNA, and epigenetic measurements were performed. Rats fed the HFS diet presented an overweight phenotype and alterations in plasma biochemical measurements. Methyl donor supplementation reverted the HFS-diet-induced hepatic triglyceride accumulation. Analysis of FASN promoter cytosine methylation showed changes in both sexes due to the obesogenic diet at -1,096, -780, -778, and -774 CpG sites with respect to the transcriptional start site. Methyl donor supplementation modified DNA methylation at -852, -833, -829, -743, and -733 CpGs depending on the sex. RT-PCR analysis confirmed that FASN expression tended to be altered in males. Our findings reinforce the hypothesis that methyl donor supplementation can prevent hepatic triglyceride accumulation induced by obesogenic diets in both sexes. Changes in liver gene expression profile and epigenetic-mediated mechanisms related to FASN DNA hypermethylation could be involved in methyl donor-induced NAFLD improvement.

Prenatal stress increases the obesogenic effects of a high-fat-sucrose diet in adult rats in a sex-specific manner.

Stress during pregnancy can induce metabolic disorders in adult offspring. To analyze the possible differential response to a high-fat-sucrose (HFS) diet in offspring affected by prenatal stress (PNS) or not, pregnant Wistar rats (n = 11) were exposed to a chronic mild stress during the third week of gestation. The aim of this study was to model a chronic depressive-like state that develops over time in response to exposure of rats to a series of mild and unpredictable stressors. Control dams (n = 11) remained undisturbed. Adult offspring were fed chow or HFS diet (20% protein, 35% carbohydrate, 45% fat) for 10 weeks. Changes in adiposity, biochemical profile, and retroperitoneal adipose tissue gene expression by real-time polymerase chain reaction were analyzed. An interaction was observed between HFS and PNS concerning visceral adiposity, with higher fat mass in HFS-fed stressed rats, statistically significant only in females. HFS modified lipid profile and increased insulin resistance biomarkers, while PNS reduced insulin concentrations and the homeostasis model assessment index. HFS diet increased gene (mRNA) expression for leptin and apelin and decreased cyclin-dependent kinase inhibitor 1A and fatty acid synthase (Fasn), whereas PNS increased Fasn and stearoyl-CoA desaturase1. An interaction between diet and PNS was observed for adiponutrin (Adpn) and peroxisome proliferator-activated receptor-γ coactivator1-α (Ppargc1a) gene expression: Adpn was increased by the PNS only in HFS-fed rats, whereas Ppargc1a was increased by the PNS only in chow-fed rats. From these results, it can be concluded that experience of maternal stress during intrauterine development can enhance predisposition to obesity induced by a HFS diet intake.

Transcriptomic and epigenetic changes in the hypothalamus are involved in an increased susceptibility to a high-fat-sucrose diet in prenatally stressed female rats.

Disturbances in the prenatal period are linked to metabolic disorders in adulthood, implying the hypothalamic systems of appetite and energy balance regulation. In order to analyze the central effects of a high-fat-sucrose (HFS) diet in prenatally stressed (PNS) female adult rats, Wistar dams were exposed to chronic-mild-stress during the third week of gestation and were then compared with unstressed controls. Adult female offspring were fed a chow or HFS diet for 10 weeks. Changes in body weight, adiposity as well as expression and methylation levels of selected hypothalamic genes were analyzed. PNS induced lower birthweight and body length with no changes in body fat mass. After the HFS diet, the expected overweight model was observed accompanied by higher adiposity and insulin resistance, which was worsened by PNS. The stress model induced higher energy intake in adulthood. Hypothalamic gene expression analysis revealed that the HFS diet decreased Slc6a3 (dopamine active transporter), NPY (neuropeptide Y) and IR (insulin receptor) and increased POMC (pro-opiomelanocortin). Hypothalamic DNA methylation levels in the promoter region of Slc6a3 revealed that Slc6a3 was hypermethylated by the HFS diet in CpG site -53 bp to the transcription start site. HFS diet also hypermethylated CpG site -167 bp of the POMC promoter only in nonstressed animals. No correlations were found between gene expression and DNA methylation levels. These results imply that early-life stress in females increased predisposition to diet-induced obesity in adulthood.

European Psychiatric Association (EPA) guidance on prevention of mental disorders.

There is considerable evidence that various psychiatric conditions can be prevented through the implementation of effective evidence-based interventions. Since a large proportion of lifetime mental illness starts before adulthood, such interventions are particularly important during childhood and adolescence. Prevention is important for the sustainable reduction of the burden of mental disorder since once it has arisen, treatment can only reduce a relatively small proportion of such burden. The challenge for clinicians is to incorporate such interventions into non-clinical and clinical practice as well as engaging with a range of other service providers including public health. Similar strategies can be employed in both the European and global contexts. Promotion of mental well-being can prevent mental disorder but is also important in the recovery from mental disorder. This guidance should be read in conjunction with the EPA Guidance on Mental Health Promotion. This guidance draws on preparatory work for the development of England policy on prevention of mental disorder which used a wide range of sources.

Maternal weight gain induced by an obesogenic diet affects adipose accumulation, liver weight, and insulin homeostasis in the rat offspring depending on the sex.

BACKGROUND: The aim of this research was to analyze the influence of the maternal dietary intake before pregnancy, as well as the parental impact on the response to a transgenerational high-fat-diet in rats. METHODS: Ten female Wistar rats were fed a standard or a high-fat-sucrose (HFS) diet in the 8 weeks prior to pregnancy. Adult offsprings were assigned to a control or obesogenic diet for 8 weeks. Then, rat tissues and plasma samples were collected for analyzing tissue weight, liver triglycerides, and biochemical parameters such as triglycerides, HDL cholesterol, glucose, and insulin levels. RESULTS: The offspring of rats fed a HFS diet gained less weight when they were fed the same diet than those fed a HFS diet combined with maternal control diet. Insulin levels were higher in rats fed a HFS diet (p<0.05) in both sexes; however, maternal HFS diet reversed, partially in males and total- ly in females, this hormonal imbalance. In male newborns, diet-induced maternal weight gain before pregnancy significantly influenced visceral (R 2 =0.373) and subcutaneous (R 2 =0.239) adipose deposition as well as liver weight (R 2 =0.130). Paternal genetic make-up was also a relevant factor affecting adiposity in both sexes (R 2 =0.333 in visceral fat; R 2 =0.183 in subcutaneous fat in males, and 0.292 and 0.282, respectively in females) as well as plasma triglycerides (R 2 =0.193 in males and R 2 =0.251 in females). CONCLUSIONS: The genetic parental background and pre-natal maternal diet are important factors in the response to a hypercaloric diet and affect body composition and glucose homeostasis traits, including insulin secretion and homeostatic model assessment index.

Regulation by chronic-mild stress of glucocorticoids, monocyte chemoattractant protein-1 and adiposity in rats fed on a high-fat diet.

Stress has been reported as a widespread problem and several studies have linked obesity and inflammation-related diseases. Moreover, the combination of suffering from chronic stress and high energy intake might be related to the onset of some metabolic diseases. To study the possible relationships between stress, inflammatory status and obesity, a chronic-mild stress (CMS) paradigm with a high-fat dietary intake model (Cafeteria diet) was implemented on male Wistar rats for 11 weeks. Stress and dietary intake effects on animal adiposity, serum biochemical as well as glucocorticoids and inflammation markers were all analyzed. As expected, consuming a high-fat diet increased body weight, adiposity and insulin resistance in non-stressed animals. A decrease of total white adipose tissue (WAT) and an increase of fecal glucocorticoids, as well as angiotensinogen, and monocyte chemoattractant protein-1 (MCP-1) expression level in retroperitoneal WAT were found only on control-stressed rats. Regarding the serum MCP-1, a decrease was observed on animals under CMS while being fed Cafeteria diet. Furthermore, 11ß-hydroxysteroid dehydrogenase activity, a glucocorticoid and obesity biomarker in the liver, was influenced by high-fat diet intake but not by stress. Finally, statistical analysis showed a strong relation between MCP-1 expression levels in retroperitoneal WAT, fecal corticosterone and total WAT. This trial proved that CMS induced a glucocorticoid-mediated response, which was reduced by the intake of a Cafeteria diet. These findings suggest that a high-fat diet could protect against a stress condition and revealed a different behavior to a stressful environment depending on the nutritional status.

Site-specific circadian expression of leptin and its receptor in human adipose tissue.

INTRODUCTION: Circadian variability of circulating leptin levels has been well established over the last decade. However, the circadian behavior of leptin in human adipose tissue remains unknown. This also applies to the soluble leptin receptor. OBJECTIVE: We investigated the ex vivo circadian behavior of leptin and its receptor expression in human adipose tissue (AT). SUBJECTS AND METHODS: Visceral and subcutaneous abdominal AT biopsies (n = 6) were obtained from morbid obese women (BMI ≥ 40 kg/m²). Anthropometric variables and fasting plasma glucose, leptin, lipids and lipoprotein concentrations were determined. In order to investigate rhythmic expression pattern of leptin and its receptor, AT explants were cultured during 24-h and gene expression was analyzed at the following times: 08:00, 14:00, 20:00, 02:00 h, using quantitative real-time PCR. RESULTS: Leptin expression showed an oscillatory pattern that was consistent with circadian rhythm in cultured AT. Similar patterns were noted for the leptin receptor. Leptin showed its achrophase (maximum expression) during the night, which might be associated to a lower degree of fat accumulation and higher mobilization. When comparing both fat depots, visceral AT anticipated its expression towards afternoon and evening hours. Interestingly, leptin plasma values were associated with decreased amplitude of LEP rhythm. This association was lost when adjusting for waist circumference. CONCLUSION: Circadian rhythmicity has been demonstrated in leptin and its receptor in human AT cultures in a site-specific manner. This new knowledge paves the way for a better understanding of the autocrine/paracrine role of leptin in human AT.

Vitamin C inhibits leptin secretion and some glucose/lipid metabolic pathways in primary rat adipocytes.

Antioxidant-based treatments are emerging as an interesting approach to possibly counteract obesity fat accumulation complications, since this is accompanied by an increased systemic oxidative stress. The aim of this study was to analyze specific metabolic effects of vitamin C (VC) on epididymal primary rat adipocytes. Cells were isolated and incubated for 72 h in culture medium, in the absence or presence of 1.6 nM insulin, within a range of VC concentrations (5-1000 microM). Glucose- and lipid-related variables as well as the secretion/expression patterns of several obesity-related genes were assessed. It was observed that VC dose dependently inhibited glucose uptake and lactate production, and also reduced glycerol release in both control and insulin-treated cells. Also, VC caused a dramatic concentration-dependent fall in leptin secretion especially in insulin-stimulated cells. In addition, VC (200 microM) induced Cdkn1a and Casp8, partially inhibited Irs3, and together with insulin drastically reduced Gpdh (listed as Gpd1 in the MGI database) gene expressions. Finally, VC and insulin down-regulatory effects were observed on extracellular and intracellular reactive oxygen species production respectively. In summary, this experimental assay describes a specific effect of VC in isolated rat adipocytes on glucose and fat metabolism, and on the secretion/expression of important obesity-related proteins.

Impact of oxygen availability on body weight management.

Obesity is nowadays a major public health problem. The World Health Organization reported that globally 400 million adults are obese, and the situation seems to raise in the future. Furthermore, obesity is a major risk factor for a number of chronic diseases such as type 2 diabetes, cardiovascular diseases and the metabolic syndrome. Interestingly, several studies have reported that appetite suppression and body weight loss are frequently observed at high altitude. This observation has opened some possibilities for losing weight under hypoxia or living in altitude. Nevertheless, the triggering mechanisms for the decrease in energy intake in hypoxic conditions still remain unclear as well as the impact on body mass components. On the other hand, obese subjects often present a chronic inflammatory state on the adipose tissue that might have a strong relationship with onset and development of obesity-related diseases. Thus, it has been consistently reported that adipose tissue of obese subjects is poorly oxygenated and that this hypoxia state is a new potential risk factor for the chronic inflammation in obesity. In this sense, oxygen therapy is a common technique used in current medicine for the treatment of several diseases, while animal studies have demonstrated that treatment with hyperoxia produces some beneficial effects in different diseases related with lack of oxygen in several organs. In this article, we review the role of oxygen availability in body weight homeostasis and hypothesize the possible applicability of hypoxia and hyperoxia for the treatment of obesity and related disorders.

Circadian expression of adiponectin and its receptors in human adipose tissue.

Adiponectin is one of the most clinically relevant cytokines associated with obesity. However, circadian rhythmicity of adiponectin in human adipose tissue (AT) has not been analyzed. To assess whether the mRNA levels of adiponectin and its receptors (ADIPOR1 and ADIPOR2) might show daily circadian rhythms in visceral and sc fat explants obtained from morbid obese women, visceral and sc abdominal AT biopsies (n = 6) were obtained from morbidly obese women (body mass index >or=40 kg/m(2)). Anthropometric variables were measured and fasting plasma glucose, lipid, and lipoprotein concentrations were analyzed. To investigate rhythmic expression pattern, AT explants were cultured during 24 h, and gene expression was analyzed at the following times: 0800, 1400, 2000, and 0200 h, using quantitative real-time PCR. All genes investigated showed a circadian rhythmicity and oscillated accurately and independently of the suprachiasmatic nucleus in both AT explants (P < 0.05). Adiponectin gene expression fluctuated in the same phase as its receptors. Correlation analyses between the genetic circadian oscillation and components of the metabolic syndrome revealed that adiposity and abdominal obesity correlated with a decrease in adiponectin and adiponectin receptors ADIPOR1 and ADIPOR2 amplitude (P < 0.05). Visceral fat showed a trend toward a phase delay and dampening of the mRNA amplitude of adiponectin as compared with sc fat. The mRNA expression of adiponectin and its receptors showed 24-h rhythmicity in human AT from morbidly obese patients.

High fat diet-induced obesity modifies the methylation pattern of leptin promoter in rats.

Leptin is an adipokine involved in body weight and food intake regulation whose promoter region presents CpG islands that could be subject to dynamic methylation. This methylation process could be affected by environmental (e.g. diet) or endogenous (e.g., adipocyte differentiation, inflammation, hypoxia) factors, and could influence adipocyte leptin gene expression. The aim of this article was to study whether a high-energy diet may affect leptin gene promoter methylation in rats. A group of eleven male Wistar rats were assigned into two dietary groups, one fed on a control diet for 11 weeks and the other on a high-fat cafeteria diet. Rats fed a high-energy diet become overweight and hyperleptinemic as compared to the controls. DNA isolated from retroperitoneal adipocytes was treated with bisulfite and a distal portion of leptin promoter (from -694 to -372 bp) including 13 CpG sites was amplified by PCR and sequenced. The studied promoter portion was slightly more methylated in the cafeteria-fed animals, which was statistically significant (p < 0.05) for one of the CpG sites (located at the position -443). In obese rats, such methylation was associated to lower circulating leptin levels, suggesting that this position could be important in the regulation of leptin gene expression, probably by being a target sequence of different transcription factors. Our findings reveal, for the first time, that leptin methylation pattern can be influenced by diet-induced obesity, and suggest that epigenetic mechanisms could be involved in obesity by regulating the expression of important epiobesigenic genes.

Individuality and epigenetics in obesity.

Excessive weight gain arises from the interactions among environmental factors, genetic predisposition and the individual behavior. However, it is becoming evident that interindividual differences in obesity susceptibility depend also on epigenetic factors. Epigenetics studies the heritable changes in gene expression that do not involve changes to the underlying DNA sequence. These processes include DNA methylation, covalent histone modifications, chromatin folding and, more recently described, the regulatory action of miRNAs and polycomb group complexes. In this review, we focus on experimental evidences concerning dietary factors influencing obesity development by epigenetic mechanisms, reporting treatment doses and durations. Moreover, we present a bioinformatic analysis of promoter regions for the search of future epigenetic biomarkers of obesity, including methylation pattern analyses of several obesity-related genes (epiobesigenes), such as FGF2, PTEN, CDKN1A and ESR1, implicated in adipogenesis, SOCS1/SOCS3, in inflammation, and COX7A1 LPL, CAV1, and IGFBP3, in intermediate metabolism and insulin signalling. The identification of those individuals that at an early age could present changes in the methylation profiles of specific genes could help to predict their susceptibility to later develop obesity, which may allow to prevent and follow-up its progress, as well as to research and develop newer therapeutic approaches.