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Our aim was to determine the incidence of type 2 diabetes mellitus in a nation-wide population based cohort from Spain (di@bet.es study). The target was the Spanish population. In total 5072 people older than 18 years,were randomly selected from all over Spain). Socio-demographic and clinical data, survey on habits (physical activity and food consumption) and weight, height, waist, hip and blood pressure were recorder. A fasting blood draw and an oral glucose tolerance test were performed. Determinations of serum glucose were made. In the follow-up the same variables were collected and HbA1c was determined. A total of 2408 subjects participated in the follow-up. In total, 154 people developed diabetes (6.4% cumulative incidence in 7.5 years of follow-up). The incidence of diabetes adjusted for the structure of age and sex of the Spanish population was 11.6 cases/1000 person-years (IC95% = 11.1-12.1). The incidence of known diabetes was 3.7 cases/1000 person-years (IC95% = 2.8-4.6). The main risk factors for developing diabetes were the presence of prediabetes in cross-sectional study, age, male sex, obesity, central obesity, increase in weight, and family history of diabetes. This work provides data about population-based incidence rates of diabetes and associated risk factors in a nation-wide cohort of Spanish population.

Background: Prediabetes and old age are both high risk factors for developing Type 2 Diabetes (T2D), while obesity is one of the most important factors triggering the disease. Nutritional interventions are the most effective tool for preventing T2D, as they improve different biochemical and anthropometric outcomes and growth-promoting/inhibiting gut microbiota populations. However, to date there are no specific dietary recommendations to stop the development of T2D in elderly groups, for whom hypocaloric diets and other commonly used weight-loss programs could be considered dangerous. The objective of our study, thus, was to understand the impact of dietary patterns on T2D risk as related to gut microbiota profile in obese and non-obese elderly prediabetic subjects., Methods: A cross-sectional study was performed in 182 subjects ≥65 years old with prediabetes, divided into obese (OB) or non-obese (NOB) subgroups, and their risk of developing T2D was measured according to FINDRISK score and biochemical parameters. Also, clusters into different dietary patterns in each group by PCA analysis was related with gut microbiota, which was analyzed from stool samples by qPCR. The creation of clusters was used to re-evaluate T2D risk., Results: OB was at higher risk of developing T2D and showed worse metabolic outcomes. Unhealthier and healthier dietary pattern clusters were observed for both OB (OB-6 and OB-5 respectively) and NOB (NOB-2 and NOB-3 respectively) groups. Results obtained from the gut microbiota showed that only Prevotella was higher in NOB, but when comparisons were made between clusters, a clear relation with dietary pattern was observed; showing in healthier dietary clusters a decrease in Prevotella, an increase of Faecalibacterium prausnitzii and an increase in lactic acid bacteria. T2D risk was greater in the obese group between unhealthier dietary clusters. No difference between healthier dietary clusters was observed., Conclusion: A healthy dietary pattern and the growth-promoting beneficial and growth-inhibiting disadvantageous gut microbiota populations linked to it provide protection against the development of T2D in an obese population with advanced age and preDM., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: This analysis aimed to evaluate efficacy and safety of empagliflozin in combination therapy in <65 y.o. patients, overweight/obese, and with uncontrolled T2DM., Methods: Pooled analysis from three phase-III trials, in <65 y.o. patients, with BMI 25-35kg/m 2 , and HbA1c ≥8% at baseline. Patients (N=439) were randomized to placebo (n=138), empagliflozin 10mg (n=160), or empagliflozin 25mg (n=141) once daily (24weeks) as add-on to metformin, to metformin plus sulfonylurea, or to pioglitazone ± metformin., Results: At week 24, adjusted mean (SE) changes from baseline in HbA1c were -0.19% (0.07) for placebo vs. -1.10% (0.07) and -1.10% (0.07) for empagliflozin 10 and 25mg, respectively (both p<0.001). Adjusted mean (SE) changes from baseline in weight were -0.33kg (0.21) for placebo vs. -1.94kg (0.19) and -2.14kg (0.20) for empagliflozin 10 and 25mg, respectively (both p<0.001). Adverse events were reported in 57.2% on placebo, 64.4% on empagliflozin 10mg and 59.6% on empagliflozin 25mg. Genital infection AEs were reported in 1.4% on placebo, 3.8% on empagliflozin 10mg, and 5.0% on empagliflozin 25mg., Conclusions: In this specific population, empagliflozin in combination with other oral agents, significantly reduced HbA1c and body weight and was well tolerated., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Recent evidence indicates that the gut microbiota plays a key role in the pathophysiology of obesity. Indeed, diet-induced obesity (DIO) has been associated to substantial changes in gut microbiota composition in rodent models. In the context of obesity, enhanced adiposity is accompanied by low-grade inflammation of this tissue but the exact link with gut microbial community remains unknown. In this report, we studied the consequences of high-fat diet (HFD) administration on metabolic parameters and gut microbiota composition over different periods of time. We found that Akkermansia muciniphila abundance was strongly and negatively affected by age and HFD feeding and to a lower extend Bilophila wadsworthia was the only taxa following an opposite trend. Different approaches, including multifactorial analysis, showed that these changes in Akkermansia muciniphila were robustly correlated with the expression of lipid metabolism and inflammation markers in adipose tissue, as well as several circulating parameters (i.e., glucose, insulin, triglycerides, leptin) from DIO mice. Thus, our data shows the existence of a link between gut Akkermansia muciniphila abundance and adipose tissue homeostasis on the onset of obesity, thus reinforcing the beneficial role of this bacterium on metabolism.

Clock gene expression was associated with different components of metabolic syndrome (MS) in human adipose tissue. However, no study has been done to compare the expression of clock genes in visceral adipose tissue (VAT) from lean and obese subjects and its clinical implications. Therefore, we studied in lean and obese women the endogenous 24 h expression of clock genes in isolated adipocytes and its association with MS components. VAT was obtained from lean (BMI 21-25 kg/m2; n = 21) and morbidly obese women (BMI >40 kg/m2; n = 28). The 24 h pattern of clock genes was analyzed every 6 hours using RT-PCR. Correlation of clinical data was studied by Spearman analysis. The 24 h pattern of clock genes showed that obesity alters the expression of CLOCK, BMAL1, PER1, CRY2 and REV-ERB ALPHA in adipocytes with changes found in CRY2 and REV-ERB ALPHA throughout the 24 h period. The same results were confirmed in VAT and stromal cells (SC) showing an upregulation of CRY2 and REV-ERB ALPHA from obese women. A positive correlation was observed for REV-ERB ALPHA gene expression with BMI and waist circumference in the obese population. Expression of ROR ALPHA was correlated with HDL levels and CLOCK with LDL. Obese subjects with MS exhibited positive correlation in the PER2 gene with LDL cholesterol, whereas REV-ERB ALPHA was correlated with waist circumference. We identified CRY2 and REV-ERB ALPHA as the clock genes upregulated in obesity during the 24 h period and that REV-ERB ALPHA is an important gene associated with MS.

Objective: The aim of this study was to examine possible associations between ambient temperature and obesity in the Spanish population using an ecological focus., Methods: The Di@bet.es study is a national, cross-sectional, population-based survey of cardiometabolic risk factors and their association with lifestyle., Sample: 5,061 subjects in 100 clusters., Variables: Clinical, demographic and lifestyle survey, physical examination, and blood sampling. The mean annual temperature (°C) for each study site was collected from the Spanish National Meteorology Agency (1971-2000)., Results: The prevalence rates of obesity in the different geographical areas divided according to mean annual temperature quartiles were 26.9% in quartile 1 (10.4-14.5°C), 30.5% in quartile 2 (14.5-15.5°C), 32% in quartile 3 (15.5-17.8°C), and 33.6% in quartile 4 (17.8-21.3°C) (P = 0.003). Logistic regression analyses including multiple socio-demographic (age, gender, educational level, marital status) and lifestyle (physical activity, Mediterranean diet score, smoking) variables showed that, as compared with quartile 1, the odd ratios for obesity were 1.20 (1.01-1.42), 1.35 (1.12-1.61), and 1.38 (1.14-1.67) in quartiles 2, 3, and 4, respectively (P = 0.001 for difference, P < 0.001 for trend)., Conclusions: Our study reports an association between ambient temperature and obesity in the Spanish population controlled for known confounders., (© 2014 The Obesity Society.)

Background and Aim: Prevalence rates of "metabolically healthy obese" (MHO) subjects vary depending on the criteria used. This study examined the prevalence and characteristics of MHO subjects and metabolically abnormal normal-weight subjects and compared the findings with the NHANES 1999-2004 study. The aims of the present study were, first, to determine the prevalence rates of MHO and MNHNO subjects using the same criteria as those of the National Health and Nutrition Examination Survey (NHANES) (1999-2004) study, and second to compare the prevalence and correlates of obese subjects who are resistant to the development of adiposity-associated cardiometabolic abnormalities (CA) and normal-weight individuals who display cardiometabolic risk factor clustering between the Spanish and the US populations., Methods and Results: Di@bet.es study is a national, cross-sectional population-based survey of 5728 adults conducted in 2009-2010. Clinical, metabolic, sociodemographic, and anthropometric data and information about lifestyle habits, such as physical activity, smoking habit, alcohol intake and food consumption, were collected. Subjects were classified according to their body mass index (BMI) (normal-weight, <25 kg/m(2); overweight, 25-29.9 kg/m(2); and obese, >30 kg/m(2)). CA included elevated blood pressure; elevated levels of triglycerides, fasting glucose, and high-sensitivity C-reactive protein (hs-CRP); and elevated homeostasis model assessment of insulin resistance (HOMA-IR) value and low high-density lipoprotein cholesterol (HDL-c) level. Two phenotypes were defined: metabolically healthy phenotype (0-1 CA) and metabolically abnormal phenotype (≥2 CA). The prevalence of metabolically abnormal normal-weight phenotype was slightly lower in the Spanish population (6.5% vs. 8.1%). The prevalence of metabolically healthy overweight and MHO subjects was 20.9% and 7.0%, respectively, while in NHANES study it was 17.9% and 9.7%, respectively. Cigarette smoking was associated with CA in each phenotype, while moderate physical activity and moderate alcohol intake were associated with being metabolically healthy. Olive oil intake was negatively associated with the prevalence of CA., Conclusions: Smoking, physical activity level, and alcohol intake contribute to the explanation of the prevalence of CA in the Spanish population, as in the US population. However in Spain, olive oil intake contributes significantly to the explanation of the variance in the prevalence of CA., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Aims/hypothesis: Comprehensive characterisation of the interrelation between the peripancreatic adipose tissue and the pancreatic islets promises novel insights into the mechanisms that regulate beta cell adaptation to obesity. Here, we sought to determine the main pathways and key molecules mediating the crosstalk between these two tissues during adaptation to obesity by the way of an integrated inter-tissue, multi-platform analysis., Methods: Wistar rats were fed a standard or cafeteria diet for 30 days. Transcriptomic variations by diet in islets and peripancreatic adipose tissue were examined through microarray analysis. The secretome from peripancreatic adipose tissue was subjected to a non-targeted metabolomic and proteomic analysis. Gene expression variations in islets were integrated with changes in peripancreatic adipose tissue gene expression and protein and metabolite secretion using an integrated inter-tissue pathway and network analysis., Results: The highest level of data integration, linking genes differentially expressed in both tissues with secretome variations, allowed the identification of significantly enriched canonical pathways, such as the activation of liver/retinoid X receptors, triacylglycerol degradation, and regulation of inflammatory and immune responses, and underscored interaction network hubs, such as cholesterol and the fatty acid binding protein 4, which were unpredicted through single-tissue analysis and have not been previously implicated in the peripancreatic adipose tissue crosstalk with beta cells., Conclusions/interpretation: The integrated analysis reported here allowed the identification of novel mechanisms and key molecules involved in peripancreatic adipose tissue interrelation with beta cells during the development of obesity; this might help the development of novel strategies to prevent type 2 diabetes.

Introduction and Objectives: The aim of this study was to compare the prevalences of obesity, diabetes and other cardiovascular risk factors in the region of Andalusia with those in the rest of Spain., Methods: The Di@bet.es study is a national, cross-sectional, population-based survey of cardiometabolic risk factors and their association with lifestyle. The sample consisted of 5103 participants ≥ 18 years. The variables analyzed were clinical, demographic and lifestyle survey, physical examination, and oral glucose tolerance test. The prevalence of cardiovascular risk factors in Andalusia (n=1517) was compared with that for the rest of Spain (n=3586)., Results: In data adjusted to the Spanish population, the prevalence of diabetes (World Health Organization, 1999), hypertension (blood pressure ≥ 140/90 mmHg), high-sensitivity CRP levels (≥ 3 mg/L) and obesity (body mass index ≥ 30 kg/m(2)) were 16.3%, 43.9%, 32.0%, and 37.0% in Andalusia compared with 12.5%, 39.9%, 28.3%, and 26.6% in the rest of Spain (P<.001 for differences except P=.01 for the difference in high-sensitivity CRP levels). The corresponding figures for the Andalusia data adjusted to the Andalusian population were 15.3%, 42.3%, 31.4%, and 34.0%, respectively. Differences in diabetes, hypertension and high-sensitivity CRP were not significant in models adjusted for age, sex, and adiposity measurements. Differences in obesity were not significant in models adjusted for age, sex, educational level, marital status, work status, and physical activity (P=.086) CONCLUSIONS: This study contributes information from a national study perspective and shows a higher prevalence of cardiovascular risk factors in southern Spain, in close relation to obesity, a sedentary lifestyle, and markers of socioeconomic disadvantage., (Copyright © 2013 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.)

Aims/hypothesis: During obesity, the increment in beta cell mass in response to the rising demand for insulin is essential to maintain normal glucose homeostasis. However, the precise cellular and molecular mechanisms involved in beta cell mass plasticity remain poorly understood. The Wnt signalling pathway has been suggested as one possible modulator of beta cell proliferation, which represents the principal process involved in beta cell mass expansion. Here, we sought to determine the mechanisms involved in beta cell mass proliferation using diet-induced obese rats., Methods: Wistar rats aged 8 weeks old were fed a standard or cafeteria diet. Global transcriptomic analysis of pancreatic rat islets was performed using microarray analysis. Genetic loss-of-function approaches were performed in dispersed primary rat islets and the beta cell line INS1E. Gene expression was measured by real-time PCR, protein levels by immunoblot analysis, proliferation rates by ELISA and apoptosis by flow cytometry., Results: Sfrp5, coding for secreted frizzled-related protein 5, is downregulated in the pancreatic islets of cafeteria-diet-fed rats as well as in the pancreatic islets of human obese patients. We demonstrate that silencing Sfrp5 increases beta cell proliferation, which correlates with activation of Wnt signalling and enhanced levels of proliferation markers. In addition, we show that expression of Sfrp5 in beta cells is modulated by IGF binding protein 3 (IGFBP3) secreted from visceral adipose tissue., Conclusions/interpretation: Together, these findings reveal an important role for SFRP5 and Wnt signalling in the regulation of beta cell proliferation in obesity.

Insulin resistance and hyperinsulinemia are generally associated with obesity. Obese nondiabetic individuals develop a compensatory β-cell response to adjust insulin levels to the increased demand, maintaining euglycemia. Although several studies indicate that this compensation relies on structural changes, the existence of β-cell functional adaptations is incompletely understood. Here, we fed female mice with a high-fat diet (HFD) for 12 weeks. These animals became obese, hyperinsulinemic, insulin-resistant, and mildly glucose-intolerant while fed, and fasting glycemia was comparable in HFD and control mice. Islets from HFD animals exhibited increased β-cell mass and hypertrophy. Additionally, they had enhanced insulin gene expression and content and augmented glucose-induced insulin secretion. Electrophysiological examination of β-cells from both groups showed no differences in KATP channel open probability and conductance. However, action potentials elicited by glucose had larger amplitude in obese mice. Glucose-induced Ca²⁺ signals in intact islets, in isolated β-cells, and individual β-cells within islets were also increased in HFD mice. Additionally, a higher proportion of glucose-responsive cells was present in obese mice. In contrast, whole-cell Ca²⁺ current densities were similar in both groups. Capacitance measurements showed that depolarization-evoked exocytosis was enhanced in HFD β-cells compared with controls. Although this augment was not significant when capacitance increases of the whole β-cell population were normalized to cell size, the exocytotic output varied significantly when β-cells were distributed by size ranges. All these findings indicate that β-cell functional adaptations are present in the islet compensatory response to obesity.

Mitofusin 2 (MFN2) plays critical roles in both mitochondrial fusion and the establishment of mitochondria-endoplasmic reticulum (ER) interactions. Hypothalamic ER stress has emerged as a causative factor for the development of leptin resistance, but the underlying mechanisms are largely unknown. Here, we show that mitochondria-ER contacts in anorexigenic pro-opiomelanocortin (POMC) neurons in the hypothalamus are decreased in diet-induced obesity. POMC-specific ablation of Mfn2 resulted in loss of mitochondria-ER contacts, defective POMC processing, ER stress-induced leptin resistance, hyperphagia, reduced energy expenditure, and obesity. Pharmacological relieve of hypothalamic ER stress reversed these metabolic alterations. Our data establish MFN2 in POMC neurons as an essential regulator of systemic energy balance by fine-tuning the mitochondrial-ER axis homeostasis and function. This previously unrecognized role for MFN2 argues for a crucial involvement in mediating ER stress-induced leptin resistance., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: This study aims at exploring the effects of sodium tungstate treatment on hypothalamic plasticity, which is known to have an important role in the control of energy metabolism., Methods: Adult lean and high-fat diet-induced obese mice were orally treated with sodium tungstate. Arcuate and paraventricular nuclei and lateral hypothalamus were separated and subjected to proteomic analysis by DIGE and mass spectrometry. Immunohistochemistry and in vivo magnetic resonance imaging were also performed., Results: Sodium tungstate treatment reduced body weight gain, food intake, and blood glucose and triglyceride levels. These effects were associated with transcriptional and functional changes in the hypothalamus. Proteomic analysis revealed that sodium tungstate modified the expression levels of proteins involved in cell morphology, axonal growth, and tissue remodeling, such as actin, CRMP2 and neurofilaments, and of proteins related to energy metabolism. Moreover, immunohistochemistry studies confirmed results for some targets and further revealed tungstate-dependent regulation of SNAP25 and HPC-1 proteins, suggesting an effect on synaptogenesis as well. Functional test for cell activity based on c-fos-positive cell counting also suggested that sodium tungstate modified hypothalamic basal activity. Finally, in vivo magnetic resonance imaging showed that tungstate treatment can affect neuronal organization in the hypothalamus., Conclusions: Altogether, these results suggest that sodium tungstate regulates proteins involved in axonal and glial plasticity. The fact that sodium tungstate could modulate hypothalamic plasticity and networks in adulthood makes it a possible and interesting therapeutic strategy not only for obesity management, but also for other neurodegenerative illnesses like Alzheimer's disease.

In obesity an increase in β-cell mass occurs to cope with the rise in insulin demand. This β-cell plasticity is essential to avoid the onset of hyperglycemia, although the molecular mechanisms that regulate this process remain unclear. This study analyzed the role of adipose tissue in the control of β-cell replication. Using a diet-induced model of obesity, we obtained conditioned media from three different white adipose tissue depots. Only in the adipose tissue depot surrounding the pancreas did the diet induce changes that led to an increase in INS1E cells and the islet replication rate. To identify the factors responsible for this proliferative effect, adipose tissue gene expression analysis was conducted by microarrays and quantitative RT-PCR. Of all the differentially expressed proteins, only the secreted ones were studied. IGF binding protein 3 (Igfbp3) was identified as the candidate for this effect. Furthermore, in the conditioned media, although the blockage of IGFBP3 led to an increase in the proliferation rate, the blockage of IGF-I receptor decreased it. Taken together, these data show that obesity induces specific changes in the expression profile of the adipose tissue depot surrounding the pancreas, leading to a decrease in IGFBP3 secretion. This decrease acts in a paracrine manner, stimulating the β-cell proliferation rate, probably through an IGF-I-dependent mechanism. This cross talk between the visceral-pancreatic adipose tissue and β-cells is a novel mechanism that participates in the control of β-cell plasticity.

Aims/hypothesis: Pancreatic beta cell hyperactivity is known to occur in obesity, particularly in insulin-resistant states. Our aim was to investigate whether changes in neuronal nitric oxide synthase (nNOS) function affect beta cell compensation in two relevant models: the Zucker fa/fa rats and pancreatic islets from obese humans., Methods: Glucose-induced insulin response was evaluated in the isolated perfused rat pancreas and in human pancreatic islets from obese individuals. Expression of nNOS (also known as NOS1) and subcellular localisation of nNOS were studied by quantitative RT-PCR, immunoblotting, immunofluorescence and electron microscopy., Results: Pancreatic beta cells from Zucker fa/fa rats and obese individuals were found to be hyper-responsive to glucose. Pharmacological blockade of nNOS was unable to modify beta cell response to glucose in fa/fa rats and in islets from obese individuals, suggesting an abnormal control of insulin secretion by the enzyme. In both cases, nNOS activity in islet cell extracts remained unchanged, despite a drastic increase in nNOS protein and an enhancement in the dimer/monomer ratio, pointing to the presence of high amounts of catalytically inactive enzyme. This relative decrease in activity could be mainly related to increases in islet asymmetric dimethyl-arginine content, an endogenous inhibitor of nNOS activity. In addition, mitochondrial nNOS level was decreased, which contrasts with a strongly increased association with insulin granules., Conclusions/interpretation: Increased nNOS production and dimerisation, together with a relative decrease in catalytic activity and relocalisation, are involved in beta cell hyperactivity in insulin-resistant rats but also in human islets isolated from obese individuals.

Background:  Obesity is associated with an increased atherothrombotic morbidity/mortality risk. However, there is no direct evidence of subclinical activation of the endothelium in obese subjects without other major cardiometabolic risk factors., Objectives:  We applied a translational approach to investigate endothelial activation occurring in response to the components secreted by visceral and subcutaneous adipose tissue and their corresponding cell fractions obtained from obese subjects without other major cardiometabolic risk factors, as compared with non-obese controls., Methods:  Fat pads and cell fractions were incubated with serum-free medium to obtain their secretomes, which were analyzed by protein arrays. Endothelial cells (ECs) were exposed to the different secretomes to evaluate changes in gene expression, composition and reactivity of the extracellular matrix (ECM), and cell growth and viability., Results:  ECs incubated in the presence of obese secretomes displayed increased proliferation, altered cell morphology, augmented expression of VCAM-1, ICAM-1, and von Willebrand factor, and higher ECM reactivity towards circulating platelets. The visceral secretomes, especially the stromal one, induced the strongest expression of these markers, together with a more reactive ECM. These changes occurred through nuclear factor-κB (NF-κB) activation., Conclusion:  This is the first translational study demonstrating that the cytokines secreted by the adipose tissue from obese individuals without other major cardiometabolic complications have a hazardous effect on the endothelium, through activation of the NF-κB pathway., (© 2011 International Society on Thrombosis and Haemostasis.)

Aims: Sodium tungstate is an anti-obesity drug targeting peripheral tissues. In vivo, sodium tungstate reduces body weight gain and food intake through increasing energy expenditure and lipid oxidation, but it also modulates hypothalamic gene expression when orally administered, raising the possibility of a direct effect of sodium tungstate on the central nervous system., Methods: Sodium tungstate was administered intraperitoneally (ip) to Wistar rats, and its levels were measured in cerebrospinal fluid through mass spectrometry. Body weight gain and food intake were monitored for 24 h after its administration in the third ventricle. Hypothalamic protein was obtained and subjected to western blot. In vitro, hypothalamic N29/4 cells were treated with 100 µM sodium tungstate or 1 nM leptin, and protein and neural gene expression were analysed., Results: Sodium tungstate crossed the blood-brain barrier, reaching a concentration of 1.31 ± 0.07 mg/l in cerebrospinal fluid 30 min after ip injection. When centrally administered, sodium tungstate decreased body weight gain and food intake and increased the phosphorylation state of the main kinases and proteins involved in leptin signalling. In vitro, sodium tungstate increased the phosphorylation of janus kinase-2 (JAK2) and extracellular signal-regulated kinase-1/2 (ERK1/2), but the activation of each kinase did not depend on each other. It regulated c-myc gene expression through the JAK2/STAT system and c-fos and AgRP (agouti-related peptide) gene expression through the ERK1/2 pathway simultaneously and independently., Conclusions: Sodium tungstate increased the activity of several kinases involved in the leptin signalling system in an independent way, making it a suitable and promising candidate as a leptin-mimetic compound in order to manage obesity., (© 2011 Blackwell Publishing Ltd.)

Aim: Considering the poor long-term success of current dietary and pharmacological interventions, we aimed to evaluate the potential effect of sodium tungstate in the treatment of grade I and II obesity (ClinicalTrials.gov identifier: NCT00555074)., Methods: Prospective, randomized, placebo-controlled, double-blind, proof-of-concept study was carried out. Following a 2-week lead-in period, 30 obese (body mass index, BMI 30.0-39.9 kg/m(2)), non-diabetic subjects were randomized to receive either sodium tungstate (100 mg bid) or placebo for 6 weeks. The primary study endpoint was the absolute change in body weight relative to the time of randomization., Results: Treatment with sodium tungstate [-0.135 ± 0.268 kg (95% CI -0.686 to +0.416 kg)] was not associated with a significant weight loss compared to placebo [-0.063 ± 0.277 kg (95% CI -0.632 to +0.507 kg)] (p = 0.854). Likewise, treatment with sodium tungstate was not associated with significant changes in fat mass (DEXA), resting energy expenditure (indirect calorimetry) or caloric consumption (3-day food records)., Conclusion: Our data do not support sodium tungstate as a pharmacological agent in the treatment of human obesity., (© 2010 Blackwell Publishing Ltd.)

Sodium tungstate is a novel agent in the treatment of obesity. In diet-induced obese rats, it is able to reduce body weight gain by increasing energy expenditure. This study evaluated the role of leptin, a key regulator of energy homeostasis, in the tungstate antiobesity effect. Leptin receptor-deficient Zucker fa/fa rats and leptin-deficient ob/ob mice were treated with tungstate. In lean animals, tungstate administration reduced body weight gain and food intake and increased energy expenditure. However, in animals with deficiencies in the leptin system, treatment did not modify these parameters. In ob/ob mice in which leptin deficiency was restored through adipose tissue transplantation, treatment restored the tungstate-induced body weight gain and food intake reduction as well as energy expenditure increase. Furthermore, in animals in which tungstate administration increased energy expenditure, changes in the expression of key genes involved in brown adipose tissue thermogenesis were detected. Finally, the gene expression of the hypothalamic neuropeptides, Npy, Agrp, and Cart, involved in the leptin regulation of energy homeostasis, was also modified by tungstate in a leptin-dependent manner. In summary, the results indicate that the effectiveness of tungstate in reducing body weight gain is completely dependent on a functional leptin system.

Context: Conflicting results on the effects of salicylates on glucose tolerance in subjects with normal glucose tolerance or type 2 diabetes have been reported., Objective: The objective of the study was to investigate the effects of a salicylate derivative (triflusal) on insulin sensitivity and insulin secretion., Design, Setting, and Participants: This was a double-blind, randomized, crossover study with three treatment periods corresponding to two dose levels of triflusal and placebo in healthy obese subjects., Main Outcome Measures: Insulin sensitivity and insulin secretion, evaluated through frequently sampled iv glucose tolerance test that was performed after each treatment period, were measured. Insulin secretion was also evaluated in vitro in mice and human islets of Langerhans., Results: The administration of triflusal led to decreased fasting serum glucose concentration in the study subjects. Insulin sensitivity did not significantly change after each treatment period. Insulin secretion, however, significantly increased in a dose-dependent fashion after each triflusal treatment period. The administration of 800 mum of the main triflusal metabolite to whole mice islets of Langerhans led to a sustained increase in intracellular calcium concentration level. This was followed by a significantly increase in insulin secretion. In human islets, 200 mum of 2-hydroxy-4-trifluoromethylbenzoic acid was sufficient to increase insulin release., Conclusions: The administration of a salicylate compound led to lowering of serum glucose concentration. We suggest that this effect was mediated through increased insulin secretion induced by salicylate directly on the beta-cell.

Background: The effects of adiponectin on glucose and lipid metabolism are mediated by the adiponectin receptors, adipoR1 and adipoR2, which are mainly in liver and muscle. We investigated the presence of adiponectin receptors in intra-abdominal adipose tissue (IAAT) in obesity and diabetes and their association with adiponectin expression and components of the metabolic syndrome and/or other metabolic factors associated with atherosclerotic cardiovascular disease (ASCVD)., Methods: AdipoR1 and adipoR2 gene expression was measured by quantitative real time reverse transcription polymerase chain reaction in IAAT from lean and obese patients with or without diabetes type 2. Correlation between metabolic characteristics of obese patients and expression of these receptors was studied., Results: Neither obesity nor diabetes were associated with changes in IAAT-adipoR1 expression. In contrast, IAAT-adipoR2 was decreased by 39.5% in obese non-diabetics and by 52.7% in obese diabetics when compared to lean subjects. AdipoR1 and adiponectin expression was associated in lean (r=0.943, P<0.005) and obese non-diabetic patients (r=0.74, P<0.01), whereas a positive correlation between adipoR2 and adiponectin expression was only found in the presence of diabetes (r=0.883, P<0.002). AdipoR1 expression was associated with plasma free fatty acids (FFA) concentration (r=0.76, P<0.04), and adipoR2 inversely correlated with plasma levels of triglycerides (r=-0.76, P<0.04) and apolipoprotein B (r=-0.74, P<0.05)., Conclusion: AdipoR1 expression in IAAT was not altered by obesity and/or diabetes and was related to plasma levels of FFA. IAAT-adipoR2 expression was reduced in obesity and diabetes and associated with components of metabolic processes leading to cardiovascular disease in obesity.

Adipose tissue plays an active role in the development of obesity, and thus characterization of the molecular changes related to obesity in this tissue is a priority. Recently, we identified tungstate as a potent body weight reducing agent in obese animals, adipose tissue being one of the targets of its action. In this study a proteomics approach combining 2-DE and MS was used to identify proteins associated with obesity and targets of tungstate in white adipose tissue. Twenty-nine proteins were found differentially expressed between lean and diet-induced obese rats. Expression changes in transferrin, vimentin, vinculin, peroxiredoxins, Rho-GTP dissociation inhibitor, grifin, guanine deaminase and 3-phosphoglycerate dehydrogenase were associated here for the first time with obesity. Furthermore, tungstate treatment of obese rats reverted expression changes of 70% of the proteins modulated by obesity and another ten proteins were regulated by tungstate independently of the body weight reduction. The results suggest that the tungstate antiobesity effect can be mediated by the modulation of cellular structure, metabolism, redox state and signalling processes in adipose tissue. These findings open new avenues for the study of the aetiology of obesity and its treatment.

The increasing worldwide incidence of obesity and the limitations of current treatments raise the need for finding novel therapeutic approaches to treat this disease. The purpose of the current study was first to investigate the effects of tungstate on body weight and insulin sensitivity in a rat model of diet-induced obesity. Second, we aimed to gain insight into the molecular mechanisms underlying its action. Oral administration of tungstate significantly decreased body weight gain and adiposity without modifying caloric intake, intestinal fat absorption, or growth rate in obese rats. Moreover, the treatment ameliorated dislipemia and insulin resistance of obese rats. These effects were mediated by an increase in whole-body energy dissipation and by changes in the expression of genes involved in the oxidation of fatty acids and mitochondrial uncoupling in adipose tissue. Furthermore, treatment increased the number of small adipocytes with a concomitant induction of apoptosis. Our results indicate that tungstate treatment may provide the basis for a promising novel therapy for obesity.

Objective: To investigate whether the association between the metabolic syndrome (MS) and cardiovascular disease (CVD) in obese adults is influenced by the criteria used to diagnose the MS., Design and Subjects: Cross-sectional study in 389 obese adults (male/female: 26%/74%; body mass index (BMI): 30.1-63.2 kg/m2; age: 18-79 y)., Measurements: To diagnose the MS by the WHO or the ATPIII criteria, body mass index, waist circumference, fasting and 2-h oral Glucose tolerance test plasma glucose, fasting plasma triglycerides and HDL cholesterol, systolic and diastolic blood pressure, 24-h albumin excretion, and fasting insulin were measured. The association between the MS diagnosed with either definition and self-referred CVD was investigated., Results: The prevalence of the MS by the WHO was higher than by the ATPIII criteria (WHO 69.1%, ATPIII 49.4%; P<0.001). The MS diagnosed by the WHO criteria was significantly associated with self-referred CVD (odds ratio (OR) 5.80, 95% CI 1.35-24.95, P<0.05), whereas the ATPIIII MS was not (OR 1.34, 95% CI 0.59-3.03). An elevated blood pressure (OR 5.04, 95% CI 1.41-18.01, P<0.05) and microalbuminuria (OR 2.61, 95% CI 1.06-6.40, P<0.05) were independently associated with CVD. Consideration of the OGTT data as part of the ATPIII MS definition improved its associations with CVD (OR 4.39, 95% CI 1.29-14.94, P<0.05)., Conclusion: The WHO criteria appear to identify a greater number of obese adults at risk for CVD. Nevertheless, the addition of an OGTT at least in nondiabetic patients with two ATPIII-defined metabolic risk factors may help to improve the association between the MS and CVD in obese adults.

Objective: To investigate the effect of S 23521, a new glucagon-like peptide-1-(7-36) amide analogue, on food intake and body weight gain in obese rats, as well as on gene expression of several proteins involved in energy homeostasis., Research Methods and Procedures: Lean and diet-induced obese rats were treated with either S 23521 or vehicle. S 23521 was given either intraperitoneally (10 or 100 microg/kg) or subcutaneously (100 microg/kg) for 14 and 20 days, respectively. Because the low-dose treatment did not affect food intake and body weight, the subcutaneous treatment at high dose was selected to test the effect on selected end-points., Results: Treated obese rats significantly decreased their cumulative energy intake in relation to vehicle-treated counterparts (3401 +/- 65 vs. 3898 +/- 72 kcal/kg per 20 days; p < 0.05). Moreover, their body weight gain was reduced by 110%, adiposity was reduced by 20%, and plasma triglyceride levels were reduced by 38%. The treatment also improved glucose tolerance and insulin sensitivity of obese rats. Regarding gene expression, no changes in uncoupling protein-1, uncoupling protein-3, leptin, resistin, and peroxisome proliferator-activated receptor (PPAR)-gamma were observed., Discussion: S 23521 is an effective glucagon-like peptide-1-(7-36) amide analogue, which induced a decrease in energy intake, body weight, and adiposity in a rat model of diet-induced obesity. In addition, the treatment also improved glucose tolerance and insulin sensitivity of obese rats. These results strongly support S 23521 as a putative molecule for the treatment of obesity.

Objective: To prospectively evaluate the short-term effects of Roux-en-Y gastric bypass (RYGBP) on ghrelin secretion and its relevance on food intake and body weight changes., Research Methods and Procedures: Ghrelin response to a standardized test meal was evaluated in eight obese patients (BMI, 43.5 to 59.1 kg/m2) before and 6 weeks after RYGBP. Ghrelin response was compared with that of an age-matched group of six normal weight individuals (BMI, 19.6 to 24.9 kg/m2)., Results: Fasting serum ghrelin levels were lower in obese subjects compared with controls (p < 0.05). Meal ingestion significantly suppressed ghrelin concentration in controls (p < 0.05) and obese subjects (p < 0.05), albeit to a lesser degree in the latter group (p < 0.05). Despite a 10.3 +/- 1.5% weight loss, fasting serum ghrelin levels were paradoxically further decreased in obese subjects 6 weeks after RYGBP (p < 0.05). Moreover, at this time-point, food intake did not elicit a significant ghrelin suppression. The changes in ghrelin secretion after RYGBP correlated with changes in insulin sensitivity (p < 0.05) and caloric intake (p < 0.05)., Discussion: This study showed that the adaptive response of ghrelin to body weight loss was already impaired 6 weeks after RYGBP. Our study provides circumstantial evidence for the potential role of ghrelin in the negative energy balance in RYGBP-operated patients., (Copyright 2004 NAASO)

Tungstate was orally administered to 7.5-week-old male Zucker diabetic fatty (ZDF) rats that already showed moderate hyperglycemia (180 +/- 16 mg/dl). The animals became normoglycemic for approximately 10 days. Then, glycemia started to rise again, although it did not reach the initial values until day 24, when levels stabilized at approximately 200 mg/dl for the duration of the experiment. Untreated ZDF rats showed steadily increased blood glucose levels between 7.5 and 10 weeks of age, when they reached a maximum value of 450 +/- 19 mg/dl, which was maintained throughout the experiment. In addition, tolerance to intraperitoneal glucose load improved in treated diabetic rats. Serum levels of triglycerides were elevated in untreated diabetic rats compared with their lean counterparts (ZLC). In the liver of diabetic animals, glucokinase (GK), glycogen phosphorylase a (GPa), liver-pyruvate kinase (L-PK), and fatty acid synthase (FAS) activities decreased by 81, 30, 54, and 35%, respectively, whereas phosphoenolpyruvate carboxykinase (PEPCK) levels increased by 240%. Intracellular glucose-6-phosphate (G6P) decreased by 40%, whereas glycogen levels remained unaffected. Tungstate treatment of these rats induced a 42% decrease in serum levels of triglycerides and normalized hepatic G6P concentrations, GPa activity, and PEPCK levels. GK activity in treated diabetic rats increased to 50% of the values of untreated ZLC rats. L-PK and FAS activity increased to higher values than those in untreated lean rats (1.7-fold L-PK and 2.4-fold FAS). Hepatic glycogen levels were 55% higher than those in untreated diabetic and healthy rats. Tungstate treatment did not significantly change the phosphotyrosine protein profile of primary cultured hepatocytes from diabetic animals. These data suggest that tungstate administration to ZDF rats causes a considerable reduction of glycemia, mainly through a partial restoration of hepatic glucose metabolism and a decrease in lipotoxicity.

Objective: The goal of this study was to evaluate the effect of two diets ('food combining' or dissociated vs balanced) on body weight and metabolic parameters during a 6-week period in an in-hospital setting., Subjects and Design: 54 obese patients were randomly assigned to receive diets containing 4.5 MJ/day (1100 kcal/day) composed of either 25% protein, 47% carbohydrates and 25% lipids (dissociated diet) or 25% protein, 42% carbohydrates and 31% lipids (balanced diet). Consequently, the two diets were equally low in energy and substrate content (protein, fat and carbohydrate) but widely differed in substrate distribution throughout the day., Results: There was no significant difference in the amount of weight loss in response to dissociated (6.2 +/- 0.6 kg) or balanced (7.5 +/- 0.4 kg) diets. Furthermore, significant decreases in total body fat and waist-to-hip circumference ratio were seen in both groups, and the magnitude of the changes did not vary as a function of the diet composition. Fasting plasma glucose, insulin, total cholesterol and triacylglycerol concentrations decreased significantly and similarly in patients receiving both diets. Both systolic and diastolic blood pressure values decreased significantly in patients eating balanced diets. The results of this study show that both diets achieved similar weight loss. Total fat weight loss was higher in balanced diets, although differences did not reach statistical significance. Total lean body mass was identically spared in both groups., Conclusion: In summary at identical energy intake and similar substrate composition, the dissociated (or 'food combining') diet did not bring any additional loss in weight and body fat.

To elucidate if there are alterations in insulin metabolic clearance in obesity under basal conditions, plasma insulin and C-peptide were measured in 22 obese patients and 8 normal subjects, and the plasma C-peptide to insulin molar ratio was used as an index of hepatic insulin extraction. In obese patients, the C-peptide to insulin molar ratio correlated indirectly with basal plasma insulin levels (r = 0.71; P less than 0.001), being low in the obese patients with higher insulin levels and within the normal range in obese patients in which insulin levels were similar to those of control subjects. It is suggested that hepatic insulin extraction is decreased in obesity, even under basal conditions, but this alteration is only manifested when plasma insulin levels are high.

Objective This study compares the patterns of visceral (VIS) and subcutaneous (SC) adipose tissue (AT)-derived metabolites from non-obese (BMI 24-26 kg/m2) and obese subjects (BMI > 40 kg/m2) with no major metabolic risk factors other than BMI. Methods SC- and VIS- AT obtained from obese (Ob) and non-obese (NOb) subjects during surgery were incubated to obtain their metabolites. Differences related to obesity or anatomical provenances of AT were assessed using an untargeted metabolomics approach based on gas chromatography-mass spectrometry. Results The overall effect of obesity on the metabolite profile resulted more remarkable than the effect of regional AT. Only the depletion of 2-ketoisocaproic (2-KIC) acid reached statistical significance for the SC-AT alone, although it was observed in both depots. Obesity induced more significant changes in several amino acids levels of the VIS-AT metabolites. On the one hand, higher released levels of glutamine and alanine were detected in the VIS- obese AT, whereas on the other, the VIS- obese AT presented a diminished uptake of essential amino acids (methionine, threonine, lysine), BCAAs, leucine, and serine. Conclusion This study shows that obesity markedly affects the amino acid metabolic signature of the AT before the clinical onset of other significant metabolic alterations aside from BMI. [ABSTRACT FROM AUTHOR]

Background: Metabolic syndrome (MetS) is a complex disease involving a set of metabolic abnormalities ranging from obesity, glucose intolerance, hypertension to dyslipidemia and insulin resistance. Recent genome wide association studies (GWAS) have identified many genetic variants associated with MetS and/or its components located in several genetic loci including the hepatocyte nuclear factor 1 alpha (HNF1A) gene. However, the association of HNF1A variants with MetS in the Middle East and North Africa region is largely unknown. This study aims to examine their association with MetS and its components in the Tunisian population. Methods: A total of 594 Tunisian individuals (295 cases/299 controls) were genotyped for two variants (rs1169288 and rs2464196) located in the HNF1A gene using KASPar technology. Statistical association analyses were performed with the R software. Results: Our results showed no association between HNF1A variants and MetS in our studied Tunisian population. However, a significant association was observed between the variant rs2464196 and both waist circumference and HDL. Conclusion: Our findings exclude the implication of HNF1A gene variants (rs1169288 and rs2464196) in the susceptibility to MetS in our studied Tunisian population. The genotyping of a third variant located in HNF1A gene will allow us to perform a haplotypic analysis. [ABSTRACT FROM AUTHOR]

Introduction: Dans l’obésité, une augmentation de la sécrétion de l’insuline et de masse cellulaire se produit pour contrecarrer le développement de la résistance à l’insuline et pour pouvoir maintenir l’homéostasie glucidique. Cette plasticité cellulaire est essentielle, cependant le mécanisme qui règle ce processus reste inconnu. Notre objectif est d’étudier les changements d’expression des gènes des ilots pancréatiques chez un modèle animal dans lequel l’obésité est induite par un régime fortement calorique dit de « cafétéria » semblable aux régimes alimentaires menant à l’obésité chez l’homme. Matériels et méthodes: Des rats Wistar ont été alimenté avec un régime standard (STD) ou de cafétéria (CAF) pendant 30 jours. Les îlots pancréatiques ont été ensuite isolés. Les profils d’expression de gène ont été réalisés par Affymetrix Rae 230 2.0 GeneChip, la normalisation et l’analyse d’expression différentielle avec les logiciels RMA et LIMMA. La quantification d’expression de gène et de protéine a été effectuée par real time PCR et Western Blot, respectivement. La lignée de cellules beta INS1E et des ilots pancréatiques dissociés ont été transfectés par un siRNA sFRP5 et leur prolifération mesurée (ELISA BrdU, Roche). Résultats: Parmi les gènes identifiés, sFRP5, un régulateur négatif de la voie de signalisation de Wnt, est sous exprimé dans les ilots CAF (Fold Change : −2,30 ; p<0,05) et cette diminution a été confirmée par real time PCR (FC : −2,08 ; p<0,05) et Western Blot. La diminution d’expression de sFRP5 par transfection (siRNA) de la lignée de cellules beta INS1E et d’ilots pancréatiques dissociés entrainent une augmentation de la prolifération (+31,6 % et +24,4 %, respectivement). Discussion: La voie de Wnt est impliquée dans des processus liés au développement, la prolifération et la croissance cellulaire. Des molécules de la voie de signalisation de Wnt sécrétés par les adipocytes pourrait entrainer la prolifération de lignées beta pancréatiques. Récemment, Ouchi et al, ont montré que sFRP5 est également une adipokine sécrétée par le tissu adipeux capable de moduler les dysfonctions métaboliques lors de l’obésité. L’étude des voies de signalisation activés par cette diminution de sFRP5 pourrait permettre l’emergence de nouvelle cible therapeutique dans le domaine de l’obésité, du diabète et des maladies métaboliques associées. [Copyright &y& Elsevier]

A number of recent studies in animals and humans have linked energy regulation and the circadian clock at the molecular, physiological and behavioural levels, concluding that disruption of clock genes results in metabolic dysregulation. The search to understand the causes of obesity and diabetes and the development of new therapeutic strategies have mostly focused on caloric intake and energy balance. In this review, we present a global overview of the circadian clock as a critical interface between nutrition and homeostasis. [ABSTRACT FROM AUTHOR]