Smad3 deficiency in mice protects against insulin resistance and obesity induced by a high-fat diet.

OBJECTIVE-Obesity and associated pathologies are major global health problems. Transforming growth factor-beta/Smad3 signaling has been implicated in various metabolic processes, including adipogenesis, insulin expression, and pancreatic beta-cell function. However, the systemic effects of Smad3 deficiency on adiposity and insulin resistance in vivo remain elusive. This study investigated the effects of Smad3 deficiency on whole-body glucose and lipid homeostasis and its contribution to the development of obesity and type 2 diabetes.RESEARCH DESIGN AND METHODS-We compared various metabolic profiles of Smad3-knockout and wild-type mice. We also determined the mechanism by which Smad3 deficiency affects the expression of genes involved in adipogenesis and metabolism. Mice were then challenged with a high-fat diet to study the impact of Smad3 deficiency on the development of obesity and insulin resistance.RESULTS-Smad3-knockout mice exhibited diminished adiposity with improved glucose tolerance and insulin sensitivity. Chromatin immunoprecipitation assay revealed that Smad3 deficiency increased CCAAT/enhancer-binding protein beta-C/EBP homologous protein 10 interaction and exerted a differential regulation on proliferator-activated receptor beta/delta and proliferator-activated receptor gamma expression in adipocytes. Focused gene expression profiling revealed an altered expression of genes involved in adipogenesis, lipid accumulation, and fatty acid beta-oxidation, indicative of altered adipose physiology. Despite reduced physical activity with no modification in food intake, these mutant mice were resistant to obesity and insulin resistance induced by a high-fat diet.CONCLUSIONS-Smad3 is a multifaceted regulator in adipose physiology and the pathogenesis of obesity and type 2 diabetes, suggesting that Smad3 may be a potential target for the treatment of obesity and its associated disorders.

Effects of four-week high-fructose diet on gene expression in skeletal muscle of healthy men.

AIMS: A high-fructose diet (HFrD) may play a role in the obesity and metabolic disorders epidemic. In rodents, HFrD leads to insulin resistance and ectopic lipid deposition. In healthy humans, a four-week HFrD alters lipid homoeostasis, but does not affect insulin sensitivity or intramyocellular lipids (IMCL). The aim of this study was to investigate whether fructose may induce early molecular changes in skeletal muscle prior to the development of whole-body insulin resistance. METHODS: Muscle biopsies were taken from five healthy men who had participated in a previous four-week HFrD study, during which insulin sensitivity (hyperinsulinaemic euglycaemic clamp), and intrahepatocellular lipids and IMCL were assessed before and after HFrD. The mRNA concentrations of 16 genes involved in lipid and carbohydrate metabolism were quantified before and after HFrD by real-time quantitative PCR. RESULTS: HFrD significantly (P<0.05) increased stearoyl-CoA desaturase-1 (SCD-1) (+50%). Glucose transporter-4 (GLUT-4) decreased by 27% and acetyl-CoA carboxylase-2 decreased by 48%. A trend toward decreased peroxisomal proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) was observed (-26%, P=0.06). All other genes showed no significant changes. CONCLUSION: HFrD led to alterations of SCD-1, GLUT-4 and PGC-1alpha, which may be early markers of insulin resistance.

Social and economic inequalities in diet and physical activity

This briefing paper describes social and economic inequalities associated with two of the key determinants of obesity - diet and physical activity. The paper also explores possible explanations for these inequalities.

Standard of Healthy Living on the Island of Ireland

Pre-requisites for health are equity, minimum income, nutrition, peace, water, sanitation, housing, education, work, political will and public support (WHO, 1986). It has long been known that social disadvantage harms health (Black, 1980, Ettner, 1996). Many researchers have documented that those in lower socio-economic groups are more at risk of developing major chronic diseases such as cardiovascular diseases (Beaglehole and Yach, 2003, WHO, 2003a), diabetes (Wilder et al., 2005), and some cancers (Brunner et al., 1993, Strong et al., 2005), and are at a higher risk of having multiple risk factors associated with these diseases (Lynch et al., 1997). The living standards that many people enjoy and the behavioural choices they make are heavily determined by their access to resources such as income, wealth, goods and services (O’Flynn and Murphy, 2001). The most prominent explanation between disadvantage and health is that lack of resources restricts access to the fundamental conditions of health such as adequate housing (Macintyre et al., 2003, Macintyre et al., 2005), good nutrition (Nelson et al., 2002) and opportunities to participate in society (McDonough et al., 2005). Each of these issues are very much influenced by material and structural factors inherent to and determined by fiscal, social and health policy (Graham and Kelly, 2004, Milio, 1986).

Family, Food & Fitness

NHS Warwickshire (NHSW), Warwickshire County Council (WCC) and partners aim to reduce childhood obesity in various ways including through the provision of evidence based structured nine week family based treatment programmes. These programmes will support families with overweight and/or obese children to maintain a healthy weight using a holistic approach. Two types of programmes will run across the county: the first programme will be aimed at families with overweight and/or obese children aged 4-7 and the second programme will be aimed at families with overweight and/or obese children aged 8-13.The target group for participating in this programme is children who are overweight (as defined by > 91st percentile) or obese (as defined by > 98th percentile). Programmes will established and delivered in a variety of venues and times. Objectives: - To deliver evidence based structured family based weight management programmes across Nuneaton, Bedworth and North Warwickshire. - To recruit families with overweight and/or obese children on to programmes, targeting the areas of highest need. - To promote sustained BMI maintenance and reduction amongst overweight (as defined by > 91st percentile) and obese (as defined by < 98th percentile) children and young people aged 4-7 and 8-13. - To support positive changes in behaviour (i.e. healthy eating, physical activity, positive mental well-being) by children and family members in order to achieve and maintain healthy weight over the course of the nine week programme. - To provide families with the information, skills and confidence to maintain healthy lifestyles in the longer term, including personalised exit strategies/sustainability plans for each participant. - To signpost families to community based and leisure services activities which contribute to maintaining a healthy weight. - To evaluate all programmes using the National Obesity Observatory Standard Evaluation Framework (SEF) and to produce a written evaluation report of the programme with recommendations on how to sustain healthy weight among children and families. - To evaluate the programme using validated diet and physical activity tools as recommended by the recent Worcester University (www.ifh.westmidlands.nhs.uk for the Worcester University Report) evaluation. Deliver eight programmes across Nuneaton and Bedworth and eight programmes across North Warwickshire for children aged 4 7 years by December 2012. Deliver eight programmes across Nuneaton and Bedworth and eight programmes across North Warwickshire for children aged 8 - 13 years by December 2012. Deliver a minimum of 32 taster sessions, with at least one prior to each programme start date. Reduce childhood obesity in primary aged children and their families. Improve healthy lifestyles in primary aged children and their families through healthy eating, physical activity and positive mental well-being.

A prospective, randomized, open label, phase iii clinical trial of novottf-100a vs best standard of care chemotherapy in patients with recurrent glioblastoma

BACKGROUND: Glioblastoma, the most common adult primary malignant brain tumor, confers poor prognosis (median survival of 15 months) notwithstanding aggressive treatment. Combination chemotherapy including carmustine (BCNU) or temozolomide (TMZ) with the MGMT inhibitor O6-benzylguanine (O6BG) has been used, but has been associated with dose-limiting hematopoietic toxicity. OBJECTIVE: To assess safety and efficacy of a retroviral vector encoding the O6BG-resistant MGMTP140K gene for transduction and autologous transplantation of hematopoietic stem cells (HSCs) in MGMT unmethylated, newly diagnosed glioblastoma patients in an attempt to chemoprotect bone marrowduring combination O6BG/TMZ therapy. METHODS: Three patients have been enrolled in the first cohort. Patients underwent standard radiation therapy without TMZ followed by G-CSF mobilization, apheresis, and conditioning with 600 mg/m2 BCNU prior to infusion of gene-modified cells. Posttransplant, patients were treated with 28-day cycles of single doseTMZ (472 mg/m2) with 48-hour intravenous O6BG (120 mg/m2 bolus, then 30 mg/m2/d). RESULTS: The BCNU dose was nonmyeloablative with ANC ,500/mL for ≤3 d and nadir thrombocytopenia of 28,000/mL. Gene marking in pre-infusion colony forming units (CFUs) was 70.6%, 79.0%, and 74.0% in Patients 1, 2, and 3, respectively, by CFU-PCR. Following engraftment, gene marking in white blood cells and sorted granulocytes ranged between 0.37-0.84 and 0.33-0.83 provirus copies, respectively, by real-time PCR. Posttransplant gene marking in CFUs from CD34-selected cells ranged from 28.5% to 47.4%. Patients have received 4, 3, and 2 cycles of O6BG/TMZ, respectively, with evidence for selection of gene-modified cells. One patient has received a single dose-escalated cycle at 590 mg/m2 TMZ. No additional extra-hematopoietic toxicity has been observed thus far and all three patients exhibit stable disease at 7-8 months since diagnosis CONCLUSIONS: We believe that these data demonstrate the feasibility of achieving significant engraftment of MGMTP140K-modified cells with a well-tolerated dose of BCNU. Further follow-up will determine whether this approach will allow for further dose escalation of TMZ and improved survival.

Executive Summary: Healthy Diet v Dietary Supplementation: improving physical fitness and quality of life in older people

Older people have the greatest barriers (mostly in terms of ability/opportunity) to participating in exercise, and thus have the highest incidence of decreased ease in carrying out tasks of daily living. In an ageing society, the negative effects of age on skeletal muscle performance would be reduced if compliance to exercise regimens could be encouraged through simple advice on timing, duration, frequency, intensity, as well as appropriate nutritional interventions. Research into the impact of optimal nutrition/diet supplementation in young and/or athletic populations is extensive. Such data are scarce when considering healthy, older populations. We therefore propose to investigate the impact of healthy eating habits with or without supplementation, on exercise responsiveness. This protocol seeks to maximise training benefits on the neural muscular and tendinous complexes.

Neuroendocrine characterization and anorexigenic effects of telmisartan in diet- and glitazone-induced weight gain.

Telmisartan is an angiotensin II receptor blocker with peroxisome proliferator-activated receptor-gamma agonistic properties. Telmisartan prevents weight gain and decreases food intake in models of obesity and in glitazone-treated rodents. This study further investigates the influence of telmisartan and pioglitazone and their association on weight gain and body composition by examining their influence on neuroendocrine mediators involved in food intake. Male C57/Black 6 mice were fed a high-fat diet, weight matched, and randomized in 4 treatment groups: vehicle, pioglitazone, telmisartan, and pioglitazone-telmisartan. Weight gain, food and water intake, body composition, plasma leptin levels, and the hypothalamic expression of neuroendocrine mediators were analyzed. Additional studies were performed with irbesartan and in angiotensin II 1(A) receptor-knockout mice. Telmisartan abolished weight and fat gain in vehicle- and pioglitazone-treated mice while decreasing food intake, the hypothalamic expression of the agouti-related protein, and plasma leptin levels. Modifications in neuropeptide Y and proopiomelanocortin were not consistent with changes in food intake. The effects on weight gain and expression of the agouti-related protein were intermediate with irbesartan. The effects of telmisartan on weight gain were even more pronounced in angiotensin II 1(A) receptor-knockout mice. This study confirms the anorexigenic effects of telmisartan in mice fed a high-fat diet and suggests for the first time a functional role of telmisartan on hypothalamic orexigenic agouti-related protein regulation. These anorexigenic properties abolish both weight gain and body composition modifications in fat-fed and glitazone-treated mice. The anorexigenic properties are independent from the angiotensin II 1(A) receptor.

Statistics on Obesity, Physical Activity and Diet, England 2006

This is a statistical bulletin from the Information Centre which presents a range of information on obesity, physical activity and diet, drawn together from a variety of sources. The topics covered include: overweight and obesity prevalence among adults and children physical activity levels among adults and children trends in purchases and consumption of food and drink, and energy intake health outcomes of being obese hospital admissions and prescriptions dispensed related to obesity. The bulletin also summarises government plans and targets in this area, as well as providing sources of further information and links to relevant documents.

Statistics on obesity, physical activity and diet: England, January 2008

This statistical report from the Information Centre presents a range of information on obesity, physical activity and diet, drawn together from a variety of sources. The publication also summarises government plans and targets in this area, as well as providing sources of further information and links to relevant documents and key sources. There are several notable additions to this, The Information Centre's second report on obesity, physical activity and diet. Waist circumference analysis has been included where possible to reflect the importance of using this measurement in conjunction with Body Mass Index (BMI) in order to identify those at increased risk of health problems associated with obesity. More regional data is presented with a greater number of tables providing government office region and Strategic Health Authority breakdowns. Where possible information at a more local level has been reported on.

Statistics on obesity, physical activity and diet: England - January 2008

This statistical report presents a range of information on obesity, physical activity and diet, drawn together from a variety of sources.

Statistics on Obesity, Physical Activity and Diet: England, 2010

This statistical report presents a range of information on obesity, physical activity and diet, drawn together from a variety of sources. The topics covered include: Overweight and obesity prevalence among adults and children; Physical activity levels among adults and children; Trends in purchases and consumption of food and drink and energy intake; and Health outcomes of being overweight or obese. refer to the resource

Statistics on obesity, physical activity and diet: England, February 2009

The Information Centre has released a report and statistics on obesity, physical activity, and diet in England.

Standard Evaluation Framework for Weight Management Interventions - Core Criteria

The National Obesity Observatory was established to provide a single point of contact for wide-ranging authoritative information on data and evidence related to obesity, overweight, underweight and their determinants. The Standard Evaluation Framework is a list of data collection criteria and supporting guidance for collecting high quality information to support the evaluation of weight management interventions. This is a quick reference guide to the core criteria of the Standard Evaluation Framework. Essential criteria are presented as the minimum recommended data for evaluating a weight management intervention. Desirable criteria are additional data that would enhance the evaluation.refer to the resource

Standard Evaluation Framework (SEF) for weight management interventions Presentation

This presentation summaries the Standard Evaluation Framework which is designed to support high quality, consistent evaluation of weight management interventions in order to increase the evidence base.