Weight loss-induced cellular stress in subcutaneous adipose tissue and the risk for weight regain in overweight and obese adults.

BACKGROUND/OBJECTIVE: Weight loss is often followed by weight regain after the dietary intervention (DI). Cellular stress is increased in adipose tissue of obese individuals. However, the relation between cellular stress and weight regain is unclear. Previously, we observed increased adipose tissue cellular stress of participants regaining weight compared with participants maintaining weight loss. In the current study, we further investigated the relation between weight regain and changes in the expression of stress-related genes and stress protein levels to determine possible predictors of weight regain. PARTICIPANTS/METHODS: In this randomized controlled trial, sixty-one healthy overweight/obese participants followed a DI of either a 5-week very-low-calorie diet (500 kcal per day) or a 12-week low-calorie diet (1250 kcal per day; WL period) with a subsequent 4-week weight stable diet (WS period), and a 9-month follow-up. The WL and WS period taken together was named the DI. Abdominal subcutaneous adipose tissue biopsies were collected in 53 participants for microarray and liquid chromatography-mass spectrometry analysis. RNA and protein levels for a broad set of stress-related genes were correlated to the weight regain percentage. RESULTS: Different gene sets correlated to weight regain percentage during WS and DI. Bioinformatics clustering suggests that during the WS phase-defined genes for actin filament dynamics, glucose handling and nutrient sensing are related to weight regain. HIF-1 (hypoxia-inducible factor-1) is indicated as an important regulator. With regard to DI, clustering of correlated genes indicate that LGALS1, ENO1 and ATF2 are important nodes for conferring risk for weight regain. CONCLUSIONS: Our present findings indicate that the risk for weight regain is related to expression changes of distinct sets of stress-related genes during the first 4 weeks after returning to energy balance, and during the DI. Further research is required to investigate the mechanistic significance of these findings and find targets for preventing weight regain.

Adipose tissue gene expression is differentially regulated with different rates of weight loss in overweight and obese humans.

BACKGROUND/OBJECTIVES: Moderate weight loss (WL) can ameliorate adverse health effects associated with obesity, reflected by an improved adipose tissue (AT) gene expression profile. However, the effect of rate of WL on the AT transcriptome is unknown. We investigated the global AT gene expression profile before and after two different rates of WL that resulted in similar total WL, and after a subsequent weight stabilization period. SUBJECTS/METHODS: In this randomized controlled trial, 25 male and 28 female individuals (body mass index (BMI): 28-35 kg m-2) followed either a low-calorie diet (LCD; 1250 kcal day-1) for 12 weeks or a very-low-calorie diet (VLCD; 500 kcal day-1) for 5 weeks (WL period) and a subsequent weight stable (WS) period of 4 weeks. The WL period and WS period together is termed dietary intervention (DI) period. Abdominal subcutaneous AT biopsies were collected for microarray analysis and gene expression changes were calculated for all three periods in the LCD group, VLCD group and between diets (ΔVLCD-ΔLCD). RESULTS: WL was similar between groups during the WL period (LCD: -8.1±0.5 kg, VLCD: -8.9±0.4 kg, difference P=0.25). Overall, more genes were significantly regulated and changes in gene expression appeared more pronounced in the VLCD group compared with the LCD group. Gene sets related to mitochondrial function, adipogenesis and immunity/inflammation were more strongly upregulated on a VLCD compared with a LCD during the DI period (positive ΔVLCD-ΔLCD). Neuronal and olfactory-related gene sets were decreased during the WL period and DI period in the VLCD group. CONCLUSIONS: The rate of WL (LCD vs VLCD), with similar total WL, strongly regulates AT gene expression. Increased mitochondrial function, angiogenesis and adipogenesis on a VLCD compared with a LCD reflect potential beneficial diet-induced changes in AT, whereas differential neuronal and olfactory regulation suggest functions of these genes beyond the current paradigm.

Diet-induced weight loss decreases adipose tissue oxygen tension with parallel changes in adipose tissue phenotype and insulin sensitivity in overweight humans.

BACKGROUND/OBJECTIVES: Although adipose tissue (AT) hypoxia is present in rodent models of obesity, evidence for this in humans is limited. Here, we investigated the effects of diet-induced weight loss (WL) on abdominal subcutaneous AT oxygen tension (pO2), AT blood flow (ATBF), AT capillary density, AT morphology and transcriptome, systemic inflammatory markers and insulin sensitivity in humans. SUBJECTS/METHODS: Fifteen overweight and obese individuals underwent a dietary intervention (DI), consisting of a 5-week very-low-calorie diet (VLCD, 500 kcal day-1; WL), and a subsequent 4-week weight stable diet (WS). Body composition, AT pO2 (optochemical monitoring), ATBF (133Xe washout), and whole-body insulin sensitivity were determined, and AT biopsies were collected at baseline, end of WL (week 5) and end of WS (week 9). RESULTS: Body weight, body fat percentage and adipocyte size decreased significantly during the DI period. The DI markedly decreased AT pO2 and improved insulin sensitivity, but did not alter ATBF. Finally, the DI increased AT gene expression of pathways related to mitochondrial biogenesis and non-mitochondrial oxygen consumption. CONCLUSIONS: VLCD-induced WL markedly decreases abdominal subcutaneous AT pO2, which is paralleled by a reduction in adipocyte size, increased AT gene expression of mitochondrial biogenesis markers and non-mitochondrial oxygen consumption pathways, and improved whole-body insulin sensitivity in humans.

Weight loss maintenance in overweight subjects on ad libitum diets with high or low protein content and glycemic index: the DIOGENES trial 12-month results.

BACKGROUND: A high dietary protein (P) content and low glycemic index (LGI) have been suggested to be beneficial for weight management, but long-term studies are scarce. OBJECTIVE: The DIOGENES randomized clinical trial investigated the effect of P and GI on weight loss maintenance in overweight or obese adults in eight centers across Europe. This study reports the 1-year results in two of the centers that extended the intervention to 1 year. METHOD: After an 8-week low-calorie diet (LCD), 256 adults (body mass index >27 kg m(-)(2)) were randomized to five ad libitum diets for 12 months: high P/LGI (HP/LGI), HP/high GI (HP/HGI), low P/LGI (LP/LGI), LP/HGI and a control diet. During the first 6 months, foods were provided for free through a shop system and during the whole 12-month period, subjects received guidance by a dietician. Primary outcome variable was the change in body weight over the 12-month intervention period. RESULTS: During the LCD period, subjects lost 11.2 (10.8, 12.0) kg (mean (95% confidence interval (CI))). Average weight regain over the 12-month intervention period was 3.9 (95% CI 3.0-4.8) kg. Subjects on the HP diets regained less weight than subjects on the LP diets. The difference in weight regain after 1 year was 2.0 (0.4, 3.6) kg (P=0.017) (completers analysis, N=139) or 2.8 (1.4, 4.1) kg (P<0.001) (intention-to-treat analysis, N=256). No consistent effect of GI on weight regain was found. There were no clinically relevant differences in changes in cardiometabolic risk factors among diet groups. CONCLUSION: A higher protein content of an ad libitum diet improves weight loss maintenance in overweight and obese adults over 12 months.

Circulating ACE is a predictor of weight loss maintenance not only in overweight and obese women, but also in men.

BACKGROUND: Circulating angiotensin-converting enzyme (ACE) was identified as a predictor of weight loss maintenance in overweight/obese women of the Diogenes project. OBJECTIVE: To investigate whether ACE acted also as a predictor in men of the Diogenes study and to compare it with that in women. DESIGN: Subjects, who lost ≥ 8% of body weight induced by low-caloric diet in an 8-week weight loss period, were assigned to weight loss maintenance with dietary intervention for 6 months. SUBJECTS: 125 overweight/obese healthy men from eight European countries who completed whole intervention. MEASUREMENTS: Concentrations and activity of serum ACE at baseline and after the 8-week weight loss, in addition to anthropometric and physiological parameters. RESULTS: Serum ACE concentration decreased by 11.3 ± 10.6% during the weight loss period in men. A greater reduction is associated with less body weight regain during the maintenance period (r=0.227, P=0.012). ACE change was able to predict a weight regain ≤ 20% after 6 months, with an odds ratio of 1.59 (95% confidence interval (CI): 1.09-2.33, P=0.016) for every 10% reduction, which was independent of body mass index and weight loss. The prediction power was weaker in men than in women, but without a significant sex difference (P=0.137). In pooled subjects (N=218), the odds ratio was 1.96 (95% CI: 1.46-2.64, P<0.001). CONCLUSIONS: A greater reduction of ACE during weight loss is favorable for weight maintenance in both men and women. This can offer useful information for personalized advice to improve weight loss maintenance. It also confirms the role of ACE in the metabolic pathways of weight regulation.

The effect of a low-fat, high-protein or high-carbohydrate ad libitum diet on weight loss maintenance and metabolic risk factors.

BACKGROUND: High-protein (HP) diets are often advocated for weight reduction and weight loss maintenance. OBJECTIVE: The aim was to compare the effect of low-fat, high-carbohydrate (HC) and low-fat, HP ad libitum diets on weight maintenance after weight loss induced by a very low-calorie diet, and on metabolic and cardiovascular risk factors in healthy obese subjects. DESIGN: Forty-eight subjects completed the study that consisted of an energy restriction period of 5-6 weeks followed by a weight maintenance period of 12 weeks. During weight maintenance subjects received maltodextrin (HC group) or protein (HP group) (casein (HPC subgroup) or whey (HPW subgroup)) supplements (2 x 25 g per day), respectively and consumed a low-fat diet. RESULTS: Subjects in the HP diet group showed significantly better weight maintenance after weight loss (2.3 kg difference, P=0.04) and fat mass reduction (2.2 kg difference, P=0.02) than subjects in the HC group. Triglyceride (0.6 mM difference, P=0.01) and glucagon (9.6 pg ml(-1) difference, P=0.02) concentrations increased more in the HC diet group, while glucose (0.3 mM difference, P=0.02) concentration increased more in the HP diet group. Changes in total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, insulin, HOMAir index, HbA1c, leptin and adiponectin concentrations did not differ between the diets. No differences were found between the casein- or whey-supplemented HP groups. CONCLUSIONS: These results show that low-fat, high-casein or whey protein weight maintenance diets are more effective for weight control than low-fat, HC diets and do not adversely affect metabolic and cardiovascular risk factors in weight-reduced moderately obese subjects without metabolic or cardiovascular complications.

Short-term beta-adrenergic regulation of leptin, adiponectin and interleukin-6 secretion in vivo in lean and obese subjects.

AIM: Adipose tissue and skeletal muscle are endocrine organs, secreting substances that have been implicated in obesity-related disorders. This study examined short-term beta-adrenergic regulation of circulating leptin, adiponectin and interleukin-6 (IL-6) concentrations and secretion from abdominal subcutaneous adipose tissue and muscle (IL-6) in vivo in lean and obese subjects. METHODS: Systemic concentrations and net fluxes of leptin, adiponectin and IL-6 across abdominal subcutaneous adipose tissue and forearm skeletal muscle (IL-6) were assessed before and during beta-adrenergic stimulation (intravenous isoprenaline infusion) in 13 lean and 10 obese men. RESULTS: Basal circulating leptin concentrations were higher in the obese (p < 0.001), while circulating adiponectin (p = 0.45) and IL-6 concentrations (p = 0.41) were not different between groups. beta-Adrenergic stimulation decreased leptin concentrations in both groups (p < 0.01), but did not reduce net abdominal subcutaneous adipose tissue leptin release. Increased leptin clearance and/or decreased leptin secretion from other fat depots may explain the reduction in leptin concentrations. Adiponectin concentrations remained unchanged during beta-adrenergic stimulation in both groups. beta-Adrenergic stimulation increased IL-6 concentration, which was more pronounced in the obese (p = 0.01 vs. lean). This cannot be explained by increased IL-6 release per unit abdominal subcutaneous adipose tissue and muscle but might be because of the increased fat mass and fat-free mass at whole-body level. CONCLUSIONS: Short-term beta-adrenergic stimulation decreases leptin concentrations, which cannot be explained by reduced net leptin release from abdominal subcutaneous adipose tissue, while it elevates IL-6 concentration partly by increased release from this fat depot and muscle. Finally, beta-adrenergic stimulation has no short-term regulatory role in adiponectin secretion.

The NHF-NRG In Balance-project: the application of Intervention Mapping in the development, implementation and evaluation of weight gain prevention at the worksite.

Very few examples of theory-driven and systematically developed weight gain prevention interventions for adults have been described in the literature. The present paper systematically describes the development, implementation and evaluation framework of a weight gain prevention programme directed at young adults at the worksite, namely the NHF-NRG In Balance-project. It not only can be used as a guide to systematically develop weight gain prevention interventions, but also gives an overview of the current theoretical and empirical knowledge-base in the field of obesity prevention. The outline of the paper follows the Intervention Mapping protocol, which includes a systematic inventory of important health issues, their risk behaviours and determinants of these risk behaviours, and specification of the proximal objectives of the programme directed at both energy intake and energy expenditure. The objectives are translated into behaviour change methods and strategies, which are combined in a stepwise intervention programme, and used for a detailed evaluation plan (process and effect evaluation). The NHF-NRG In Balance-project combines mass media and individually tailored communications with worksite environmental changes to raise awareness, to motivate and to enable energy balance behaviour changes. A quasi-experimental pre-test-multiple post-test control group design was applied in 12 worksites (>500 employees).

Prevalence of overweight and obesity in the Netherlands.

This paper shows the trends in the prevalence of overweight (body mass index [BMI] >or= 25 kg m-2) and obesity (BMI >or= 30 kg m-2) in the Netherlands. Overweight (obesity) prevalence in adult males increased from 37% (4%) in 1981 to 51% (10%) in 2004, and in adult females from 30% (6%) in 1981 to 42% (12%) in 2004, according to self-reported data. In boys and girls, obesity prevalence doubled or even tripled from 1980 to 1997, and again from 1997 to 2002-2004 a two- or threefold increase was seen for almost all ages. According to the most recent data, overweight (obesity) prevalence figures range, depending on age, from 9.2% to 17.3% (2.5-4.3%) in boys, and from 14.6% to 24.6% (2.3-6.5%) in girls. There is a lack of data on the national prevalence of overweight and obesity based on measured height and weight and on prevalences in different subgroups of the population. Regular national representative health examination surveys that measure height and weight are needed to assess the prevalence of overweight and obesity and its distribution over subgroups in the population, and to properly direct and evaluate prevention activities.

Thermophysiological adaptations to passive mild heat acclimation.

Passive mild heat acclimation (PMHA) reflects realistic temperature challenges encountered in everyday life. Active heat acclimation, combining heat exposure and exercise, influences several important thermophysiological parameters; for example, it decreases core temperature and enhances heat exchange via the skin. However, it is unclear whether PMHA elicits comparable adaptations. Therefore, this study investigated the effect of PMHA on thermophysiological parameters. Participants were exposed to slightly increased temperatures (∼33°C/22% RH) for 6 h/d over 7 consecutive days. To study physiologic responses before and after PMHA, participants underwent a temperature ramp (UP), where ambient temperature increased from a thermoneutral value (28.8 ± 0.3°C) to 37.5 ± 0.6°C. During UP, core and skin temperature, water loss, cardiovascular parameters, skin blood flow and energy expenditure were measured. Three intervals were selected to compare data before and after PMHA: baseline (minutes 30-55: 28.44 ± 0.21°C), T1 (minutes 105-115: 33.29 ± 0.4°C) and T2 (minutes 130-140: 35.68 ± 0.61°C). After 7 d of PMHA, core (T1: -0.13 ± 0.13°C, P = 0.011; T2: -0.14 ± 0.15°C, P = 0.026) and proximal skin temperature (T1: -0.22 ± 0.29°C, P = 0.029) were lower during UP, whereas distal skin temperature was higher in a thermoneutral state (baseline: +0.74 ± 0.77°C, P = 0.009) and during UP (T1: +0.49 ± 0.76°C, P = .057 (not significant), T2:+0.51 ± 0.63°C, P = .022). Moreover, water loss was reduced (-30.5 ± 33.3 ml, P = 0.012) and both systolic (-7.7 ± 7.7 mmHg, P = 0.015) and diastolic (-4.4 ± 4.8 mmHg, P = 0.001) blood pressures were lowered in a thermoneutral state. During UP, only systolic blood pressure was decreased (T2: -6.1 ± 4.4 mmHg, P = 0.003). Skin blood flow was significantly decreased at T1 (-28.35 ± 38.96%, P = 0.037), yet energy expenditure remained unchanged. In conclusion, despite the mild heat stimulus, we show that PMHA induces distinct thermophysiological adaptations leading to increased resilience to heat.

Evaluation of an 18-month commercial multidisciplinary obesity treatment programme.

The treatment of obesity is an often studied subject. Although reductions in weight and improvements in cardiometabolic risk factors are important aims of obesity treatment, improvements in quality of life and eating behaviour are also relevant outcomes. In this practice-based study, we evaluated an 18-month commercial multidisciplinary obesity treatment programme and report on treatment results for weight, cardiometabolic risk factors, eating behaviour and quality of life. From a local commercial obesity treatment centre, 426 subjects (65% female; 45.4 ± 12.2 years; body mass index 40.0 ± 6.6 kg m(-2)) were recruited. Measurements of body weight, height, body composition, waist circumference and blood pressure were scheduled at baseline and every 3 months, whereas fasting blood collections were scheduled at baseline and every 6 months. At the same time points, participants were asked to fill in questionnaires on dietary intake, eating behaviour and quality of life. After 18 months of treatment programme, average weight change [mean (95% confidence interval)] was -10.9 kg (-14.8 to -7.0; P < 0.001) for the completers (n = 181) and -10.8 kg (-14.2 to -7.4; P < 0.001) for the intention-to-treat population (n = 426). Waist circumference (mean ± standard error of the mean) (-0.13 ± 0.01 cm; P < 0.001), fat mass (-7.8 ± 1.3 kg; P < 0.001) systolic (-11.4 ± 2.0; P < 0.001) and diastolic (-7.0 ± 1.3; P < 0.001) blood pressure, triglycerides (-0.4 ± 0.1; P = 0.004) and plasma glucose (-0.6 ± 0.2; P = 0.001) were significantly reduced. The PCS scale of the SF-36 and all three scales of the three-factor eating questionnaire improved significantly over the 18-month treatment period. All collected data in this study provide evidence that a multidisciplinary treatment programme based on lifestyle modification results in significant weight loss and improvements in cardiometabolic risk factors, quality of life and eating behaviour.

beta2-adrenergic receptor polymorphisms and salbutamol-stimulated energy expenditure.

The beta-adrenergic system is involved in the control of energy metabolism and expenditure. The beta2-adrenergic receptor (beta2-AR) gene shows polymorphisms that have been associated with obesity in several studies. In vitro and in vivo studies suggest differences in beta2-AR-mediated function between these polymorphisms. The aim of this study was to investigate the influence of genetic variation in codon 16 of the beta2-AR gene on energy metabolism in humans. Thirty-four subjects were recruited [Gly16Gly (n = 13), Gly16Arg (n = 16), or Arg16Arg (n = 5)]. The beta2-AR was stimulated with two doses of salbutamol (50 and 100 ng/kg fat-free mass per minute) after blockade of the beta1-adrenergic receptors with atenolol. Energy expenditure and plasma substrate and hormone concentrations were measured. The increase in energy expenditure (DeltaEE) was significantly different among groups in which the Arg16Arg group showed the lowest increase (P < 0.05 vs. Gly carriers). In a multiple regression model, variations in the increase in nonesterified fatty acid concentration during salbutamol infusion (partial r = 0.51) and the polymorphism contributed significantly to the variation in DeltaEE. Thirty-five percent of the variation in DeltaEE was explained by these two factors. We conclude that subjects with the Arg16Arg polymorphism of the beta2-AR gene have a reduced thermogenic response to beta2-adrenergic stimulation. Although this relatively small study needs confirmation, the findings support a role for this polymorphism in the development and maintenance of overweight and obesity.

Plasma free Fatty Acid uptake and oxidation are already diminished in subjects at high risk for developing type 2 diabetes.

The objective of this study was to investigate to what extent disturbances in fatty acid metabolism found in type 2 diabetes are already present in subjects at high risk for developing diabetes (i.e., impaired glucose tolerance [IGT]). Components of fatty acid metabolism were measured in male subjects with IGT during postabsorptive conditions and during 60 min of exercise (50% VO(2max)) with the use of the stable isotope tracer [U-(13)C]palmitate in combination with indirect calorimetry, and those values were compared with previously published findings in male type 2 diabetic and male obese subjects. No differences were found between groups in energy expenditure and in total fat and carbohydrate oxidation. Rate of appearance and rate of disappearance of plasma free fatty acid (FFA) were lower in subjects with IGT and type 2 diabetes compared with obese subjects (P < 0.05). Plasma FFA oxidation was lower in subjects with IGT and type 2 diabetes compared with obese subjects at rest and tended to be lower during exercise (rest: 3.7 +/- 0.3, 4.4 +/- 0.6, and 6.9 +/- 1.0 micromol. kg fat-free mass [FFM](-1). min(-1), P < 0.01; exercise: 15.0 +/- 1.7, 14.1 +/- 1.9, and 19.6 +/- 1.5 micromol. kg FFM(-1). min(-1) for IGT, type 2 diabetic, and obese subjects, respectively, P = 0.07). Triglyceride-derived fatty acid oxidation, however, was elevated in subjects with IGT and type 2 diabetes during exercise (3.6 +/- 1.4, 1.4 +/- 1.4, and -4.0 +/- 2.0 micromol. kg FFM(-1). min(-1) for IGT, type 2 diabetic, and obese subjects, respectively; P < 0.05). These data demonstrate that male subjects with a prediabetic condition (IGT) have the same defects in fatty acid utilization as subjects with type 2 diabetes, suggesting that these disturbances may play an important role in the progression from IGT to type 2 diabetes.

Impaired oxidation of plasma-derived fatty acids in type 2 diabetic subjects during moderate-intensity exercise.

The present study was intended to investigate the different components of fatty acid utilization during a 60-min period of moderate-intensity cycling exercise (50% of VO2max) in eight male type 2 diabetic subjects (aged 52.6 +/- 3.1 years, body fat 35.8 +/- 1.3%) and eight male obese control subjects (aged 45.1 +/- 1.4 years, body fat 34.2 +/- 1.3%) matched for age, body composition, and maximal aerobic capacity. To quantitate the different components of fatty acid metabolism, an isotope infusion of [U-13C]-palmitate was used in combination with indirect calorimetry. In separate experiments, the 13C label recovery in expired air was determined during infusion of [1,2-13C]-acetate (acetate recovery factor). There were no differences in energy expenditure or carbohydrate and total fat oxidation between the groups. The rate of appearance (Ra) of free fatty acid (FFA) (P < 0.05) and the exercise-induced increase in Ra of FFA were significantly lower (P < 0.05) in type 2 diabetic subjects compared with control subjects (baseline vs. exercise [40-60 min]; type 2 diabetes 11.9 +/- 0.9 vs. 19.6 +/- 2.2 micromol x kg(-1) fat-free mass [FFM] x min(-1) and control 15.8 +/- 1.8 vs. 28.6 +/- 2.1 micromol x kg(-1) FFM x min(-1)). The oxidation of plasma-derived fatty acids was significantly lower in type 2 diabetic subjects during both conditions (P < 0.05, baseline vs. exercise [40-60 min]; type 2 diabetes 4.2 +/- 0.5 vs. 14.1 +/- 1.9 micromol x kg(-1) FFM x min(-1) and control 6.2 +/- 0.6 vs. 20.4 +/- 1.9 micromol x kg(-1) FFM x min(-1)), whereas the oxidation of triglyceride-derived fatty acids was higher (P < 0.05). It is hypothesized that these impairments in fatty acid utilization may play a role in the etiology of skeletal muscle and hepatic insulin resistance.

Netherlands research programme weight gain prevention (NHF-NRG): rationale, objectives and strategies.

OBJECTIVE: To outline the rationale, objectives and strategies used in a systematically designed research programmme to study specific weight gain-inducing behaviours, their social-psychological as well as environmental determinants, and the effects of interventions aimed at the prevention of weight gain. DESIGN: The evidence for potential behavioural determinants and strategies to prevent weight gain was reviewed, and the methods applied within the Netherlands Research programme weight gain prevention (NHF-NRG) project were described. The project is designed according to the Intervention Mapping protocol. SETTING: The Netherlands. SUBJECTS: The main target groups are (a) adolescents (12-16 y) in secondary school, (b) young adults (20-40 y) at the workplace and (c) recently retired people (55-65 y) at home. INTERVENTIONS: Each intervention includes an individual component, in which computer-tailored information is provided. Additionally, interventions are aimed at changing environmental components. RESULTS: The short-term results of this project can be expected by the beginning of 2005. Guidelines for nationwide weight gain prevention, based on this research programme, will become available in 2007. CONCLUSIONS: Based on the few interventions that were evaluated to date, no robust conclusions can be drawn regarding the effectiveness of obesity prevention. The systematic and multidisciplinary design of the NHF-NRG programme enables the identification of potentially effective methods and strategies for the prevention of weight gain.

Effect of a high-protein diet on maintenance of blood pressure levels achieved after initial weight loss: the DiOGenes randomized study.

Randomized trials have shown significant blood pressure (BP) reductions after increased protein compared with carbohydrate intake, but the effect on BP maintenance after initial weight loss is unclear. We examined the effect of a high-protein diet on the maintenance of reduced BP after weight loss in 420 overweight adults from the Diet, Obesity and Genes study. After an 8-week weight-loss period (>8% BW), subjects (42±6 years) were randomized to either a high-protein diet (23-28 en% protein) or a lower-protein control diet (10-15 en% protein) for 26 weeks. BMI after weight loss was 30.3±4.3 kg m(-2), BP was 118/73 mm Hg and 28 subjects (6.5%) used antihypertensive agents. Systolic BP during 26 weeks of weight maintenance dietary intervention increased in both treatment groups, but it was 2.2 mm Hg less (95% CI: -4.6 to 0.2 mm Hg, P=0.08) in the high-protein group than in the lower-protein control group. In 191 (pre)hypertensive subjects (baseline systolic BP⩾120 mm Hg), a larger difference was observed (-4.2 mm Hg (-7.7, -0.7), P=0.02). The effect was attenuated after adjustment for initial BP (-3.4 mm Hg (-6.9, -0.03), P=0.048), and after additional adjustment for weight change (-2.7 mm Hg (-6.1, 0.4), P=0.11). Adjustment for 24-h urinary excretion of sodium and potassium did not change the results. Diastolic BP yielded similar results. These findings suggest that a BP reduction after weight loss is better maintained when the intake of protein is increased at the expense of carbohydrates. This effect is partly mediated by body weight.

Beta-adrenergically stimulated fat oxidation is diminished in middle-aged compared to young subjects.

The effect of aging on beta-adrenergically mediated substrate utilization was investigated in nine young (25.2 +/- 1.7 yr old) and eight older males (52.9 +/- 2.1 yr old), matched for body weight and body composition. In a first experiment, the nonselective beta-agonist isoprenaline (ISO) was infused in increasing standardized doses, and during each infusion period energy expenditure and substrate utilization were determined by indirect calorimetry. In a second experiment, forearm skeletal muscle metabolism was studied during a standardized infusion dose of ISO (19 ng/kg fat-free mass x min). During beta-adrenergic stimulation there was an increased carbohydrate oxidation (at an ISO infusion dose of 24 ng/kg fat-free mass x min, 31% vs. 21% of total energy expenditure; P < 0.05) and a decreased fat oxidation (51 vs. 62 of total energy expenditure; P < 0.05) in older compared to young subjects. Skeletal muscle lactate release significantly increased in the older subjects (from -175 +/- 32 to -366 +/- 66 nmol/100 mL forearm tissue x min), whereas there was no change in young subjects (from -32 +/- 21 to 23 +/- 57 nmol/100 mL forearm tissue x min; interaction group x ISO, P < 0.01). Additionally, there was a tendency toward a blunted ISO-induced increase in nonesterified fatty acid uptake in the older subjects (interaction group x ISO, P = 0.062). Thus, middle-aged subjects have a blunted ability to oxidize fat during beta-adrenergic stimulation compared to young subjects. This diminished fat oxidation may be an important etiological factor in the age-related increase in body fatness and obesity by favoring fat storage above oxidation.

Angiotensin II-induced effects on adipose and skeletal muscle tissue blood flow and lipolysis in normal-weight and obese subjects.

The present study was designed to investigate the effects of angiotensin II (Ang II) on adipose and skeletal muscle tissue blood flow and lipolysis in normal-weight and obese subjects using the microdialysis technique. Microdialysis probes were placed in the abdominal sc adipose tissue left and right from the umbilicus and in the gastrocnemius muscle of both legs in eight normal-weight and eight obese men. Probes were consecutively perfused with 1.0 nM Ang II, 1.0 microM Ang II, and 1.0 microM Ang II + 48 microM hydralazine or with Ringer solution (control). Ethanol and glycerol concentrations in the dialysate were measured as an indicator of local blood flow and lipolysis, respectively. Ang II caused an increase in ethanol outflow/inflow ratio, compared with baseline values both in adipose tissue (average of both groups, Ang 1.0 nM: 0.03 +/- 0.01, P = 0.02; Ang 1.0 microM: 0.05 +/- 0.01, P < 0.01) and muscle (average of both groups, Ang 1.0 nM: 0.02 +/- 0.01, P = 0.09; Ang 1.0 microM: 0.04 +/- 0.01, P = 0.01), indicating a decrease in local blood flow. These effects were not significantly different in obese and normal-weight subjects. The decrease in local blood flow was accompanied by unchanged interstitial glycerol concentrations in adipose tissue (except during the supraphysiological dose) and skeletal muscle, suggesting that Ang II inhibits lipolysis in both tissues. Thus, the present data suggest that Ang II decreases local blood flow in a dose-dependent manner and inhibits lipolysis both in adipose and skeletal muscle tissue. These effects were not significantly different in obese and normal-weight subjects in both tissues.

beta(1)- and beta(2)-Adrenoceptor-mediated thermogenesis and lipid utilization in obese and lean men.

The aim of this study was to elucidate the roles of the beta(1)- and the beta(2)-adrenoceptors in thermogenesis and lipid utilization in obesity. The beta(1)-adrenoceptor study was performed in 9 obese and 10 lean men and consisted of 4 30-min periods during which subjects received consecutive infusions of 0, 3, 6, and 9 microg/kg fat-free mass (FFM).min dobutamine. Energy expenditure, lipid oxidation, and plasma nonesterified fatty acids and glycerol concentrations increased similarly in both groups during beta(1)-adrenergic stimulation. The beta(2)-adrenoceptor study was performed in 10 obese and 11 lean men and involved 3 45-min periods during which 0, 50, and 100 ng/kg FFM.min salbutamol were given in combination 1.2 microg/kg FFM.min atenolol (bolus, 50 microg/kg FFM). During beta(2)-adrenergic stimulation, the increases in energy expenditure and plasma nonesterified fatty acids and glycerol concentrations were reduced in the obese group. Furthermore, lipid oxidation significantly increased in the normal weight group, but remained similar in the overweight group. In conclusion, these data suggest that beta(1)-adrenoceptor-mediated metabolic processes are similar in both groups, but beta(2)-adrenoceptor-mediated increases in thermogenesis and lipid utilization are impaired in the obese.

The peripheral sympathetic nervous system in human obesity.

The peripheral sympathetic nervous system is a key factor in the regulation of energy balance in humans. Differences in sympathetic nervous system activity may contribute to variations in 24 h energy expenditure between individuals. beta-Adrenoceptors play a more important role than alpha-adrenoceptors in this regulation. The involvement of both beta 1- and beta 2-adrenoceptor subtypes has been demonstrated, the role of the beta 3-adrenoceptor subtype is not yet clear. Normal or increased levels of sympathetic nervous system activity and reduced reactivity appear to be present in established obesity. Furthermore, the sensitivity for beta-adrenoceptor stimulation is impaired in obesity. The blunted reactivity and sensitivity may contribute to the maintenance of the obese state. There are data to suggest that they may also play a role in the aetiology of obesity, because the impairments often remain after weight reduction. Furthermore, a negative correlation between baseline sympathetic nervous system activity and weight gain during follow-up has been found in Pima Indians. Recently, genetic evidence about the involvement of adrenoceptors in obesity has become available. Although the results of association and linkage studies on polymorphisms in the beta 2-, beta 3- and alpha 2-adrenoceptor genes are inconsistent, the functional correlates of some of these polymorphisms (changes in agonist-promoted down-regulation, protein expression levels, lipolytic sensitivity, basal metabolic rate, sympathetic nervous system activity) suggest that they may be important in the aetiology of obesity.