Thomas Meinert Larsen

The Diet, Obesity and Genes (Diogenes) Dietary Study in eight European countries – a comprehensive design for long-term intervention

Diogenes is a Pan‐European, randomized, controlled dietary intervention study investigating the effects of dietary protein and glycaemic index on weight (re)gain, metabolic and cardiovascular risk factors in obese and overweight families in eight European centres. The article is methodological in character, and the presentation of ‘results’ will be limited to baseline characteristics of the study populations included. A total of 891 families with at least one overweight/obese parent underwent screening. The parents started an initial 8‐week low‐calorie diet and families with minimum one parent attaining a weight loss of ≥8%, were randomized to one of five energy ad libitum, low‐fat (25–30 E%) diets for 6 or 12 months: low protein/low glycaemic index, low protein/high glycaemic index, high protein/low glycaemic index, high protein/high glycaemic index or control (national dietary guidelines). At two centres the families were provided dietary instruction plus free foods for 6 months followed by 6‐month dietary instruction only. At the remaining six centres the families received dietary instruction only for 6 months. The median weight loss during the low‐calorie diet was 10.3 kg (inter‐quartile range: 8.7–12.8 kg, n = 775). A total of 773 adults and 784 children were randomized to the 6‐month weight (re)gain prevention phase. Despite major cultural and dietary regional differences in Europe, interventions addressing effects of dietary factors are feasible with a reasonable attrition.

Diets with high or low protein content and glycemic index for weight-loss maintenance

BACKGROUND Studies of weight-control diets that are high in protein or low in glycemic index have reached varied conclusions, probably owing to the fact that the studies had insufficient power. METHODS We enrolled overweight adults from eight European countries who had lost at least 8% of their initial body weight with a 3.3-MJ (800-kcal) low-calorie diet. Participants were randomly assigned, in a two-by-two factorial design, to one of five ad libitum diets to prevent weight regain over a 26-week period: a low-protein and low-glycemic-index diet, a low-protein and high-glycemic-index diet, a high-protein and low-glycemic-index diet, a high-protein and high-glycemic-index diet, or a control diet. RESULTS A total of 1209 adults were screened (mean age, 41 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 34), of whom 938 entered the low-calorie-diet phase of the study. A total of 773 participants who completed that phase were randomly assigned to one of the five maintenance diets; 548 completed the intervention (71%). Fewer participants in the high-protein and the low-glycemic-index groups than in the low-protein-high-glycemic-index group dropped out of the study (26.4% and 25.6%, respectively, vs. 37.4%; P=0.02 and P=0.01 for the respective comparisons). The mean initial weight loss with the low-calorie diet was 11.0 kg. In the analysis of participants who completed the study, only the low-protein-high-glycemic-index diet was associated with subsequent significant weight regain (1.67 kg; 95% confidence interval [CI], 0.48 to 2.87). In an intention-to-treat analysis, the weight regain was 0.93 kg less (95% CI, 0.31 to 1.55) in the groups assigned to a high-protein diet than in those assigned to a low-protein diet (P=0.003) and 0.95 kg less (95% CI, 0.33 to 1.57) in the groups assigned to a low-glycemic-index diet than in those assigned to a high-glycemic-index diet (P=0.003). The analysis involving participants who completed the intervention produced similar results. The groups did not differ significantly with respect to diet-related adverse events. CONCLUSIONS In this large European study, a modest increase in protein content and a modest reduction in the glycemic index led to an improvement in study completion and maintenance of weight loss. (Funded by the European Commission; ClinicalTrials.gov number, NCT00390637.).

Atkins and other low-carbohydrate diets: hoax or an effective tool for weight loss?

CONTEXT The Atkins diet books have sold more than 45 million copies over 40 years, and in the obesity epidemic this diet and accompanying Atkins food products are popular. The diet claims to be effective at producing weight loss despite ad-libitum consumption of fatty meat, butter, and other high-fat dairy products, restricting only the intake of carbohydrates to under 30 g a day. Low-carbohydrate diets have been regarded as fad diets, but recent research questions this view. STARTING POINT A systematic review of low-carbohydrate diets found that the weight loss achieved is associated with the duration of the diet and restriction of energy intake, but not with restriction of carbohydrates. Two groups have reported longer-term randomised studies that compared instruction in the low-carbohydrate diet with a low-fat calorie-reduced diet in obese patients (N Engl J Med 2003; 348: 2082-90; Ann Intern Med 2004; 140: 778-85). Both trials showed better weight loss on the low-carbohydrate diet after 6 months, but no difference after 12 months. WHERE NEXT?: The apparent paradox that ad-libitum intake of high-fat foods produces weight loss might be due to severe restriction of carbohydrate depleting glycogen stores, leading to excretion of bound water, the ketogenic nature of the diet being appetite suppressing, the high protein-content being highly satiating and reducing spontaneous food intake, or limited food choices leading to decreased energy intake. Long-term studies are needed to measure changes in nutritional status and body composition during the low-carbohydrate diet, and to assess fasting and postprandial cardiovascular risk factors and adverse effects. Without that information, low-carbohydrate diets cannot be recommended.

PPARgamma agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy?

The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the PPAR family. The endogenous activators of all members of the PPAR family are a variety of fatty acids, which suggests that the PPARs are highly involved in lipid metabolism. In the present paper, the current understanding of the involvement of PPARγ in adipocyte proliferation and adipose tissue formation is extensively reviewed, and it is stressed that PPARγ seems to be a major regulator in the differentiation of adipocytes. Thiazoledinediones (TZDs) are a group of PPARγ-agonists used in the treatment of type 2 diabetes (T2D) since 1997. They are characterized by their ability to decrease insulin resistance, and have been suggested to slow down the progression of insulin resistance. Treatment with TZD requires several weeks of treatment to decrease plasma glucose levels, but in addition they markedly decrease plasma triglycerides and free fatty acids. A major drawback of treatment with TZD is body fat gain, but some evidence suggests that the fat is redistributed in a favourable direction, that is, from visceral to subcutaneous depots. However, the effect of long-term treatment on weight gain following TZD treatment is unknown, and it may be questioned whether the use of these ‘adipogenic compounds’ is appropriate, considering that excess body fat is almost a prerequisite for the development of type 2 diabetes.

Efficacy and safety of dietary supplements containing CLA for the treatment of obesity evidence from animal and human studies

Dietary supplements containing conjugated linoleic acid (CLA) are widely promoted as weight loss agents available over the counter and via the Internet. In this review, we evaluate the efficacy and safety of CLA supplementation based on peer-reviewed published results from randomized, placebo-controlled, human intervention trials lasting more than 4 weeks. We also review findings from experimental studies in animals and studies performed in vitro. CLA appears to produce loss of fat mass and increase of lean tissue mass in rodents, but the results from 13 randomized, controlled, short-term (<6 months) trials in humans find little evidence to support that CLA reduces body weight or promotes repartitioning of body fat and fat-free mass in man. However, there is increasing evidence from mice and human studies that the CLA isomer trans-10, cis-12 may produce liver hypertrophy and insulin resistance via a redistribution of fat deposition that resembles lipodystrophy. CLA also decreases the fat content of both human and bovine milk. In conclusion, although CLA appears to attenuate increases in body weight and body fat in several animal models, CLA isomers sold as dietary supplements are not effective as weight loss agents in humans and may actually have adverse effects on human health.

Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial.

BACKGROUND Weight-loss drugs produce an additional mean weight loss of only 3-5 kg above that of diet and placebo over 6 months, and more effective pharmacotherapy of obesity is needed. We assessed the efficacy and safety of tesofensine-an inhibitor of the presynaptic uptake of noradrenaline, dopamine, and serotonin-in patients with obesity. METHODS We undertook a phase II, randomised, double-blind, placebo-controlled trial in five Danish obesity management centres. After a 2 week run-in phase, 203 obese patients (body-mass index 30-</=40 kg/m(2)) were prescribed an energy restricted diet and randomly assigned with a list of randomisation numbers to treatment with tesofensine 0.25 mg (n=52), 0.5 mg (n=50), or 1.0 mg (n=49), or placebo (n=52) once daily for 24 weeks. The primary outcome was percentage change in bodyweight. Analysis was by modified intention to treat (all randomised patients with measurement after at least one dose of study drug or placebo). The study is registered with ClinicalTrials.gov, number NCT00394667. FINDINGS 161 (79%) participants completed the study. After 24 weeks, the mean weight loss produced by diet and placebo was 2.0% (SE 0.60). Tesofensine 0.25 mg, 0.5 mg, and 1.0 mg and diet induced a mean weight loss of 4.5% (0.87), 9.2% (0.91), and 10.6% (0.84), respectively, greater than diet and placebo (p<0.0001). The most common adverse events caused by tesofensine were dry mouth, nausea, constipation, hard stools, diarrhoea, and insomnia. After 24 weeks, tesofensine 0.25 mg and 0.5 mg showed no significant increases in systolic or diastolic blood pressure compared with placebo, whereas heart rate was increased by 7.4 beats per min in the tesofensine 0.5 mg group (p=0.0001). INTERPRETATION Our results suggest that tesofensine 0.5 mg might have the potential to produce a weight loss twice that of currently approved drugs. However, these findings of efficacy and safety need confirmation in phase III trials.

Health effect of the New Nordic Diet in adults with increased waist circumference: a 6-mo randomized controlled trial

BACKGROUND The regional Mediterranean Diet has been associated with lower risk of disease. OBJECTIVE We tested the health effects of the New Nordic Diet (NND), which is a gastronomically driven regional, organic, and environmentally friendly diet, in a carefully controlled but free-living setting. DESIGN A total of 181 centrally obese men and women, with a mean (range) age of 42 y (20-66 y), body mass index (in kg/m(2)) of 30.2 (22.6-47.3), and waist circumference of 100 cm (80-138 cm) were randomly assigned to receive either the NND (high in fruit, vegetables, whole grains, and fish) or an average Danish diet (ADD) for 26 wk. Participants received cookbooks and all foods ad libitum and free of charge by using a shop model. The primary endpoint was the weight change analyzed by both completer and intention-to-treat analyses. RESULTS A total of 147 subjects [81% (NND 81%; ADD 82%)] completed the intervention. A high dietary compliance was achieved, with significant differences in dietary intakes between groups. The mean (±SEM) weight change was -4.7 ± 0.5 kg for the NND compared with -1.5 ± 0.5 kg for the ADD (adjusted difference: -3.2 kg; 95% CI: -4.6, -1.8 kg; P < 0.001) for the completer analysis, and the difference was -3.0 kg (95% CI: -4.0, -2.1 kg) for the intention-to-treat analysis. The NND produced greater reductions in systolic blood pressure (adjusted difference: -5.1 mm Hg; 95% CI: -8.2, -2.1 mm Hg) and diastolic blood pressure (adjusted difference: -3.2 mm Hg; 95% CI: -5.7, -0.8 mm Hg) than did the ADD. CONCLUSION An ad libitum NND produces weight loss and blood pressure reduction in centrally obese individuals. This trial was registered at www.clinicaltrials.gov as NCT01195610.

A critical review of the cannabinoid receptor as a drug target for obesity management.

The discovery of cannabinoids, with the well‐known stimulatory effect of Cannabis sativa on appetite, has offered a new drug target for obesity treatment. Cannabinoids act on two different receptors: CB1 receptors which are sited in the brain and many peripheral tissues, and CB2 receptors which are primarily found in immune system cells. Cannabinoid receptor antagonists act centrally by blocking CB1 receptors, thereby reducing food intake. Moreover, they probably also act peripherally by increasing thermogenesis and therefore energy expenditure, as has been suggested by animal experiments. Despite these promising mechanisms of action, recent clinical studies examining the effect of the two CB1 receptor antagonists rimonabant and taranabant showed that the attained weight loss did not exceed that attained with other currently approved anti‐obesity medications. Moreover, potentially severe psychiatric adverse effects limit their clinical use. As several new CB1 receptor antagonists are presently undergoing development, it remains to be elucidated to what extent they differ in terms of efficacy and safety. This review primarily discusses how close cannabinoid receptor antagonists are to the ideal anti‐obesity drug, with respect to their mechanisms of action, clinical effectiveness and safety.

The Effect of Protein and Glycemic Index on Children's Body Composition: The DiOGenes Randomized Study

OBJECTIVE: To investigate the effect of protein and glycemic index (GI) on body composition among European children in the randomized, 6-month dietary intervention DiOGenes (diet, obesity, and genes) family-based study. PATIENTS AND METHODS: In the study, 827 children (381 boys and 446 girls), aged 5 to 18 years, completed baseline examinations. Families with parents who lost ≥8% of their weight during an 8-week run-in low-calorie diet period were randomly assigned to 1 of 5 ad libitum diets: low protein (LP)/low glycemic index (LGI); LP/high GI (HGI); high protein (HP)/LGI; HP/HGI; and control diet. The target difference was 15 GI U between the LGI/HGI groups and 13 protein percentage points between the LP/HP groups. There were 658 children examined after 4 weeks. Advice on food-choice modification was provided at 6 visits during this period. No advice on weight loss was provided because the focus of the study was the ability of the diets to affect outcomes through appetite regulation. Anthropometric measurements and body composition were assessed at baseline, week 4, and week 26. RESULTS: In the study, 465 children (58.1%) completed all assessments. The achieved differences between the GI and protein groups were 2.3 GI U and 4.9 protein percentage points, respectively. The LP/HGI group increased body fat percentage significantly more than the other groups (P = .040; partial η2 = 0.039), and the percentage of overweight/obese children in the HP/LGI group decreased significantly during the intervention (P = .031). CONCLUSIONS: Neither GI nor protein had an isolated effect on body composition. However, the LP/HGI combination increased body fat, whereas the HP/LGI combination was protective against obesity in this sample of children.

Untargeted metabolomics as a screening tool for estimating compliance to a dietary pattern.

There is a growing interest in studying the nutritional effects of complex diets. For such studies, measurement of dietary compliance is a challenge because the currently available compliance markers cover only limited aspects of a diet. In the present study, an untargeted metabolomics approach was used to develop a compliance measure in urine to distinguish between two dietary patterns. A parallel intervention study was carried out in which 181 participants were randomized to follow either a New Nordic Diet (NND) or an Average Danish Diet (ADD) for 6 months. Dietary intakes were closely monitored over the whole study period, and 24 h urine samples as well as weighed dietary records were collected several times during the study. The urine samples were analyzed by UPLC-qTOF-MS, and a partial least-squares discriminant analysis with feature selection was applied to develop a compliance model based on data from 214 urine samples. The optimized model included 52 metabolites and had a misclassification rate of 19% in a validation set containing 139 samples. The metabolites identified in the model were markers of individual foods such as citrus, cocoa-containing products, and fish as well as more general dietary traits such as high fruit and vegetable intake or high intake of heat-treated foods. It was easier to classify the ADD diet than the NND diet probably due to seasonal variation in the food composition of NND and indications of lower compliance among the NND subjects. In conclusion, untargeted metabolomics is a promising approach to develop compliance measures that cover the most important discriminant metabolites of complex diets.