The association between vitamin D receptor polymorphisms and tissue-specific insulin resistance in human obesity.

BACKGROUND/OBJECTIVES: To investigate (1) the association of four VDR polymorphisms (TaqI/rs731236, ApaI/rs7975232, FokI/rs10735810, and Bsml/rs1544410) with markers of adiposity and tissue-specific insulin resistance at baseline, after weight loss and weight maintenance; (2) the effect of the VDR polymorphisms in the SAT transcriptome in overweight/obese Caucasians of the DiOGenes cohort. METHODS: We included 553 adult obese individuals (mean BMI 34.8 kg/m2), men (n = 197) and women (n = 356) at baseline, following an 8-week weight loss intervention and 26 weeks weight maintenance. Genotyping was performed using an Illumina 660W-Quad SNP chip on the Illumina iScan Genotyping System. Tissue-specific IR was determined using Hepatic Insulin Resistance Index (HIRI), Muscle Insulin Sensitivity Index (MISI), and Adipose Tissue Insulin Resistance Index (Adipo-IR). Expression quantitative trait loci (eQTL) analysis was performed to determine the effect of SNPs on SAT gene expression. RESULTS: None of the VDR polymorphisms were associated with HIRI or MISI. Interestingly, carriers of the G allele of VDR FokI showed higher Adipo-IR (GG + GA 7.8 ± 0.4 vs. AA 5.6 ± 0.5, P = 0.010) and higher systemic FFA (GG + GA: 637.8 ± 13.4 vs. AA: 547.9 ± 24.7 µmol/L, P = 0.011), even after adjustment with age, sex, center, and FM. However, eQTL analysis showed minor to no effect of these genotypes on the transcriptional level in SAT. Also, VDR polymorphisms were not related to changes in body weight and IR as result of dietary intervention (P > 0.05 for all parameters). CONCLUSIONS: The VDR Fokl variant is associated with elevated circulating FFA and Adipo-IR at baseline. Nevertheless, minor to no effect of VDR SNPs on the transcriptional level in SAT, indicating that putative mechanisms of action remain to be determined. Finally, VDR SNPs did not affect dietary intervention outcome in the present cohort.

Correction to: Impact of whole dairy matrix on musculoskeletal health and aging-current knowledge and research gaps.

The article Impact of whole dairy matrix on musculoskeletal health and aging-current knowledge and research gaps written by N.R.W. Geiker, C. Mølgaard, S. Iuliano, R. Rizzoli,Y. Manios, L.J.C. van Loon, J.-M. Lecerf, G. Moschonis, J.-Y. Reginster, I. Givens, A. Astrup.

Impact of whole dairy matrix on musculoskeletal health and aging-current knowledge and research gaps.

Dairy products are included in dietary guidelines worldwide, as milk, yoghurt, and cheese are good sources of calcium and protein, vital nutrients for bones and muscle mass maintenance. Bone growth and mineralization occur during infancy and childhood, peak bone mass being attained after early adulthood. A low peak bone mass has consequences later in life, including increased risk of osteoporosis and fractures. Currently, more than 200 million people worldwide suffer from osteoporosis, with approximately 9 million fractures yearly. This poses a tremendous economic burden on health care. Between 5% and 10% of the elderly suffer from sarcopenia, the loss of muscle mass and strength, further increasing the risk of fractures due to falls. Evidence from interventional and observational studies support that fermented dairy products in particular exert beneficial effects on bone growth and mineralization, attenuation of bone loss, and reduce fracture risk. The effect cannot be explained by single nutrients in dairy, which suggests that a combined or matrix effect may be responsible similar to the matrix effects of foods on cardiometabolic health. Recently, several plant-based beverages and products have become available and marketed as substitutes for dairy products, even though their nutrient content differs substantially from dairy. Some of these products have been fortified, in efforts to mimic the nutritional profile of milk, but it is unknown whether the additives have the same bioavailability and beneficial effect as dairy. We conclude that the dairy matrix exerts an effect on bone and muscle health that is more than the sum of its nutrients, and we suggest that whole foods, not only single nutrients, need to be assessed in future observational and intervention studies of health outcomes. Furthermore, the importance of the matrix effect on health outcomes argues in favor of making future dietary guidelines food based.

Pre-treatment microbial Prevotella-to-Bacteroides ratio, determines body fat loss success during a 6-month randomized controlled diet intervention.

On the basis of the abundance of specific bacterial genera, the human gut microbiota can be divided into two relatively stable groups that might have a role in personalized nutrition. We studied these simplified enterotypes as prognostic markers for successful body fat loss on two different diets. A total of 62 participants with increased waist circumference were randomly assigned to receive an ad libitum New Nordic Diet (NND) high in fiber/whole grain or an Average Danish Diet for 26 weeks. Participants were grouped into two discrete enterotypes by their relative abundance of Prevotella spp. divided by Bacteroides spp. (P/B ratio) obtained by quantitative PCR analysis. Modifications of dietary effects of pre-treatment P/B group were examined by linear mixed models. Among individuals with high P/B the NND resulted in a 3.15 kg (95% confidence interval (CI): 1.55; 4.76, P<0.001) larger body fat loss compared with ADD, whereas no differences was observed among individuals with low P/B (0.88 kg (95% CI: -0.61; 2.37, P=0.25)). Consequently, a 2.27 kg (95% CI: 0.09; 4.45, P=0.041) difference in responsiveness to the diets were found between the two groups. In summary, subjects with high P/B ratio appeared more susceptible to lose body fat on diets high in fiber and whole grain than subjects with a low P/B ratio.

Pre-treatment microbial Prevotella-to-Bacteroides ratio, determines body fat loss success during a 6-month randomized controlled diet intervention.

This corrects the article DOI: 10.1038/ijo.2017.220.

Dietary supplementation with flaxseed mucilage alone or in combination with calcium in dogs: effects on apparent digestibility of fat and energy and fecal characteristics.

BACKGROUND: In humans, dietary supplementation with flaxseed mucilage and calcium decrease apparent digestibility of fat and energy. These supplements could prove useful for weight management in dogs. OBJECTIVE: To examine dry matter, energy and fat apparent digestibility, and fecal characteristics following dietary flaxseed mucilage supplementation alone or in combination with calcium. METHODS: A single-blinded crossover feeding trial was conducted on 11 privately owned dogs. During three consecutive 14-day periods, dogs where fed commercial dog food supplemented with potato starch (control diet), flaxseed mucilage or flaxseed mucilage and calcium. Feces from the past 2 days of each period were collected for analysis. Owners recorded fecal score (1-7: 1=very hard/dry feces, 2-3=ideal and 7=diarrhea). RESULTS: Apparent digestibility of fat was lower in both flaxseed mucilage diet (94.5±0.8%), and flaxseed mucilage and calcium diet (92.9±0.9%) compared with control diet (96.9±0.2%, P<0.0001) with fat digestibility in flaxseed mucilage and calcium diet being significantly lower than the diet supplemented with only flaxseed mucilage. Dry matter and energy digestibility was not significantly affected by diet. Fecal wet weight, dry weight and dry matter percentage was not affected by diet despite a higher fecal score for test diets (3.7±0.3) compared with control (2.8±0.2, P<0.007). CONCLUSION: In dogs, flaxseed mucilage decreased fat apparent digestibility and this effect was enhanced when combined with calcium. Dry matter and energy apparent digestibility was not affected. Decreased fecal quality may limit the acceptable level of supplementation. Further studies on incorporating flaxseed mucilage in pet food products for weight management are needed.

Effects of RYGB on energy expenditure, appetite and glycaemic control: a randomized controlled clinical trial.

OBJECTIVES: Increased energy expenditure (EE) has been proposed as an important mechanism for weight loss following Roux-en-Y gastric bypass (RYGB). However, this has never been investigated in a controlled setting independent of changes in energy balance. Similarly, only few studies have investigated the effect of RYGB on glycaemic control per se. Here, we investigated the effect of RYGB on EE, appetite, glycaemic control and specific signalling molecules compared with a control group in comparable negative energy balance. SUBJECTS/METHODS: Obese normal glucose-tolerant participants were randomized to receive RYGB after 8 (n=14) or 12 weeks (n=14). The protocol included a visit at week 0 and three visits (weeks 7, 11 and 78) where 24-h EE, appetite and blood parameters were assessed. Participants followed a low-calorie diet from weeks 0-11, with those operated at week 12 serving as a control group for those operated at week 8. RESULTS: Compared with controls, RYGB-operated participants had lower body composition-adjusted 24-h EE and basal EE 3 weeks postoperatively (both P<0.05) but EE parameters at week 78 were not different from preoperative values (week 7). Surgery changed the postprandial response of glucagon-like peptide-1 (GLP-1), peptide YY3-36 (PYY), ghrelin, cholecystokinin, fibroblast growth factor-19 and bile acids (all P<0.05). Particularly, increases in GLP-1, PYY and decreases in ghrelin were associated with decreased appetite. None of HOMA-IR (homeostasis model assessment-estimated insulin resistance), Matsuda index, the insulinogenic index, the disposition index and fasting hepatic insulin clearance were different between the groups, but RYGB operated had lower fasting glucose (P<0.05) and the postprandial glucose profile was shifted to the left (P<0.01). CONCLUSIONS: Our data do not support that EE is increased after RYGB. More likely, RYGB promotes weight loss by reducing appetite, partly mediated by changes in gastrointestinal hormone secretion. Furthermore, we found that the early changes in glycaemic control after RYGB is to a large extent mediated by caloric restriction.

Associations between adiposity, hormones, and gains in height, whole-body height-adjusted bone size, and size-adjusted bone mineral content in 8- to 11-year-old children.

UNLABELLED: We examined fat-independent associations of hormones with height and whole-body bone size and mineral content in 633 school children. IGF-1 and osteocalcin predict growth in height, while fat, osteocalcin, and in girls also, IGF-1 predict growth in bone size. Leptin and ghrelin are inversely associated with bone size in girls. INTRODUCTION: Obesity causes larger bone size and bone mass, but the role of hormones in this up-regulation of bone in obesity is not well elucidated. We examined longitudinal associations between baseline body fat mass (FM), and fat-independent fasting levels of ghrelin, adiponectin, leptin, insulin, insulin-like growth factor-I (IGF-1), osteocalcin, and intact parathyroid hormone, and subsequent changes in height and in whole-body height-adjusted bone area "BAheight" and size-adjusted bone mineral content "BMCsize" in 8- to 11-year-olds. METHODS: Analyses were carried out separately for boys (n = 325) and girls (n = 308) including data from baseline, 3 and 6 months from OPUS School Meal Study. RESULTS: In both sexes: gain in BAheight was positively associated with baseline FM (≥2.05 cm(2)/kg, both p ≤ 0.003). Furthermore, gain in height was positively associated with baseline IGF-1 (≥0.02 cm/ng/ml, p = 0.001) and osteocalcin (≥0.13 cm/ng/ml, p ≤ 0.009); and gain in BAheight was positively associated with baseline osteocalcin (≥0.35 cm(2)/ng/ml, p ≤ 0.019). In girls only, gain in BAheight was also positively associated with baseline IGF-1 (0.06 cm(2)/ng/ml, p = 0.017) and inversely associated with both baseline ghrelin (-0.01 cm(2)/pg/ml, p = 0.001) and leptin (-1.21 cm(2)/µg/ml, p = 0.005). In boys, gain in BMCsize was positively associated with osteocalcin (0.18 g/ng/ml, p = 0.030). CONCLUSIONS: This large longitudinal study suggests that in 8- to 11-year-old children, IGF-1 and osteocalcin predict growth in height, while FM, osteocalcin, and in girls also, IGF-1 predict growth in BAheight. Fat-independent inverse associations of leptin and ghrelin with BAheight in girls' are contrary to proposed growth-stimulating effects of leptin. Osteocalcin in boys predicts gain in BMCsize.

The role of higher protein diets in weight control and obesity-related comorbidities.

The importance of the relative dietary content of protein, carbohydrate and the type of carbohydrate (that is, glycemic index (GI)) for weight control under ad libitum conditions has been controversial owing to the lack of large scale studies with high diet adherence. The Diet, Obesity and Genes (DioGenes) European multicentre trial examined the importance of a slight increase in dietary protein content, reduction in carbohydrate and the importance of choosing low (LGI) vs high GI (HGI) carbohydrates for weight control in 932 obese families. Only the adults underwent a diet of 800 kcal per day for 8 weeks, and after losing ~11kg they were randomized to one of five energy ad libitum diets for 6 months. The diets differed in protein content and GI. The high-protein (HP) diet groups consumed 5.4% points more energy from protein than the normal protein (NP) groups, and the LGI diet groups achieved 5.1% lower GI than the HGI groups. The effect of HP and LGI was additive on weight loss and maintenance, and the combination was successful in preventing weight regain and reducing drop-out rate among the adults after the 11kg weight loss. This diet also reduced body fatness and prevalence of overweight and obesity among their children and had consistent beneficial effects on blood pressure, blood lipids and inflammation in both parents and children. After 1 year, mainly the HP effects were maintained. Putative genes have been identified that suggest this diet to be particularly effective in 67% of the population. In conclusion, the DioGenes diet has shown to be effective for prevention of weight regain and for weight reduction in overweight children under ad libitum conditions. The less-restrictive dietary approach fits into a normal food culture, and has been translated into popular diet and cook books in several languages.

Dietary protein and urinary nitrogen in relation to 6-year changes in fat mass and fat-free mass.

BACKGROUND: In contrast to the physiological expectation, observational studies show that greater protein intake is associated with subsequent body weight (BW) gain. An increase in fat-free mass (FFM) due to the anabolic effects of protein could explain this. OBJECTIVE: To examine associations between protein intake and subsequent changes in fat mass (FM) and FFM in longitudinal, observational data. DESIGN: A health examination, including measures of FM and FFM by bioelectrical impedance at baseline and follow-up 6 years later, was conducted. Diet history interviews (DHI) were performed, and 24-h urinary nitrogen collection at baseline was done. In total, 330 participants with DHI, of whom 227 had validated and complete 24-h urine collection data, were analyzed. Macronutrient energy substitution models were used. RESULTS: Mean estimated protein intake was 14.6 E% from DHI and 11.3 E% from urinary nitrogen. Estimated from DHI, FM increased 46 g per year, with every 1 E% protein substituted for fat (95% confidence interval (CI) = 13, 79; P = 0.006), and FFM increased 15 g per year (1, 30; P = 0.046). Results were similar in other substitution models. Estimated from urinary nitrogen, FM increased 53 g per year, with 1 E% protein substituted for other macronutrients (24, 81; P < 0.0005), and FFM increased 18 g per year (6, 31; P = 0.004). CONCLUSION: Within a habitual range, a greater protein intake was associated with BW gain, mostly in FM. This is in contrast to the expectations based on physiological and clinical trials, and calls for a better understanding of how habitual dietary protein influences long-term energy balance, versus how greater changes in dietary proteins may influence short-term energy balance.

Glycemic index, glycemic load and glycemic response: An International Scientific Consensus Summit from the International Carbohydrate Quality Consortium (ICQC).

BACKGROUND AND AIMS: The positive and negative health effects of dietary carbohydrates are of interest to both researchers and consumers. METHODS: International experts on carbohydrate research held a scientific summit in Stresa, Italy, in June 2013 to discuss controversies surrounding the utility of the glycemic index (GI), glycemic load (GL) and glycemic response (GR). RESULTS: The outcome was a scientific consensus statement which recognized the importance of postprandial glycemia in overall health, and the GI as a valid and reproducible method of classifying carbohydrate foods for this purpose. There was consensus that diets low in GI and GL were relevant to the prevention and management of diabetes and coronary heart disease, and probably obesity. Moderate to weak associations were observed for selected cancers. The group affirmed that diets low in GI and GL should always be considered in the context of diets otherwise understood as healthy, complementing additional ways of characterizing carbohydrate foods, such as fiber and whole grain content. Diets of low GI and GL were considered particularly important in individuals with insulin resistance. CONCLUSIONS: Given the high prevalence of diabetes and pre-diabetes worldwide and the consistency of the scientific evidence reviewed, the expert panel confirmed an urgent need to communicate information on GI and GL to the general public and health professionals, through channels such as national dietary guidelines, food composition tables and food labels.

Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults.

BACKGROUND: Liraglutide 3.0 mg, with diet and exercise, produced substantial weight loss over 1 year that was sustained over 2 years in obese non-diabetic adults. Nausea was the most frequent side effect. OBJECTIVE: To evaluate routinely collected data on nausea and vomiting among individuals on liraglutide and their influence on tolerability and body weight. DESIGN: A randomized, placebo-controlled, double-blind 20-week study with an 84-week extension (sponsor unblinded at 20 weeks, open-label after 1 year) in eight European countries (Clinicaltrials.gov: NCT00422058). SUBJECTS: After commencing a 500-kcal/day deficit diet plus exercise, 564 participants (18-65 years, body mass index (BMI) 30-40 kg m(-2)) were randomly assigned (after a 2-week run-in period) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg), placebo or open-label orlistat (120 mg × 3 per day). After 1 year, participants on liraglutide/placebo switched to liraglutide 2.4 mg, and subsequently, to liraglutide 3.0 mg (based on 20-week and 1-year results, respectively). RESULTS: The intention-to-treat population comprised 561 participants (n=90-98 per arm, age 45.9±10.3 years, BMI 34.8±2.7 kg m(-2) (mean±s.d.)). In year 1, more participants reported ⩾1 episode of nausea/vomiting on treatment with liraglutide 1.2-3.0 mg (17-38%) than with placebo or orlistat (both 4%, P⩽0.001). Most episodes occurred during dose escalation (weeks 1-6), with 'mild' or 'moderate' symptoms. Among participants on liraglutide 3.0 mg, 48% reported some nausea and 13% some vomiting, with considerable variation between countries, but only 4 out of 93 (4%) reported withdrawals. The mean 1-year weight loss on treatment with liraglutide 3.0 mg from randomization was 9.2 kg for participants reporting nausea/vomiting episodes, versus 6.3 kg for those with none (a treatment difference of 2.9 kg (95% confidence interval 0.5-5.3); P=0.02). Both weight losses were significantly greater than the respective weight losses for participants on placebo (P<0.001) or orlistat (P<0.05). Quality-of-life scores at 20 weeks improved similarly with or without nausea/vomiting on treatment with liraglutide 3.0 mg. CONCLUSION: Transient nausea and vomiting on treatment with liraglutide 3.0 mg was associated with greater weight loss, although symptoms appeared tolerable and did not attenuate quality-of-life improvements. Improved data collection methods on nausea are warranted.

Short sleep duration and large variability in sleep duration are independently associated with dietary risk factors for obesity in Danish school children.

BACKGROUND: Lack of sleep and increased consumption of energy-dense foods and sugar-sweetened beverages (SSBs) have all been suggested as factors contributing to the increased prevalence of overweight and obesity. OBJECTIVE: To evaluate whether objectively measured sleep duration (average and day-to-day variability) as well as parent-reported sleep problems are independently associated with proposed dietary risk factors for overweight and obesity in 8-11-year-old children. DESIGN: In this cross-sectional study, data on sleep duration and day-to-day variability in sleep duration were measured in 676 Danish, apparently healthy children by an objective measure (actigraphy) for 8 nights, and the Children's Sleep Habits Questionnaire (CSHQ) was filled out by the parents. Diet was recorded using a web-based food record for 7 consecutive days. Fasting blood samples were obtained for measurements of plasma leptin and ghrelin levels. RESULTS: Sleep duration (h per night) was negatively associated with energy density (ED) of the diet (ß = -0.32 kJ g(-1)), added sugar (ß = -1.50 E%) and SSBs (ß = -1.07 E%) (all P ≤ 0.003). Furthermore, variability in sleep duration (10-min per night) was positively associated with SSBs (ß = 0.20 E%, P = 0.03), independent of sleep duration, and CSHQ score was positively associated with ED (ß = 0.16 kJ g(-1), P = 0.04). All of these associations were independent of potential confounders (age, sex, pubertal status, height, weight, screen time, moderate-to-vigorous physical activity and parental education and ethnicity). CONCLUSION: Our study suggests that short sleep duration, high sleep duration variability and experiencing sleep problems are all associated with a poor, obesity-promoting diet in children.

Fatness predicts decreased physical activity and increased sedentary time, but not vice versa: support from a longitudinal study in 8- to 11-year-old children.

OBJECTIVE: To examine independent and combined cross-sectional associations between movement behaviors (physical activity (PA), sedentary time, sleep duration, screen time and sleep disturbance) and fat mass index (FMI), as well as to examine longitudinal associations between movement behaviors and FMI. METHODS: Cross-sectional and longitudinal analyses were done using data from the OPUS school meal study on 785 children (52% boys, 13.4% overweight, ages 8-11 years). Total PA, moderate-to-vigorous PA (MVPA), sedentary time and sleep duration (7 days and 8 nights) were assessed by an accelerometer and FMI was determined by dual-energy X-ray absorptiometry (DXA) on three occasions over 200 days. Demographic characteristics, screen time and sleep disturbance (Children's Sleep Habits Questionnaire) were also obtained. RESULTS: Total PA, MVPA and sleep duration were negatively associated with FMI, while sedentary time and sleep disturbances were positively associated with FMI (P⩽0.01). However, only total PA, MVPA and sleep duration were independently associated with FMI after adjustment for multiple covariates (P<0.001). Nevertheless, combined associations revealed synergistic effects among the different movement behaviors. Changes over time in MVPA were negatively associated with changes in FMI (P<0.001). However, none of the movement behaviors at baseline predicted changes in FMI (P>0.05), but higher FMI at baseline predicted a decrease in total PA and MVPA, and an increase in sedentary time (P⩽0.001), even in normal-weight children (P⩽0.03). CONCLUSION: Total PA, MVPA and sleep duration were independently associated with FMI, and combined associations of movement behaviors showed a synergistic effect with FMI. In the longitudinal study design, a high FMI at baseline was associated with lower PA and higher sedentary time after 200 days but not vice versa, even in normal-weight children. Our results suggest that adiposity is a better predictor of PA and sedentary behavior changes than the other way around.

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.

Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes.

AIMS/HYPOTHESIS: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. METHODS: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. RESULTS: Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10(-10)). CONCLUSIONS/INTERPRETATION: We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.

Acute effects of mustard, horseradish, black pepper and ginger on energy expenditure, appetite, ad libitum energy intake and energy balance in human subjects.

Chilli peppers have been shown to enhance diet-induced thermogenesis (DIT) and reduce energy intake (EI) in some studies, but there are few data on other pungent spices. The primary aim of the present study was to test the acute effects of black pepper (pepper), ginger, horseradish and mustard in a meal on 4 h postprandial DIT. The secondary aim was to examine the effects on subjective appetite measures, ad libitum EI and energy balance. In a five-way placebo-controlled, single-blind, cross-over trial, twenty-two young (age 24·9 (SD 4·6) years), normal-weight (BMI 21·8 (SD 2·1) kg/m²) males were randomly assigned to receive a brunch meal with either pepper (1·3 g), ginger (20 g), horseradish (8·3 g), mustard (21 g) or no spices (placebo). The amounts of spices were chosen from pre-testing to make the meal spicy but palatable. No significant treatment effects were observed on DIT, but mustard produced DIT, which tended to be larger than that of placebo (14 %, 59 (SE 3) v. 52 (SE 2) kJ/h, respectively, P=0·08). No other spice induced thermogenic effects approaching statistical significance. Subjective measures of appetite (P>0·85), ad libitum EI (P=0·63) and energy balance (P=0·67) also did not differ between the treatments. Finally, horseradish decreased heart rate (P=0·048) and increased diastolic blood pressure (P= 0·049) compared with placebo. In conclusion, no reliable treatment effects on appetite, EI or energy balance were observed, although mustard tended to be thermogenic at this dose. Further studies should explore the possible strength and mechanisms of the potential thermogenic effect of mustard actives, and potential enhancement by, for example, combinations with other food components.

Flaxseed dietary fibers suppress postprandial lipemia and appetite sensation in young men.

BACKGROUND AND AIM: Dietary fibers (DF) are linked to a reduced risk of life-style diseases, which relate to their physiological effects in the gastrointestinal tract. The aim was to examine whether flaxseed DF-enriched meals suppress postprandial lipemia and reduce appetite. METHODS AND RESULTS: Four different iso-caloric meals were tested in 18 young men in a double-blind randomized crossover design. Test meals were served after an overnight fast. DF content and source were: control (C): 1.4 g/MJ; whole flaxseed (WF): 2.4 g/MJ from whole flaxseeds; low-mucilage dose (LM): 2.4 g/MJ from flaxseed DF; high-mucilage dose (HM): 3.4 g/MJ from flaxseed DF. During the 7 h test day, subjective appetite sensation was assessed using visual analogue scales and appetite-regulating hormones, and lipemia and glycemia were measured, after which ad libitum energy intake was recorded. There was a significant time × meal effect on triacylglycerols (TG) (p = 0.02) and an 18% smaller area under the curve (AUC) for TG after meal HM compared to meal C was observed (p < 0.01). AUC for insulin was smaller after both LM and HM meals compared to C and WF meals. Higher mean ratings of satiety (p < 0.01) and fullness (p = 0.03) was seen following the HM meal compared to meal C. AUC for ghrelin, CCK and GLP-1 and ad libitum energy intake did not differ between meals, but ghrelin response exhibited a different response pattern after the mucilage-containing meals. CONCLUSION: These findings suggest that flaxseed DF may suppress postprandial lipemia and appetite although subsequent energy intake was not affected.

Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide.

OBJECTIVE: Having demonstrated short-term weight loss with liraglutide in this group of obese adults, we now evaluate safety/tolerability (primary outcome) and long-term efficacy for sustaining weight loss (secondary outcome) over 2 years. DESIGN: A randomized, double-blind, placebo-controlled 20-week study with 2-year extension (sponsor unblinded at 20 weeks, participants/investigators at 1 year) in 19 European clinical research centers. SUBJECTS: A total of 564 adults (n=90-98 per group; body mass index 30-40 kg m(-2)) enrolled, 398 entered the extension and 268 completed the 2-year trial. Participants received diet (500 kcal deficit per day) and exercise counseling during 2-week run-in, before being randomly assigned (with a telephone or web-based system) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg, n=90-95), placebo (n=98) or open-label orlistat (120 mg × 3, n=95). After 1 year, liraglutide/placebo recipients switched to liraglutide 2.4 mg, then 3.0 mg (based on 20-week and 1-year results, respectively). The trial ran from January 2007-April 2009 and is registered with Clinicaltrials.gov, number NCT00480909. RESULTS: From randomization to year 1, liraglutide 3.0 mg recipients lost 5.8 kg (95% confidence interval 3.7-8.0) more weight than those on placebo and 3.8 kg (1.6-6.0) more than those on orlistat (P0.0001; intention-to-treat, last-observation-carried-forward). At year 2, participants on liraglutide 2.4/3.0 mg for the full 2 years (pooled group, n=184) lost 3.0 kg (1.3-4.7) more weight than those on orlistat (n=95; P<0.001). Completers on liraglutide 2.4/3.0 mg (n=92) maintained a 2-year weight loss of 7.8 kg from screening. With liraglutide 3.0 mg, 20-week body fat decreased by 15.4% and lean tissue by 2.0%. The most frequent drug-related side effects were mild to moderate, transient nausea and vomiting. With liraglutide 2.4/3.0 mg, the 2-year prevalence of prediabetes and metabolic syndrome decreased by 52 and 59%, with improvements in blood pressure and lipids. CONCLUSION: Liraglutide is well tolerated, sustains weight loss over 2 years and improves cardiovascular risk factors.

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.