Results from three phase 1 trials of NNC9204-1177, a glucagon/GLP-1 receptor co-agonist: Effects on weight loss and safety in adults with overweight or obesity.

OBJECTIVE: Glucagon/glucagon-like peptide-1 (GLP-1) receptor co-agonists may provide greater weight loss than agonists targeting the GLP-1 receptor alone. We report results from three phase 1 trials investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of the glucagon/GLP-1 receptor co-agonist NNC9204-1177 (NN1177) for once-weekly subcutaneous use in adults with overweight or obesity. METHODS: Our focus was a 12-week, multiple ascending dose (MAD), placebo-controlled, double-blind trial in which adults (N = 99) received NN1177 (on an escalating dose regimen of 200, 600, 1300, 1900, 2800, 4200 and 6000 µg) or placebo. Two other trials also contributed to the findings reported in this article: a first human dose (FHD)/single ascending dose (SAD), placebo-controlled, double-blind trial in which adults (N = 49) received NN1177 (treatment doses of 10, 40, 120, 350, 700 and 1100 µg) or placebo, and a drug-drug interaction, open-label, single-sequence trial in which adults (N = 45) received a 4200-µg dose of NN1177, following administration of a Cooperstown 5 + 1 index cocktail. Safety, tolerability, pharmacokinetic and pharmacodynamic endpoints were assessed. RESULTS: For the FHD/SAD and MAD trials, baseline characteristics were generally balanced across treatment cohorts. The geometric mean half-life of NN1177 at steady state was estimated at between 77 and 111 h, and clinically relevant weight loss was achieved (up to 12.6% at week 12; 4200 µg in the MAD trial). Although NN1177 appeared tolerable across trials, several unexpected treatment-related safety signals were observed; increased heart rate, decreased reticulocyte count, increased markers of inflammation (fibrinogen and C-reactive protein), increased aspartate and alanine aminotransferase, impaired glucose tolerance and reduced blood levels of some amino acids. CONCLUSION: Although treatment with NN1177 was associated with dose-dependent and clinically relevant weight loss, the observed safety signals precluded further clinical development.

The effect of three different ad libitum diets for weight loss maintenance: a randomized 18-month trial.

PURPOSE: To test the effect of three diets in their ability to sustain weight loss and improve type 2 diabetes (T2D) and cardiovascular disease (CVD) risk markers after 18-month intervention. METHODS: Following a ≥8 % weight loss, 131 healthy, overweight/obese (BMI ± SD 31.5 ± 2.6 kg/m2) men (n = 55) and women (n = 76) aged 28.2 ± 4.8 years were randomized to either 1. Moderate fat (40 E%) with 20 E% MUFA and low in glycemic index (GI) (MUFA, n = 54), 2. Low fat (25 E%) and medium in GI (LF, n = 51) or 3. Control (35 E% fat) and high in GI (CTR, n = 26) all with similar protein content, and all provided ad libitum. First 6-month intervention with 100 % food provision (previously reported) following 12 months of moderately intensive intervention with 20 % food provision now reported. RESULTS: Attrition rate was higher in MUFA (63 %) than in LF (37 %, P = 0.019) and CTR (42 %, P = 0.09) group. Weight regain in completers was not different between groups (mean ± SEM), MUFA 7.1 ± 2.1 % versus LF 5.6 ± 1.3 % versus CTR 7.2 ± 1.5 %, nor was body fat regain, MUFA 4.8 ± 1.0 % versus LF 4.7 ± 0.8 % versus CTR 5.7 ± 0.6 %. The MUFA group reduced LDL/HDL ratio by -0.47 ± 0.09 compared with -0.23 ± 0.11 in LF (P < 0.05) and 0.06 ± 0.14 (P < 0.005) in CTR groups. CONCLUSIONS: Weight regain or body composition did not differ between diets over 18 months. No effects on risk markers for T2D or CVD were found, with the exception of an improvement in the LDL/HDL ratio by the MUFA diet compared to the CTR diet. The LF diet was generally more satisfactory and the MUFA diet seemed more difficult to follow.

Long-Term Effect of Interactive Online Dietician Weight Loss Advice in General Practice (LIVA) Protocol for a Randomized Controlled Trial.

Background. Internet-based complex interventions aiming to promote weight loss and optimize healthy behaviors have attracted much attention. However, evidence for effect is lacking. Obesity is a growing problem, resulting in an increasing demand for cost efficient weight loss programs suitable for use on a large scale, for example, as part of standard primary care. In a previous pilot project by Brandt et al. (2011) without a control group, we examined the effects of online dietician counseling and found an average weight loss of 7.0 kg (95% CI: 4.6 to 9.3 kg) after 20 months. Aims and Methods. To analyze the effects of a complex intervention using trained dieticians in a general practice setting combined with internet-based interactive and personalized weight management support compared with conventional advice with a noninteractive internet support as placebo treatment in 340 overweight patients during a 2-year period. Primary endpoints are weight loss and lowering of cholesterol (LDL). We will also explore patients' sociodemographics and use of the intervention as well as the health professionals' views and perceptions of the intervention (their role and the advice and support that they provide). Perspective. The project will generate knowledge on the cost-effectiveness of a complex internet-based intervention in a general practice setting and on barriers and acceptability among professionals and patients.

Thermic effect of a meal and appetite in adults: an individual participant data meta-analysis of meal-test trials.

BACKGROUND: Thermic effect of a meal (TEF) has previously been suggested to influence appetite. OBJECTIVE: The aim of this study was to assess whether there is an association between appetite and TEF. Second, to examine whether protein intake is associated with TEF or appetite. DESIGN: Individual participant data (IPD) meta-analysis on studies were performed at the Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark. Five randomized meal-test studies, with 111 participants, were included. The included studies measured energy expenditure (EE) in respiration chambers and pre- and postprandial appetite sensations using Visual Analog Scales (VAS). The primary meta-analysis was based on a generic-inverse variance random-effects model, pooling individual study Spearman's correlation coefficients, resulting in a combined r-value with 95% confidence interval (95% CI). The I (2) value quantifies the proportion (%) of the variation in point estimates due to among-study differences. RESULTS: The IPD meta-analysis found no association between satiety and TEF expressed as the incremental area under the curve (TEFiAUC) (r=0.06 [95% CI -0.16 to 0.28], P=0.58; I (2)=15.8%). Similarly, Composite Appetite Score (CAS) was not associated with TEFiAUC (r=0.08 [95% CI -0.12 to 0.28], P=0.45; I (2)=0%). Posthoc analyses showed no association between satiety or CAS and TEF expressed as a percentage of energy intake (EI) (P>0.49) or TEF expressed as a percentage of baseline EE (P>0.17). When adjusting for covariates, TEFiAUC was associated with protein intake (P=0.0085). CONCLUSIONS: This IPD meta-analysis found no evidence supporting an association between satiety or CAS and TEF at protein intakes ∼15 E% (range 11-30 E%).

Linseed dietary fibers reduce apparent digestibility of energy and fat and weight gain in growing rats.

Dietary fibers (DF) may affect energy balance, an effect often ascribed to the viscous nature of some water soluble DF, which affect luminal viscosity and thus multiple physiological processes. We have tested the hypothesis that viscous linseed DF reduce apparent nutrient digestibility, and limit weight gain, in a randomized feeding trial where 60 male, growing, Wistar rats, with an initial weight of ~200 g, were fed different diets (n = 10 per group): low DF control (C), 5% DF from cellulose (5-CEL), CEL + 5% DF from whole (5-WL) or ground linseed (5-GL), CEL + 5% DF from linseed DF extract (5-LDF), and CEL + 10% DF from linseed DF extract (10-LDF). Diets were provided ad libitum for 21 days. Feed intake and faecal output were measured during days 17-21. Faecal fat excretion increased with increasing DF content and was highest in the 10-LDF group. Apparent fat digestibility was highest with the C diet (94.9% ± 0.8%) and lowest (74.3% ± 0.6%) with the 10-LDF diet, and decreased in a non-linear manner with increasing DF (p < 0.001). Apparent fat digestibility also decreased with increased accessibility of DF (5-WL vs. 5-GL) and when the proportion of viscous DF increased (5-GL vs. 5-LDF). The 10-LDF resulted in a lower final body weight (258 ± 6.2 g) compared to C (282 ± 5.9 g), 5-CEL (281 ± 5.9 g), and 5-WL (285 ± 5.9 g) (p < 0.05). The 10-LDF diet reduced body fat compared to 5-CEL (p < 0.01). In conclusion, DF extracted from linseed reduced apparent energy and fat digestibility and resulted in restriction of body weight gain in growing rats.

Whole grain compared with refined wheat decreases the percentage of body fat following a 12-week, energy-restricted dietary intervention in postmenopausal women.

Observational studies show inverse associations between intake of whole grain and adiposity and cardiovascular risk; however, only a few dietary intervention trials have investigated the effect of whole-grain consumption on health outcomes. We studied the effect of replacing refined wheat (RW) with whole-grain wheat (WW) for 12 wk on body weight and composition after a 2-wk run-in period of consumption of RW-containing food intake. In this open-label randomized trial, 79 overweight or obese postmenopausal women were randomized to an energy-restricted diet (deficit of ~1250 kJ/d) with RW or WW foods providing 2 MJ/d. Body weight and composition, blood pressure, and concentration of circulating risk markers were measured at wk 0, 6, and 12. Fecal output and energy excretion were assessed during run-in and wk 12. Plasma alkylresorcinol analysis indicated good compliance with the intervention diets. Body weight decreased significantly from baseline in both the RW (-2.7 ± 1.9 kg) and WW (-3.6 ± 3.2 kg) groups, but the decreases did not differ between the groups (P = 0.11). The reduction in body fat percentage was greater in the WW group (-3.0%) than in the RW group (-2.1%) (P = 0.04). Serum total and LDL cholesterol increased by ~5% (P < 0.01) in the RW group but did not change in the WW group; hence, the changes differed between the groups (P = 0.02). In conclusion, consumption of whole-grain products resulted in a greater reduction in the percentage fat mass, whereas body weight changes did not differ between the RW and WW groups. Serum total and LDL cholesterol, two important risk factors of cardiovascular disease, increased with RW but not WW consumption, which may suggest a cardioprotective role for whole grain.

Weight maintenance through behaviour modification with a cooking course or neurolinguistic programming.

We compared the effect on weight regain of behaviour modification consisting of either a gourmet cooking course or neurolinguistic programming (NLP) therapy. Fifty-six overweight and obese subjects participated. The first step was a 12-week weight loss program. Participants achieving at least 8% weight loss were randomized to five months of either NLP therapy or a course in gourmet cooking. Follow-up occurred after two and three years. Forty-nine participants lost at least 8% of their initial body weight and were randomized to the next step. The NLP group lost an additional 1.8 kg and the cooking group lost 0.2 kg during the five months of weight maintenance (NS). The dropout rate in the cooking group was 4%, compared with 26% in the NLP group (p=0.04). There was no difference in weight maintenance after two and three years of follow-up. In conclusion, weight loss in overweight and obese participants was maintained equally efficiently with a healthy cooking course or NLP therapy, but the dropout rate was lower during the active cooking treatment.

Molecular determinants for selective recognition of antidepressants in the human serotonin and norepinephrine transporters.

Inhibitors of the serotonin transporter (SERT) and norepinephrine transporter (NET) are widely used in the treatment of major depressive disorder. Although SERT/NET selectivity is a key determinant for the therapeutic properties of these drugs, the molecular determinants defining SERT/NET selectivity are poorly understood. In this study, the structural basis for selectivity of the SERT selective inhibitor citalopram and the structurally closely related NET selective inhibitor talopram is delineated. A systematic structure-activity relationship study allowed identification of the substituents that control activity and selectivity toward SERT and NET and revealed a common pattern showing that SERT and NET have opposite preference for the stereochemical configuration of these inhibitors. Mutational analysis of nonconserved SERT/NET residues within the central substrate binding site was performed to determine the molecular basis for inhibitor selectivity. Changing only five residues in NET to the complementary residues in SERT transferred a SERT-like affinity profile for R- and S-citalopram into NET, showing that the selectivity of these compounds is determined by amino acid differences in the central binding site of the transporters. In contrast, the activity of R- and S-talopram was largely unaffected by any mutations within the central substrate binding site of SERT and NET and in the outer vestibule of NET, suggesting that citalopram and talopram bind to distinct sites on SERT and NET. Together, these findings provide important insight into the molecular basis for SERT/NET selectivity of antidepressants, which can be used to guide rational development of unique transporter inhibitors with fine-tuned transporter selectivity.

Associations between APOE variants and metabolic traits and the impact of psychological stress.

OBJECTIVE: In a previous study, we observed that associations between APOE rs439401 and metabolic traits were moderated by chronic stress. Thus, in a population of stressed and non-stressed Danish men, we examined whether associations between APOE rs439401 and a panel of metabolic quantitative traits, all metabolic traits which may lead to T2D and CVD were moderated by psychological stress. METHODS: Obese young men (n = 475, BMI ≥ 31.0 kg/m(2)) and a randomly selected control group (n = 709) identified from a population of 141,800 men were re-examined in two surveys (S-46: mean age 46, S-49: mean age 49 years) where anthropometric and biochemical measures were available. Psychological stress factors were assessed by a self-administered 7-item questionnaire. Each item had the possible response categories "yes" and "no" and assessed familial problems and conflicts. Summing positive responses constituted a stress item score, which was then dichotomized into stressed and non-stressed. Logistic regression analysis, applying a recessive genetic model, was used to assess odds ratios (OR) of the associations between APOE rs439401 genotypes and adverse levels of metabolic traits. RESULTS: The APOE rs439401 TT-genotype associated positively with BMI (OR = 1.09 [1.01; 1.17]), waist circumference (OR = 1.09 [1.02; 1.17]) in stressed men at S-46. Positive associations were observed for fasting plasma glucose (OR = 1.42 [1.07; 1.87]), serum triglycerides (OR = 1.41 [1.05; 1.91]) and with fasting plasma insulin (OR = 1.48 [1.05; 2.08]) in stressed men at S-49. Rs439401 TT-genotype also associated positively with surrogate measures of insulin resistance (HOMA-IR; OR = 1.21 [1.03; 1.41]) and inversely with insulin sensitivity (Stumvoll index; OR = 0.90 [0.82; 0.99], BIGTT-S(I); OR = 0.60 [0.43; 0.85]) in stressed men. No significant associations were observed in non-stressed men, albeit the estimates showed similar but weaker trends as in stressed men. CONCLUSION: The present results suggest that the APOE rs439401 TT-genotype is associated with an adverse metabolic profile in a population of psychologically stressed Danish men.

Center-size as a predictor of weight-loss outcome in multicenter trials including a low-calorie diet.

It has not been studied yet whether factors such as the number of subjects recruited by specialized centers for multicenter trials may influence weight loss during a low-calorie diet (LCD). This study aimed at determining whether the number of recruited subjects per center might predict relative weight loss. This is a post hoc analysis of an existing database: 701 obese subjects (77% women, 23% men, mean BMI: 38.9 kg/m(2)) were enrolled at 22 sites (4-85 subjects/site) in five countries to follow a LCD providing 800-1,000 kcal/day during 8 weeks. The main outcome measure was the percentage weight loss after the 8-week LCD. Mean weight loss differed significantly between participating centers (5.8-11.8% of the initial weight; P < 0.001). There was a significant positive correlation between relative weight loss and the number of recruited subjects per center (r = 0.38; P < 0.001). In a multiple stepwise regression analysis, the number of recruited subjects per center appeared to be the main predictive factor of weight loss (R(2) = 0.07; P < 0.001). As the number of participants within each center is clustered, we applied a hierarchical model to model the average weight loss vs. the number of participants included at each center. This model allows to predict that for 10 extra patients in a center, the average weight loss would increase by 0.5%. This is the first study suggesting that the number of recruited subjects per center may impact weight loss, and could therefore be considered as a new predictor for weight loss that is independent from the individual.

A randomized trial of lifestyle modification and taranabant for maintaining weight loss achieved with a low-calorie diet.

Improving the maintenance of weight loss remains a critical challenge for obesity researchers. The present 1-year, randomized, placebo-controlled trial evaluated the safety and efficacy of weight maintenance counseling combined with either placebo or the cannabinoid-1 receptor inverse agonist, taranabant, for sustaining prior weight loss achieved on a low-calorie diet (LCD). Seven hundred eighty-four individuals who had lost ≥ 6% of body weight during six initial weeks of treatment with an 800 kcal/day liquid LCD were randomly assigned to placebo or once-daily taranabant in doses of 0.5, 1, or 2 mg. All participants were provided monthly, on-site behavioral weight maintenance counseling, as well as monthly phone calls. The primary end point was change in body weight from randomization to week 52. The randomized participants lost an average of 9.6 kg (9.5% of initial weight) during the 6-week LCD. The model-adjusted mean change in body weight during the subsequent 1 year was +1.7 kg for placebo, compared with -0.1, -0.6, and -1.2 kg for the taranabant 0.5, 1, and 2 mg doses, respectively (all P values ≤ 0.007 vs. placebo). The incidences of psychiatric-related adverse events, including irritability, were higher for taranabant 1 and 2 mg vs. placebo (P ≤ 0.038). In addition to reporting data on the safety and efficacy of taranabant, this study provides a method for studying the combination of lifestyle modification and pharmacotherapy for weight maintenance after diet-induced weight loss.

[Obesity: one of this century's greatest health challenge?]. / Adipositas: en af århundredets største sundhedsudfordringer?

The prevalence of overweight and obesity exceed 50% in many European countries. Obesity is responsible for 2-8% of all health costs and 10-13% of all deaths in Europe. Only a fraction of patients obtain a medically relevant weight loss of 5-10% through lifestyle intervention. Surgery is limited to severe obesity and is very costly; therefore pharmaceuticals are a relevant alternative. Such treatment is hampered by the lack of official guidelines and a relatively limited effect compared to the expectations of patients as well as medical staff. Guidelines and official subsidies are debated.

Weight loss, HbA1c reduction, and tolerability of cetilistat in a randomized, placebo-controlled phase 2 trial in obese diabetics: comparison with orlistat (Xenical).

The objective of this multicenter, randomized, double-blind study was to determine the efficacy and safety of cetilistat and orlistat relative to placebo in obese patients with type 2 diabetes, on metformin. Following a 2-week run-in, patients were randomized to placebo, cetilistat (40, 80, or 120 mg three times daily), or orlistat 120 mg t.i.d., for 12 weeks. The primary endpoint was absolute change in body weight from baseline. Secondary endpoints included other measures of obesity and glycemic control. Similar reductions in body weight were observed in patients receiving cetilistat 80 or 120 mg t.i.d. or 120 mg t.i.d. orlistat; these reductions were significant vs. placebo (3.85 kg, P = 0.01; 4.32 kg, P = 0.0002; 3.78 kg, P = 0.008). In the 40 mg t.i.d. and placebo groups, reductions were 2.94 kg, P = 0.958 and 2.86 kg, respectively. Statistically significant reductions in glycosylated hemoglobin (HbA(1c)) were noted. Cetilistat was well tolerated, and showed fewer discontinuations due to adverse events (AEs) than in the placebo and orlistat groups. Discontinuation in the orlistat group was significantly worse than in the 120 mg cetilistat and placebo groups and was entirely due to gastrointestinal (GI) AEs. Treatment with cetilistat 80 or 120 mg t.i.d., or with orlistat 120 mg t.i.d., significantly reduced body weight and improved glycemic control relative to placebo in obese diabetic patients. Cetilistat was well tolerated with the number of discontinuations due to AEs being similar to placebo.

Wholegrain vs. refined wheat bread and pasta. Effect on postprandial glycemia, appetite, and subsequent ad libitum energy intake in young healthy adults.

Wholegrain foods have received much attention in recent years, and have been proposed to play a role in energy regulation through lowering of postprandial glycemia and appetite. This randomized crossover single meal study in 16 young adults was conducted to test the effect of iso-caloric meals based on wholemeal wheat breads and pasta in comparison to similar refined wheat products on postprandial glycemia, appetite and ad libitum energy intake (EI). Test meals (50 g carbohydrates; 2MJ) consisted of refined wheat bread (RWB), wholegrain wheat bread (WWB), refined wheat pasta (RWP) and wholegrain wheat pasta (WWP) and were served after an overnight fast. Appetite ratings and blood glucose were assessed for 180 min after which an ad libitum lunch meal was served and EI measured. The 180 min glucose responses were similar for wholemeal and refined products, but pasta meals gave significantly lower glucose responses. Only RWP had a lower glycemic index compared to RWB. WWB, but not WWP, resulted in increased satiety and reduced hunger compared to RWB. Ad libitum EI did not differ. In conclusion, the results show that wholemeal breads increased satiety measures compared to their refined counterparts; however no significant effect on subsequent EI was observed.

Past and current body size affect validity of reported energy intake among middle-aged Danish men.

Our objectives were to estimate the degree of misreporting energy intake (EI) and analyze associations with previous BMI, current BMI, or both. The study was part of the Adiposity and Genetics Study follow-up study including 309 Danish men (age 40-65 y) originally sampled from the obligatory draft board examination. Height and weight were measured at the mean ages of 20 (draft board), 33, 44, and 49 y (current age). Obesity was categorized as BMI >or= 31 kg/m(2). Dietary intake for 7 d and physical activity (PA) level (PAL) were self-reported. Resting metabolic rate (RMR) was measured in a ventilated hood system. By comparing EI with energy expenditure and assuming energy balance, reporting accuracy (RA) was estimated as EI/(RMR.PAL). A plausibility interval was calculated to encompass specific variation components of EI, RMR, and PAL; the specific 95% plausibility interval was 1.00 +/- 0.35. Participants were categorized as underreporters (RA 1.35) of EI. The relation between RA and BMI was studied through linear regression analysis. Overall, the RA was (mean +/- SE) 0.76 +/- 0.01. Of 309 participants, 35% underreported and 7% overreported. Whether stratified for current BMI or draft board BMI, the obese men were more likely to underreport than those who were not obese. Among those currently not obese, underreporting was more prevalent among those who were obese at the draft board examination (44%) than among those who were not (21%). Regression analysis showed that both previous and current BMI and their combination were significantly associated with RA. Thus, underreporting of dietary intake seems to be associated with not only current BMI but also with current BMI in combination with previous BMI.

Polymorphisms of serotonin receptor 2A and 2C genes and COMT in relation to obesity and type 2 diabetes.

BACKGROUND: Candidate genes of psychological importance include 5HT2A, 5HT2C, and COMT, implicated in the serotonin, noradrenaline and dopamine pathways, which also may be involved in regulation of energy balance. We investigated the associations of single nucleotide polymorphisms (SNPs) of these genes with obesity and metabolic traits. METHODOLOGY/PRINCIPAL FINDINGS: In a population of 166 200 young men examined at the draft boards, obese men (n = 726, BMI> or =31.0 kg/m(2)) and a randomly selected group (n = 831) were re-examined at two surveys at mean ages 46 and 49 years (S-46, S-49). Anthropometric, physiological and biochemical measures were available. Logistic regression analyses were used to assess age-adjusted odds ratios. No significant associations were observed of 5HT2A rs6311, 5HT2C rs3813929 and COMT rs4680 with obesity, except that COMT rs4680 GG-genotype was associated with fat-BMI (OR = 1.08, CI = 1.01-1.16). The SNPs were associated with a number of physiological variables; most importantly 5HT2C rs3813929 T-allele was associated with glucose (OR = 4.56, CI = 1.13-18.4) and acute insulin response (OR = 0.65, CI = 0.44-0.94) in S-49. COMT rs4680 GG-genotype was associated with glucose (OR = 1.04, CI = 1.00-1.09). Except for an association between 5HT2A rs6311 and total-cholesterol at both surveys, significant in S-46 (OR = 2.66, CI = 1.11-6.40), no significant associations were observed for the other phenotypes. Significant associations were obtained when combined genotype of 5HT2C rs3813929 and COMT rs4680 were examined in relation to BMI (OR = 1.12, CI = 1.03-1.21), fat-BMI (OR = 1.22, CI = 1.08-1.38), waist (OR = 1.13, CI = 1.04-1.22), and cholesterol (OR = 5.60, CI = 0.99-31.4). Analyses of impaired glucose tolerance (IGT) and type 2 diabetes (T2D) revealed, a 12.3% increased frequency of 5HT2C rs3813929 T-allele and an 11.6% increased frequency of COMT rs4680 GG-genotype in individuals with IGT or T2D (chi(2), p = 0.05 and p = 0.06, respectively). Examination of the combined genotypes of 5HT2C and COMT showed a 34.0% increased frequency of IGT or T2D (chi(2), p = 0.01). CONCLUSIONS: The findings lend further support to the involvement of serotonin, noradrenaline and dopamine pathways on obesity and glucose homeostasis, in particular when combined genotype associations are explored.

Conjugated linoleic acids reduce body fat in healthy postmenopausal women.

Isomers of conjugated linoleic acids (CLA) reduce fat mass (FM) and increase insulin sensitivity in some, but not all, murine studies. In humans, this effect is still debatable. In this study, we compared the effect of 2 CLA supplements on total and regional FM assessed by dual energy X-ray absorptiometry, changes in serum insulin and glucose concentrations, and adipose tissue (AT) gene expression in humans. In a double-blind, parallel, 16-wk intervention, we randomized 81 healthy postmenopausal women to 1) 5.5 g/d of 40/40% of cis9,trans11-CLA (c9,t11-CLA) and trans10,cis12-CLA (t10,c12-CLA) (CLA-mix); 2) cis9, trans11-CLA (c9,t11-CLA); or 3) control (olive oil). We assessed all variables before and after the intervention. The CLA-mix group had less total FM (4%) and lower-body FM (7%) than the control (P = 0.02 and < 0.001, respectively). Post hoc analyses showed that serum insulin concentrations were greater in the CLA-mix group (34%) than the control group (P = 0.02) in the highest waist circumference tertile only. AT mRNA expression of glucose transporter 4, leptin, and lipoprotein lipase was lower, whereas expression of tumor necrosis factor-alpha was higher in the CLA-mix group than in the control group (P < 0.04). In conclusion, a 50:50 mixture of c9,t11- and t10,c12-CLA isomers resulted in less total and lower-body FM in postmenopausal women and greater serum insulin concentrations in the highest waist circumference tertile. Future research is needed to confirm the insulin desensitizing effect of the CLA mixture and the effect on the mRNA expression of adipocyte-specific genes in humans.

FTO gene associated fatness in relation to body fat distribution and metabolic traits throughout a broad range of fatness.

BACKGROUND: A common single nucleotide polymorphism (SNP) of FTO (rs9939609, T/A) is associated with total body fatness. We investigated the association of this SNP with abdominal and peripheral fatness and obesity-related metabolic traits in middle-aged men through a broad range of fatness present already in adolescence. METHODOLOGY/PRINCIPAL FINDINGS: Obese young Danish men (n = 753, BMI > or = 31.0 kg/m(2)) and a randomly selected group (n = 879) from the same population were examined in three surveys (mean age 35, 46 and 49 years, respectively). The traits included anthropometrics, body composition, oral glucose tolerance test, blood lipids, blood pressure, fibrinogen and aspartate aminotransferase. Logistic regression analysis was used to assess the age-adjusted association between the phenotypes and the odds ratios for the FTO rs9939609 (TT and TA genotype versus the AA genotype), for anthropometrics and body composition estimated per unit z-score. BMI was strongly associated with the AA genotype in all three surveys: OR = 1.17, p = 1.1*10(-6), OR = 1.20, p = 1.7*10(-7), OR = 1.17, p = 3.4*10(-3), respectively. Fat body mass index was also associated with the AA genotype (OR = 1.21, p = 4.6*10(-7) and OR = 1.21, p = 1.0*10(-3)). Increased abdominal fatness was associated with the AA genotype when measured as waist circumference (OR = 1.21, p = 2.2*10(-6) and OR = 1.19, p = 5.9*10(-3)), sagittal abdominal diameter (OR = 1.17, p = 1.3*10(-4) and OR = 1.18, p = 0.011) and intra-abdominal adipose tissue (OR = 1.21, p = 0.005). Increased peripheral fatness measured as hip circumference (OR = 1.19, p = 1.3*10(-5) and OR = 1.18, p = 0.004) and lower body fat mass (OR = 1.26, p = 0.002) was associated with the AA genotype. The AA genotype was significantly associated with decreased Stumvoll insulin sensitivity index (OR = 0.93, p = 0.02) and with decreased non-fasting plasma HDL-cholesterol (OR = 0.57, p = 0.037), but not with any other of the metabolic traits. However, all significant results for both body fat distribution and metabolic traits were explained by a mediating effect of total fat mass. CONCLUSION: The association of the examined FTO SNP to general fatness throughout the range of fatness was confirmed, and this association explains the relation between the SNP and body fat distribution and decreased insulin sensitivity and HDL-cholesterol. The SNP was not significantly associated with other metabolic traits suggesting that they are not derived from the general accumulation of body fat.

Comparison of the effects on insulin resistance and glucose tolerance of 6-mo high-monounsaturated-fat, low-fat, and control diets.

BACKGROUND: The effect of dietary fat and carbohydrate on glucose metabolism has been debated for decades. OBJECTIVE: The objective was to compare the effect of 3 ad libitum diets, different in type and amount of fat and carbohydrate, on insulin resistance and glucose tolerance subsequent to weight loss. DESIGN: Forty-six nondiabetic, obese [mean (+/-SEM) body mass index (in kg/m(2)): 31.2 +/- 0.3] men (n = 20) and premenopausal women (n = 26) aged 28.0 +/- 0.7 y were randomly assigned to 1 of 3 diets after > or = 8% weight loss: 1) MUFA diet (n = 16): moderate in fat (35-45% of energy) and high in monounsaturated fatty acids ( > 20% of energy); 2) LF diet (n = 18): low-fat diet (20-30% of energy), and 3) control diet (n = 12): 35% of energy as fat ( > 15% of energy as saturated fatty acids). Protein accounted for 15% of energy in all 3 diets. A 2-h oral-glucose-tolerance test (OGTT) was performed before and after the 6-mo dietary intervention. All foods were provided by a purpose-built supermarket. RESULTS: After 6 mo, the MUFA diet reduced fasting glucose (-3.0%), insulin (-9.4%), and the homeostasis model assessment of insulin resistance score (-12.1%). Compared with the MUFA diet, the control diet increased these variables [1.4% (P = 0.014), 21.2% (P = 0.030), and 22.8% (P = 0.015), respectively], as did the LF diet [1.4% (P = 0.090), 13.1% (P = 0.078), and 15.5% (P = 0.095), respectively]. No significant group differences were detected in glucose or insulin concentrations during the OGTT, in the Matsudas index, in body weight, or in body composition. CONCLUSION: A diet high in monounsaturated fat has a more favorable effect on glucose homeostasis than does the typical Western diet in the short term and may also be more beneficial than the official recommended low-fat diet during a period of weight regain subsequent to weight loss.