Acute and two-week effects of neotame, stevia rebaudioside M and sucrose-sweetened biscuits on postprandial appetite and endocrine response in adults with overweight/obesity-a randomised crossover trial from the SWEET consortium.

BACKGROUND: Sweeteners and sweetness enhancers (S&SE) are used to replace energy yielding sugars and maintain sweet taste in a wide range of products, but controversy exists about their effects on appetite and endocrine responses in reduced or no added sugar solid foods. The aim of the current study was to evaluate the acute (1 day) and repeated (two-week daily) ingestive effects of 2 S&SE vs. sucrose formulations of biscuit with fruit filling on appetite and endocrine responses in adults with overweight and obesity. METHODS: In a randomised crossover trial, 53 healthy adults (33 female, 20 male) with overweight/obesity in England and France consumed biscuits with fruit filling containing 1) sucrose, or reformulated with either 2) Stevia Rebaudioside M (StRebM) or 3) Neotame daily during three, two-week intervention periods with a two-week washout. The primary outcome was composite appetite score defined as [desire to eat + hunger + (100 - fullness) + prospective consumption]/4. FINDINGS: Each formulation elicited a similar reduction in appetite sensations (3-h postprandial net iAUC). Postprandial insulin (2-h iAUC) was lower after Neotame (95% CI (0.093, 0.166); p < 0.001; d = -0.71) and StRebM (95% CI (0.133, 0.205); p < 0.001; d = -1.01) compared to sucrose, and glucose was lower after StRebM (95% CI (0.023, 0.171); p < 0.05; d = -0.39) but not after Neotame (95% CI (-0.007, 0.145); p = 0.074; d = -0.25) compared to sucrose. There were no differences between S&SE or sucrose formulations on ghrelin, glucagon-like peptide 1 or pancreatic polypeptide iAUCs. No clinically meaningful differences between acute vs. two-weeks of daily consumption were found. INTERPRETATION: In conclusion, biscuits reformulated to replace sugar using StRebM or Neotame showed no differences in appetite or endocrine responses, acutely or after a two-week exposure, but can reduce postprandial insulin and glucose response in adults with overweight or obesity. FUNDING: The present study was funded by the Horizon 2020 program: Sweeteners and sweetness enhancers: Impact on health, obesity, safety and sustainability (acronym: SWEET, grant no: 774293).

Increases in physical activity are associated with a faster rate of weight loss during dietary energy restriction in women with overweight and obesity.

This secondary analysis examined the influence of changes in physical activity (PA), sedentary time and energy expenditure (EE) during dietary energy restriction on the rate of weight loss (WL) and 1-year follow-up weight change in women with overweight/obesity.Measurements of body weight and composition (air-displacement plethysmography), resting metabolic rate (indirect calorimetry), total daily (TDEE) and activity EE (AEE), minutes of PA and sedentary time (PA monitor) were taken at baseline, after 2 weeks, after ≥5% WL or 12 weeks of continuous (25% daily energy deficit) or intermittent (75% daily energy deficit alternated with ad libitum day) energy restriction, and at 1-year post-WL. The rate of WL was calculated as total %WL/number of dieting weeks. Data from both groups were combined for analyses.Thirty-seven participants (age=35±10y; BMI=29.1±2.3kg/m2) completed the intervention (WL=-5.9±1.6%) and 18 returned at 1-year post-WL (weight change=+4.5±5.2%). Changes in sedentary time at 2 weeks were associated with the rate of WL during energy restriction (r=-0.38; p=0.03). Changes in total (r=0.54; p<0.01), light (r=0.43; p=0.01) and moderate-to-vigorous PA (r=0.55; p<0.01), sedentary time (r=-0.52; p<0.01), steps per day (r=0.39; p=0.02), TDEE (r=0.46; p<0.01) and AEE (r=0.51; p<0.01) during energy restriction were associated with the rate of WL. Changes in total (r=-0.50; p=0.04) and moderate-to-vigorous PA (r=-0.61; p=0.01) between post-WL and follow-up were associated with 1-year weight change (r=-0.51; p=0.04).These findings highlight that PA and sedentary time could act as modifiable behavioural targets to promote better weight outcomes during dietary energy restriction and/or weight maintenance.

Evaluation of Existing QSAR Models and Structural Alerts and Development of New Ensemble Models for Genotoxicity Using a Newly Compiled Experimental Dataset.

Regulatory agencies world-wide face the challenge of performing risk-based prioritization of thousands of substances in commerce. In this study, a major effort was undertaken to compile a large genotoxicity dataset (54,805 records for 9299 substances) from several public sources (e.g., TOXNET, COSMOS, eChemPortal). The names and outcomes of the different assays were harmonized, and assays were annotated by type: gene mutation in Salmonella bacteria (Ames assay) and chromosome mutation (clastogenicity) in vitro or in vivo (chromosome aberration, micronucleus, and mouse lymphoma Tk +/- assays). This dataset was then evaluated to assess genotoxic potential using a categorization scheme, whereby a substance was considered genotoxic if it was positive in at least one Ames or clastogen study. The categorization dataset comprised 8442 chemicals, of which 2728 chemicals were genotoxic, 5585 were not and 129 were inconclusive. QSAR models (TEST and VEGA) and the OECD Toolbox structural alerts/profilers (e.g., OASIS DNA alerts for Ames and chromosomal aberrations) were used to make in silico predictions of genotoxicity potential. The performance of the individual QSAR tools and structural alerts resulted in balanced accuracies of 57-73%. A Naïve Bayes consensus model was developed using combinations of QSAR models and structural alert predictions. The 'best' consensus model selected had a balanced accuracy of 81.2%, a sensitivity of 87.24% and a specificity of 75.20%. This in silico scheme offers promise as a first step in ranking thousands of substances as part of a prioritization approach for genotoxicity.

Effects of oral semaglutide on energy intake, food preference, appetite, control of eating and body weight in subjects with type 2 diabetes.

AIM: To evaluate the effect of oral semaglutide on energy intake and appetite in subjects with type 2 diabetes (T2D). MATERIALS AND METHODS: In this randomized, double-blind, placebo-controlled, two-period cross-over trial, 15 subjects with T2D received 12 weeks of treatment with once-daily oral semaglutide (4-week dose escalation from 3 to 7 to 14 mg) followed by placebo, or vice versa. Energy intake was measured during an ad libitum lunch, evening meal and snack box after a standard breakfast. Appetite ratings were measured using a visual analogue scale after standard and fat-rich breakfasts. Other assessments included eating and craving control (using the Control of Eating Questionnaire), and changes in body weight and composition. RESULTS: Following a standard breakfast, total daily ad libitum energy intake was significantly lower (38.9%) with oral semaglutide versus placebo in 13 evaluable subjects (estimated treatment difference, -5096.0 kJ; 95% CI -7000.0, -3192.1; P = .0001). After a fat-rich breakfast, there were significant differences in favour of oral semaglutide versus placebo for measures of satiety, hunger and for overall appetite score, with no significant differences following a standard breakfast. Fewer food cravings and better eating control were seen with oral semaglutide versus placebo. Overall, mean body weight decreased by 2.7 kg with oral semaglutide and 0.1 kg with placebo, mostly attributable to body fat mass loss. CONCLUSION: After 12 weeks of treatment, ad libitum energy intake was lower with oral semaglutide versus placebo, resulting in reduced body fat mass, and was associated with increased satiety and fullness after a fat-rich breakfast, and improved eating control. TRIAL REGISTRATION NUMBER: NCT02773381.

Integrating publicly available information to screen potential candidates for chemical prioritization under the Toxic Substances Control Act: A proof of concept case study using genotoxicity and carcinogenicity.

The Toxic Substances Control Act (TSCA) became law in the U.S. in 1976 and was amended in 2016. The amended law requires the U.S. EPA to perform risk-based evaluations of existing chemicals. Here, we developed a tiered approach to screen potential candidates based on their genotoxicity and carcinogenicity information to inform the selection of candidate chemicals for prioritization under TSCA. The approach was underpinned by a large database of carcinogenicity and genotoxicity information that had been compiled from various public sources. Carcinogenicity data included weight-of-evidence human carcinogenicity evaluations and animal cancer data. Genotoxicity data included bacterial gene mutation data from the Salmonella (Ames) and Escherichia coli WP2 assays and chromosomal mutation (clastogenicity) data. Additionally, Ames and clastogenicity outcomes were predicted using the alert schemes within the OECD QSAR Toolbox and the Toxicity Estimation Software Tool (TEST). The evaluation workflows for carcinogenicity and genotoxicity were developed along with associated scoring schemes to make an overall outcome determination. For this case study, two sets of chemicals, the TSCA Active Inventory non-confidential portion list available on the EPA CompTox Chemicals Dashboard (33,364 chemicals, 'TSCA Active List') and a representative proof-of-concept (POC) set of 238 chemicals were profiled through the two workflows to make determinations of carcinogenicity and genotoxicity potential. Of the 33,364 substances on the 'TSCA Active List', overall calls could be made for 20,371 substances. Here 46.67%% (9507) of substances were non-genotoxic, 0.5% (103) were scored as inconclusive, 43.93% (8949) were predicted genotoxic and 8.9% (1812) were genotoxic. Overall calls for genotoxicity could be made for 225 of the 238 POC chemicals. Of these, 40.44% (91) were non-genotoxic, 2.67% (6) were inconclusive, 6.22% (14) were predicted genotoxic, and 50.67% (114) genotoxic. The approach shows promise as a means to identify potential candidates for prioritization from a genotoxicity and carcinogenicity perspective.

The compensatory effect of exercise on physical activity and energy intake in young men with overweight: The EFECT randomised controlled trial.

BACKGROUND: The compensatory effect of exercise on total volume of physical activity and food intake has been described as a possible explanation for the limited body weight loss observed during exercise interventions. OBJECTIVE: To investigate the effect of different exercise intensities on total volume of physical activity and energy intake amongst active men with overweight. DESIGN: Young men with overweight from a naval academy (n = 72; mean ± SD, age 21 ± 2 years, BMI 27.9 ± 2.13 kg/m2) were randomised to a control group (CG), moderate-intensity (MEG), or vigorous-intensity exercise group (VEG). MEG and VEG performed exercise sessions three times per week, for 60 min, during a 2-week period. Physical activity was assessed using triaxial accelerometers for 13 days. Energy intake was assessed at four time-points by 24-hour food recall. Intention-to-treat analyses were performed using linear mixed effect models. RESULTS: MEG and VEG presented a greater compensatory effect in the total volume of physical activity over time compared to CG, with a significant difference in the rate of change between VEG and CG (∆ = -250,503 counts vs. ∆ = -61,306 counts, respectively; p = 0.01), and MEG and CG (∆ = -253,336 counts vs. ∆ = -61,306 counts, respectively; p = 0.01). There was no difference between MEG and VEG (p = 0.97). Changes in energy intake were not different between groups (p = 0.18); however, MEG presented greater energy intake compared to CG (ß=491 kcal/day; p = 0.01) and VEG (ß=319 kcal/day; p = 0.07). VEG presented a greater reduction in body weight compared to MEG (-1.3 kg vs. -0.4 kg; p = 0.03) and CG (-1.3 kg vs. -0.6 kg; p = 0.07). CONCLUSIONS: Two weeks of exercise promoted a compensatory effect in total volume of physical activity in active men with overweight, regardless of exercise intensity. The compensatory effect was not observed for energy intake, although there was a trend for higher absolute energy intake in the MEG. Consequently, individuals in the VEG showed greater reduction in body weight over the intervention period.

The Key Characteristics of Carcinogens: Relationship to the Hallmarks of Cancer, Relevant Biomarkers, and Assays to Measure Them.

The key characteristics (KC) of human carcinogens provide a uniform approach to evaluating mechanistic evidence in cancer hazard identification. Refinements to the approach were requested by organizations and individuals applying the KCs. We assembled an expert committee with knowledge of carcinogenesis and experience in applying the KCs in cancer hazard identification. We leveraged this expertise and examined the literature to more clearly describe each KC, identify current and emerging assays and in vivo biomarkers that can be used to measure them, and make recommendations for future assay development. We found that the KCs are clearly distinct from the Hallmarks of Cancer, that interrelationships among the KCs can be leveraged to strengthen the KC approach (and an understanding of environmental carcinogenesis), and that the KC approach is applicable to the systematic evaluation of a broad range of potential cancer hazards in vivo and in vitro We identified gaps in coverage of the KCs by current assays. Future efforts should expand the breadth, specificity, and sensitivity of validated assays and biomarkers that can measure the 10 KCs. Refinement of the KC approach will enhance and accelerate carcinogen identification, a first step in cancer prevention.See all articles in this CEBP Focus section, "Environmental Carcinogenesis: Pathways to Prevention."

Proposed Key Characteristics of Male Reproductive Toxicants as an Approach for Organizing and Evaluating Mechanistic Evidence in Human Health Hazard Assessments.

BACKGROUND: Assessing chemicals for their potential to cause male reproductive toxicity involves the evaluation of evidence obtained from experimental, epidemiological, and mechanistic studies. Although mechanistic evidence plays an important role in hazard identification and evidence integration, the process of identifying, screening and analyzing mechanistic studies and outcomes is a challenging exercise due to the diversity of research models and methods and the variety of known and proposed pathways for chemical-induced toxicity. Ten key characteristics of carcinogens provide a valuable tool for organizing and assessing chemical-specific data by potential mechanisms for cancer-causing agents. However, such an approach has not yet been developed for noncancer adverse outcomes. OBJECTIVES: The objective in this study was to identify a set of key characteristics that are frequently exhibited by exogenous agents that cause male reproductive toxicity and that could be applied for identifying, organizing, and summarizing mechanistic evidence related to this outcome. DISCUSSION: The identification of eight key characteristics of male reproductive toxicants was based on a survey of known male reproductive toxicants and established mechanisms and pathways of toxicity. The eight key characteristics can provide a basis for the systematic, transparent, and objective organization of mechanistic evidence relevant to chemical-induced effects on the male reproductive system. https://doi.org/10.1289/EHP5045.

Issues in Measuring and Interpreting Human Appetite (Satiety/Satiation) and Its Contribution to Obesity.

PURPOSE OF REVIEW: The goals of this paper are to report current research practices in investigations of human appetite control and to assess their relationships with emerging theoretical principles. Appetite is often distinguished by the separation of homeostatic and hedonic processes. RECENT FINDINGS: This report assesses the validity of a homeostatic toolkit to measure subjectively perceived hunger and its relationship to the developing processes of satiation (control of meal size) and satiety (control of the post-eating period). The capacity of a procedure to measure the influence of hedonic processes on food intake is also evaluated. A major issue is the relationship between the pattern of eating behaviour (influenced by the underlying drive to eat and the inhibition induced by the act of eating itself) and the parallel underlying profile of hormonal and other metabolic biomarkers. Increasing recognition is being given to individual variability in the expression of appetite, and the fact that the use of the average (mean) response conceals important information about the nature of appetite control. There is a growing interest in the identification of satiety phenotypes that operate in parallel to metabolic phenotypes. Interestingly, energy expenditure (metabolic and behavioural) contributes to an energy balance framework for understanding energy intake (appetite).

Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity.

AIM: The aim of this trial was to investigate the mechanism of action for body weight loss with semaglutide. MATERIALS AND METHODS: This randomised, double-blind, placebo-controlled, two-period crossover trial investigated the effects of 12 weeks of treatment with once-weekly subcutaneous semaglutide, dose-escalated to 1.0 mg, in 30 subjects with obesity. Ad libitum energy intake, ratings of appetite, thirst, nausea and well-being, control of eating, food preference, resting metabolic rate, body weight and body composition were assessed. RESULTS: After a standardised breakfast, semaglutide, compared with placebo, led to a lower ad libitum energy intake during lunch (-1255 kJ; P < .0001) and during the subsequent evening meal ( P = .0401) and snacks ( P = .0034), resulting in a 24% reduction in total energy intake across all ad libitum meals throughout the day (-3036 kJ; P < .0001). Fasting overall appetite suppression scores were improved with semaglutide vs placebo, while nausea ratings were similar. Semaglutide was associated with less hunger and food cravings, better control of eating and a lower preference for high-fat foods. Resting metabolic rate, adjusted for lean body mass, did not differ between treatments. Semaglutide led to a reduction from baseline in mean body weight of 5.0 kg, predominantly from body fat mass. CONCLUSION: After 12 weeks of treatment, ad libitum energy intake was substantially lower with semaglutide vs placebo with a corresponding loss of body weight observed with semaglutide. In addition to reduced energy intake, likely mechanisms for semaglutide-induced weight loss included less appetite and food cravings, better control of eating and lower relative preference for fatty, energy-dense foods.

Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis.

BACKGROUND: A recent review by the International Agency for Research on Cancer (IARC) updated the assessments of the > 100 agents classified as Group 1, carcinogenic to humans (IARC Monographs Volume 100, parts A-F). This exercise was complicated by the absence of a broadly accepted, systematic method for evaluating mechanistic data to support conclusions regarding human hazard from exposure to carcinogens. OBJECTIVES AND METHODS: IARC therefore convened two workshops in which an international Working Group of experts identified 10 key characteristics, one or more of which are commonly exhibited by established human carcinogens. DISCUSSION: These characteristics provide the basis for an objective approach to identifying and organizing results from pertinent mechanistic studies. The 10 characteristics are the abilities of an agent to 1) act as an electrophile either directly or after metabolic activation; 2) be genotoxic; 3) alter DNA repair or cause genomic instability; 4) induce epigenetic alterations; 5) induce oxidative stress; 6) induce chronic inflammation; 7) be immunosuppressive; 8) modulate receptor-mediated effects; 9) cause immortalization; and 10) alter cell proliferation, cell death, or nutrient supply. CONCLUSION: We describe the use of the 10 key characteristics to conduct a systematic literature search focused on relevant end points and construct a graphical representation of the identified mechanistic information. Next, we use benzene and polychlorinated biphenyls as examples to illustrate how this approach may work in practice. The approach described is similar in many respects to those currently being implemented by the U.S. EPA's Integrated Risk Information System Program and the U.S. National Toxicology Program. CITATION: Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ, Lambert P, Hecht SS, Bucher JR, Stewart BW, Baan R, Cogliano VJ, Straif K. 2016. Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect 124:713-721; http://dx.doi.org/10.1289/ehp.1509912.

Human health effects of dichloromethane: key findings and scientific issues.

BACKGROUND: The U.S. EPA's Integrated Risk Information System (IRIS) completed an updated toxicological review of dichloromethane in November 2011. OBJECTIVES: In this commentary we summarize key results and issues of this review, including exposure sources, identification of potential health effects, and updated physiologically based pharmacokinetic (PBPK) modeling. METHODS: We performed a comprehensive review of primary research studies and evaluation of PBPK models. DISCUSSION: Hepatotoxicity was observed in oral and inhalation exposure studies in several studies in animals; neurological effects were also identified as a potential area of concern. Dichloromethane was classified as likely to be carcinogenic in humans based primarily on evidence of carcinogenicity at two sites (liver and lung) in male and female B6C3F1 mice (inhalation exposure) and at one site (liver) in male B6C3F1 mice (drinking-water exposure). Recent epidemiologic studies of dichloromethane (seven studies of hematopoietic cancers published since 2000) provide additional data raising concerns about associations with non-Hodgkin lymphoma and multiple myeloma. Although there are gaps in the database for dichloromethane genotoxicity (i.e., DNA adduct formation and gene mutations in target tissues in vivo), the positive DNA damage assays correlated with tissue and/or species availability of functional glutathione S-transferase (GST) metabolic activity, the key activation pathway for dichloromethane-induced cancer. Innovations in the IRIS assessment include estimation of cancer risk specifically for a presumed sensitive genotype (GST-theta-1+/+), and PBPK modeling accounting for human physiological distributions based on the expected distribution for all individuals 6 months to 80 years of age. CONCLUSION: The 2011 IRIS assessment of dichloromethane provides insights into the toxicity of a commonly used solvent.

The influence of physical activity on appetite control: an experimental system to understand the relationship between exercise-induced energy expenditure and energy intake.

Investigations of the impact of physical activity on appetite control have the potential to throw light on the understanding of energy balance and therefore, upon body weight regulation and the development of obesity. Given the complexity of the landscape influencing weight regulation,research strategies should reflect this complexity. We have developed a research approach based on the concept of the psychobiological system (multi-level measurement and analysis) and an experimental platform that respects the operations of an adaptive regulating biological system. It is important that both sides of the energy balance equation (activity and diet) receive similar detailed levels of analysis. The experimental platform uses realistic and fully supervised levels of physical activity, medium-term (not acute) interventions, measurement of body composition, energy metabolism (indirect calorimetry), satiety physiology(gut peptides), homeostatic and hedonic processes of appetite control, non-exercise activity, obese adult participants and both genders. This research approach has shown that the impact of physical activity on appetite control is characterised by large individual differences. Changes in body composition, waist circumference and health benefits are more meaningful than changes in weight. Further, we are realising that the acute effects do not predict what will happen in the longer term. The psychobiological systems approach offers a strategy for simultaneously investigating biological and behavioural processes relevant to understanding obese people and how obesity can be managed. This experimental platform provides opportunities for industry to examine the impact of foods under scientifically controlled conditions relevant to the real world.

Spontaneous and radiation-induced genomic instability in human cell lines differing in cellular TP53 status.

Structural chromosomal rearrangements are commonly observed in tumor karyotypes and in radiation-induced genomic instability. Here we report the effects of TP53 deficiency on karyotypic stability before and after irradiation using related cells and clones differing in cellular TP53 status. The parental cell line, TK6, is a TP53 wild-type human B-lymphoblastoid line with a highly stable karyotype. In the two TK6 derivatives used here, TP53 has been inactivated by biochemical means (expression of HPV16 E6; TK6-5E) or genetic means (allelic inactivation; NH32). Biochemical inactivation of TP53 (TK6-5E) had little effect on the spontaneous karyotype, whereas allelic inactivation of TP53 (NH32) resulted in a modest increase in spontaneous karyotypic instability. After 2 Gy gamma irradiation, the number of unstable clones derived from TP53-deficient cells was significantly elevated compared to the TP53 wild-type counterpart. Extensively destabilized clones were common after irradiation in the set of clones derived from NH32 cells, and one was observed in the set of TK6-5E clones; however, they were never observed in TK6-derived clones. In two of the irradiated NH32 clones, whole chromosomes or chromosome bands were preferentially involved in alterations. These results suggest that genomic instability may differ both quantitatively and qualitatively as a consequence of altered TP53 expression. Some of the results showing repeated and preferential chromosome involvement in aberrations support a model in which instability may be driven by cis mechanisms.