Design and conduct of a randomized controlled feeding trial in a residential setting with mitigation for COVID-19.

BACKGROUND: Evaluating effects of different macronutrient diets in randomized trials requires well defined infrastructure and rigorous methods to ensure intervention fidelity and adherence. METHODS: This controlled feeding study comprised two phases. During a Run-in phase (14-15 weeks), study participants (18-50 years, BMI, ≥27 kg/m2) consumed a very-low-carbohydrate (VLC) diet, with home delivery of prepared meals, at an energy level to promote 15 ± 3% weight loss. During a Residential phase (13 weeks), participants resided at a conference center. They received a eucaloric VLC diet for three weeks and then were randomized to isocaloric test diets for 10 weeks: VLC (5% energy from carbohydrate, 77% from fat), high-carbohydrate (HC)-Starch (57%, 25%; including 20% energy from refined grains), or HC-Sugar (57%, 25%; including 20% sugar). Outcomes included measures of body composition and energy expenditure, chronic disease risk factors, and variables pertaining to physiological mechanisms. Six cores provided infrastructure for implementing standardized protocols: Recruitment, Diet and Meal Production, Participant Support, Assessments, Regulatory Affairs and Data Management, and Statistics. The first participants were enrolled in May 2018. Participants residing at the conference center at the start of the COVID-19 pandemic completed the study, with each core implementing mitigation plans. RESULTS: Before early shutdown, 77 participants were randomized, and 70 completed the trial (65% of planned completion). Process measures indicated integrity to protocols for weighing menu items, within narrow tolerance limits, and participant adherence, assessed by direct observation and continuous glucose monitoring. CONCLUSION: Available data will inform future research, albeit with less statistical power than originally planned.

Increased low-density lipoprotein cholesterol on a low-carbohydrate diet in adults with normal but not high body weight: A meta-analysis.

BACKGROUND: Low-density lipoprotein (LDL) cholesterol change with consumption of a low-carbohydrate diet (LCD) is highly variable. Identifying the source of this heterogeneity could guide clinical decision-making. OBJECTIVES: To evaluate LDL cholesterol change in randomized controlled trials involving LCDs, with a focus on body mass index (BMI) in kg/m2. METHODS: Three electronic indexes (Pubmed, EBSCO, and Scielo) were searched for studies between 1 January, 2003 and 20 December, 2022. Two independent reviewers identified randomized controlled trials involving adults consuming <130 g/d carbohydrate and reporting BMI and LDL cholesterol change or equivalent data. Two investigators extracted relevant data, which were validated by other investigators. Data were analyzed using a random-effects model and contrasted with results of pooled individual participant data. RESULTS: Forty-one trials with 1379 participants and a mean intervention duration of 19.4 wk were included. In a meta-regression accounting for 51.4% of the observed variability on LCDs, mean baseline BMI had a strong inverse association with LDL cholesterol change [ß = -2.5 mg/dL/BMI unit, 95% confidence interval (CI): -3.7, -1.4], whereas saturated fat amount was not significantly associated with LDL cholesterol change. For trials with mean baseline BMI <25, LDL cholesterol increased by 41 mg/dL (95% CI: 19.6, 63.3) on the LCD. By contrast, for trials with a mean of BMI 25-<35, LDL cholesterol did not change, and for trials with a mean BMI ≥35, LDL cholesterol decreased by 7 mg/dL (95% CI: -12.1, -1.3). Using individual participant data, the relationship between BMI and LDL cholesterol change was not observed on higher-carbohydrate diets. CONCLUSIONS: A substantial increase in LDL cholesterol is likely for individuals with low but not high BMI with consumption of an LCD, findings that may help guide individualized nutritional management of cardiovascular disease risk. As carbohydrate restriction tends to improve other lipid and nonlipid risk factors, the clinical significance of isolated LDL cholesterol elevation in this context warrants investigation. This trial was registered at PROSPERO as CRD42022299278.

Sugar-sweetened or artificially-sweetened beverage consumption, physical activity, and risk of cardiovascular disease in adults: a prospective cohort study.

BACKGROUND: Whether physical activity could mitigate the adverse impacts of sugar-sweetened beverages (SSBs) or artificially sweetened beverages (ASBs) on incident cardiovascular disease (CVD) remains uncertain. OBJECTIVES: This study aimed to examine the independent and joint associations between SSB or ASB consumption and physical activity and risk of CVD, defined as fatal and nonfatal coronary artery disease and stroke, in adults from 2 United States-based prospective cohort studies. METHODS: Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% CIs between SSB or ASB intake and physical activity with incident CVD among 65,730 females in the Nurses' Health Study (1980-2016) and 39,418 males in the Health Professional's Follow-up Study (1986-2016), who were free from chronic diseases at baseline. SSBs and ASBs were assessed every 4-y and physical activity biannually. RESULTS: A total of 13,269 CVD events were ascertained during 3,001,213 person-years of follow-up. Compared with those who never/rarely consumed SSBs or ASBs, the HR for CVD for participants consuming ≥2 servings/d was 1.21 (95% CI: 1.12, 1.32; P-trend < 0.001) for SSBs and 1.03 (95% CI: 0.97, 1.09; P-trend = 0.06) for those consuming ≥2 servings/d of ASBs. The HR for CVD per 1 serving increment of SSB per day was 1.18 (95% CI: 1.10, 1.26) and 1.12 (95% CI: 1.04, 1.20) for participants meeting and not meeting physical activity guidelines (≥7.5 compared with <7.5 MET h/wk), respectively. Compared with participants who met physical activity guidelines and never/rarely consumed SSBs, the HR for CVD was 1.47 (95% CI: 1.37, 1.57) for participants not meeting physical activity guidelines and consuming ≥2 servings/wk of SSBs. No significant associations were observed for ASB when stratified by physical activity. CONCLUSIONS: Higher SSB intake was associated with CVD risk regardless of physical activity levels. These results support current recommendations to limit the intake of SSBs even for physically active individuals.

Physiologic Adaptation to Macronutrient Change Distorts Findings from Short Dietary Trials: Reanalysis of a Metabolic Ward Study.

An influential 2-wk cross-over feeding trial without a washout period purported to show advantages of a low-fat diet (LFD) compared with a low-carbohydrate diet (LCD) for weight control. In contrast to several other macronutrient trials, the diet order effect was originally reported as not significant. In light of a new analysis by the original investigative group identifying an order effect, we aimed to examine, in a reanalysis of publicly available data (16 of 20 original participants; 7 female; mean BMI, 27.8 kg/m2), the validity of the original results and the claims that trial data oppose the carbohydrate-insulin model of obesity (CIM). We found that energy intake on the LCD was much lower when this diet was consumed first compared with second (a difference of -1164 kcal/d, P = 3.6 × 10-13); the opposite pattern was observed for the LFD (924 kcal/d, P = 2.0 × 10-16). This carry-over effect was significant (P interaction = 0.0004) whereas the net dietary effect was not (P = 0.4). Likewise, the between-arm difference (LCD - LFD) was -320 kcal/d in the first period and +1771 kcal/d in the second. Body fat decreased with consumption of the LCD first and increased with consumption of this diet second (-0.69 ± 0.33 compared with 0.57 ± 0.32 kg, P = 0.007). LCD-first participants had higher ß-hydroxybutyrate levels while consuming the LCD and lower respiratory quotients while consuming LFD when compared with LFD-first participants on their respective diets. Change in insulin secretion as assessed by C-peptide in the first diet period predicted higher energy intake and less fat loss in the second period. These findings, which tend to support rather than oppose the CIM, suggest that differential (unequal) carry-over effects and short duration, with no washout period, preclude causal inferences regarding chronic macronutrient effects from this trial.

Association between changes in carbohydrate intake and long term weight changes: prospective cohort study.

OBJECTIVE: To comprehensively examine the associations between changes in carbohydrate intake and weight change at four year intervals. DESIGN: Prospective cohort study. SETTING: Nurses' Health Study (1986-2010), Nurses' Health Study II (1991-2015), and Health Professionals Follow-Up Study (1986-2014). PARTICIPANTS: 136 432 men and women aged 65 years or younger and free of diabetes, cancer, cardiovascular disease, respiratory disease, neurodegenerative disorders, gastric conditions, chronic kidney disease, and systemic lupus erythematosus before baseline. MAIN OUTCOME MEASURE: Weight change within a four year period. RESULTS: The final analyses included 46 722 women in the Nurses' Health Study, 67 186 women in the Nurses' Health Study II, and 22 524 men in the Health Professionals Follow-up Study. On average, participants gained 1.5 kg (5th to 95th centile -6.8 to 10.0) every four years, amounting to 8.8 kg on average over 24 years. Among men and women, increases in glycemic index and glycemic load were positively associated with weight gain. For example, a 100 g/day increase in starch or added sugar was associated with 1.5 kg and 0.9 kg greater weight gain over four years, respectively, whereas a 10 g/day increase in fiber was associated with 0.8 kg less weight gain. Increased carbohydrate intake from whole grains (0.4 kg less weight gain per 100 g/day increase), fruit (1.6 kg less weight gain per 100 g/day increase), and non-starchy vegetables (3.0 kg less weight gain per 100 g/day increase) was inversely associated with weight gain, whereas increased intake from refined grains (0.8 kg more weight gain per 100 g/day increase) and starchy vegetables (peas, corn, and potatoes) (2.6 kg more weight gain per 100 g/day increase) was positively associated with weight gain. In substitution analyses, replacing refined grains, starchy vegetables, and sugar sweetened beverages with equal servings of whole grains, fruit, and non-starchy vegetables was associated with less weight gain. The magnitude of these associations was stronger among participants with overweight or obesity compared with those with normal weight (P<0.001 for interaction). Most of these associations were also stronger among women. CONCLUSIONS: The findings of this study highlight the potential importance of carbohydrate quality and source for long term weight management, especially for people with excessive body weight. Limiting added sugar, sugar sweetened beverages, refined grains, and starchy vegetables in favor of whole grains, fruit, and non-starchy vegetables may support efforts to control weight.

Carbohydrate-insulin model: does the conventional view of obesity reverse cause and effect?

Conventional obesity treatment, based on the First Law of Thermodynamics, assumes that excess body fat gain is driven by overeating, and that all calories are metabolically alike in this regard. Hence, to lose weight one must ultimately eat less and move more. However, this prescription rarely succeeds over the long term, in part because calorie restriction elicits predictable biological responses that oppose ongoing weight loss. The carbohydrate-insulin model posits the opposite causal direction: overeating doesn't drive body fat increase; instead, the process of storing excess fat drives overeating. A diet high in rapidly digestible carbohydrates raises the insulin-to-glucagon ratio, shifting energy partitioning towards storage in adipose, leaving fewer calories for metabolically active and fuel sensing tissues. Consequently, hunger increases, and metabolic rate slows in the body's attempt to conserve energy. A small shift in substrate partitioning though this mechanism could account for the slow but progressive weight gain characteristic of common forms of obesity. From this perspective, the conventional calorie-restricted, low-fat diet amounts to symptomatic treatment, failing to target the underlying predisposition towards excess fat deposition. A dietary strategy to lower insulin secretion may increase the effectiveness of long-term weight management and chronic disease prevention. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part II)'.

Low-fat diet Redux at WHO.

Worldwide dietary guidelines in the late 20th century promoted a low-fat diet, based, in part, on the notion that dietary fat, the most energy dense macronutrient, causes excess weight gain. However, high-quality evidence accumulating since then refute a direct association between dietary fat and adiposity. Moreover, substitution of carbohydrates for unsaturated fat can increase insulin resistance and cardiometabolic disease, especially among populations with highly prevalent insulin resistance. In this context, the recent WHO conditional recommendation to carry forward the guidance to limit dietary fat to ≤30% seems ill advised and should be reconsidered.

Sugar- or artificially-sweetened beverage consumption, physical activity, and risk of cardiovascular disease in US adults.

Background: The extent to which physical activity attenuates the detrimental effects of sugar (SSBs)- or artificially-sweetened beverages (ASBs) on the risk of cardiovascular disease is unknown. Methods: We used Cox proportional-hazards models to calculate hazard ratios and 95% confidence interval [HR (CI)] between SSB or ASB intake and physical activity with cardiovascular disease risk among 65,730 women in the Nurses' Health Study (1980-2016) and 39,418 men in the Health Professional's Follow-up Study (1986-2016), who were free from chronic diseases at baseline. SSBs and ASBs were assessed every 4-years and physical activity biannually. Results: A total of 13,269 cardiovascular events were ascertained during 3,001,213 person-years of follow-up. Compared with those that never/rarely consumed SSBs or ASBs, HR and 95% CI for cardiovascular disease for participants consuming ≥2 servings/day were 1.21 (95% CI,1.12 to 1.32; P-trend<0.001) and 1.03 (95% CI, 0.97 to 1.09; P-trend=0.06), respectively. In the joint analyses, for participants meeting and not meeting physical activity guidelines (<7.5 vs ≥7.5 MET-h/week) as well as consuming ≥2 servings/day of SSBs or ASBs, the HRs for cardiovascular disease were 1.15 (95% CI, 1.08 to 1.23) and 0.96 (95% CI, 0.91 to 1.02), and 1.47 (95% CI, 1.37 to 1.57) and 1.29 (95% CI, 1.22 to 1.37) respectively, compared with participants who met physical activity guidelines and never/rarely consumed these beverages. Similar patterns were observed when coronary heart disease and stroke were analyzed. Conclusions: Our findings suggest that among physically active participants, higher SSB intake, but not ASBs, is associated with a higher cardiovascular risk. Our results support current recommendations to limit the intake of SSB and maintain adequate physical activity levels.

Obesogens and Obesity: State-of-the-Science and Future Directions Summary from a Healthy Environment and Endocrine Disruptors Strategies Workshop.

On September 7 and 8, 2022, Healthy Environment and Endocrine Disruptors Strategies, an Environmental Health Sciences program, convened a scientific workshop of relevant stakeholders involved in obesity, toxicology, or obesogen research to review the state of the science regarding the role of obesogenic chemicals that might be contributing to the obesity pandemic. The workshop's objectives were to examine the evidence supporting the hypothesis that obesogens contribute to the etiology of human obesity; to discuss opportunities for improved understanding, acceptance, and dissemination of obesogens as contributors to the obesity pandemic; and to consider the need for future research and potential mitigation strategies. This report details the discussions, key areas of agreement, and future opportunities to prevent obesity. The attendees agreed that environmental obesogens are real, significant, and a contributor at some degree to weight gain at the individual level and to the global obesity and metabolic disease pandemic at a societal level; moreover, it is at least, in theory, remediable.

Childhood Obesity at the Crossroads of Science and Social Justice.

This Viewpoint considers the best approaches for treating obesity in youth and argues that better funding is needed for new dietary treatments and reimbursement for behavioral interventions.

Monitoring body composition change for intervention studies with advancing 3D optical imaging technology in comparison to dual-energy X-ray absorptiometry.

BACKGROUND: Recent 3-dimensional optical (3DO) imaging advancements have provided more accessible, affordable, and self-operating opportunities for assessing body composition. 3DO is accurate and precise in clinical measures made by DXA. However, the sensitivity for monitoring body composition change over time with 3DO body shape imaging is unknown. OBJECTIVES: This study aimed to evaluate the ability of 3DO in monitoring body composition changes across multiple intervention studies. METHODS: A retrospective analysis was performed using intervention studies on healthy adults that were complimentary to the cross-sectional study, Shape Up! Adults. Each participant received a DXA (Hologic Discovery/A system) and 3DO (Fit3D ProScanner) scan at the baseline and follow-up. 3DO meshes were digitally registered and reposed using Meshcapade to standardize the vertices and pose. Using an established statistical shape model, each 3DO mesh was transformed into principal components, which were used to predict whole-body and regional body composition values using published equations. Body composition changes (follow-up minus the baseline) were compared with those of DXA using a linear regression analysis. RESULTS: The analysis included 133 participants (45 females) in 6 studies. The mean (SD) length of follow-up was 13 (5) wk (range: 3-23 wk). Agreement between 3DO and DXA (R2) for changes in total FM, total FFM, and appendicular lean mass were 0.86, 0.73, and 0.70, with root mean squared errors (RMSEs) of 1.98 kg, 1.58 kg, and 0.37 kg, in females and 0.75, 0.75, and 0.52 with RMSEs of 2.31 kg, 1.77 kg, and 0.52 kg, in males, respectively. Further adjustment with demographic descriptors improved the 3DO change agreement to changes observed with DXA. CONCLUSIONS: Compared with DXA, 3DO was highly sensitive in detecting body shape changes over time. The 3DO method was sensitive enough to detect even small changes in body composition during intervention studies. The safety and accessibility of 3DO allows users to self-monitor on a frequent basis throughout interventions. This trial was registered at clinicaltrials.gov as NCT03637855 (Shape Up! Adults; https://clinicaltrials.gov/ct2/show/NCT03637855); NCT03394664 (Macronutrients and Body Fat Accumulation: A Mechanistic Feeding Study; https://clinicaltrials.gov/ct2/show/NCT03394664); NCT03771417 (Resistance Exercise and Low-Intensity Physical Activity Breaks in Sedentary Time to Improve Muscle and Cardiometabolic Health; https://clinicaltrials.gov/ct2/show/NCT03771417); NCT03393195 (Time Restricted Eating on Weight Loss; https://clinicaltrials.gov/ct2/show/NCT03393195), and NCT04120363 (Trial of Testosterone Undecanoate for Optimizing Performance During Military Operations; https://clinicaltrials.gov/ct2/show/NCT04120363).

Evidence for the carbohydrate-insulin model in a reanalysis of the Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) trial.

BACKGROUND: The Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) trial demonstrated that meaningful weight loss can be achieved with either a "healthy low-carbohydrate diet" (LCD) or "healthy low-fat diet" (LFD). However, because both diets substantially decreased glycemic load (GL), the dietary factors mediating weight loss remain unclear. OBJECTIVES: We aimed to explore the contribution of macronutrients and GL to weight loss in DIETFITS and examine a hypothesized relationship between GL and insulin secretion. DESIGN: This study is a secondary data analysis of the DIETFITS trial, in which participants with overweight or obesity (aged 18-50 y) were randomized to a 12-mo LCD (N = 304) or LFD (N = 305). RESULTS: Measures related to carbohydrate intake (total amount, glycemic index, added sugar, and fiber) showed strong associations with weight loss at 3-, 6-, and 12-mo time points in the full cohort, whereas those related to total fat intake showed weak to no associations. A biomarker of carbohydrate (triglyceride/HDL cholesterol ratio) predicted weight loss at all time points (3-mo: ß [kg/biomarker z-score change] = 1.1, P = 3.5 × 10-9; 6-mo: ß = 1.7, P = 1.1 × 10-9; and 12-mo: ß = 2.6, P = 1.5 × 10-15), whereas that of fat (low-density lipoprotein cholesterol + HDL cholesterol) did not (all time points: P = NS). In a mediation model, GL explained most of the observed effect of total calorie intake on weight change. Dividing the cohort into quintiles of baseline insulin secretion and GL reduction revealed evidence of effect modification for weight loss, with P = 0.0009 at 3 mo, P = 0.01 at 6 mo, and P = 0.07 at 12 mo. CONCLUSIONS: As predicted by the carbohydrate-insulin model of obesity, weight loss in both diet groups of DIETFITS seems to have been driven by the reduction of GL more so than dietary fat or calories, an effect that may be most pronounced among those with high insulin secretion. These findings should be interpreted cautiously in view of the exploratory nature of this study. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01826591).

Are methods of estimating fat-free mass loss with energy-restricted diets accurate?

BACKGROUND/OBJECTIVES: Fat-free mass (FFM) often serves as a body composition outcome variable in weight loss studies. An important assumption is that the proportions of components that make up FFM remain stable following weight loss; some body composition models rely on these "constants". This exploratory study examined key FFM component proportions before and following weight loss in two studies of participants with overweight and obesity. SUBJECTS/METHODS: 201 men and women consumed calorie-restricted moderate- or very-low carbohydrate diets leading to 10-18% weight loss in 9-15 weeks. Measured total body fat, lean mass, bone mineral, total body water (TBW), and body weight at baseline and follow-up were used to derive FFM and its chemical proportions using a four-component model. RESULTS: A consistent finding in both studies was a non-significant reduction in bone mineral and a corresponding increase (p < 0.001) in bone mineral/FFM; FFM density increased significantly in one group of women and in all four participant groups combined (both, p < 0.05). FFM hydration (TBW/FFM) increased in all groups of men and women, one significantly (p < 0.01), and in the combined sample (borderline, p < 0.10). The proportion of FFM as protein decreased across all groups, two significantly (p < 0.05-0.01) and in the combined sample (p < 0.05). CONCLUSION: FFM relative proportions of chemical components may not be identical before and after short-term weight loss, an observation impacting some widely used body composition models and methods. Caution is thus needed when applying FFM as a safety signal or to index metabolic evaluations in clinical trials when these body composition approaches are used.

Competing paradigms of obesity pathogenesis: energy balance versus carbohydrate-insulin models.

The obesity pandemic continues unabated despite a persistent public health campaign to decrease energy intake ("eat less") and increase energy expenditure ("move more"). One explanation for this failure is that the current approach, based on the notion of energy balance, has not been adequately embraced by the public. Another possibility is that this approach rests on an erroneous paradigm. A new formulation of the energy balance model (EBM), like prior versions, considers overeating (energy intake > expenditure) the primary cause of obesity, incorporating an emphasis on "complex endocrine, metabolic, and nervous system signals" that control food intake below conscious level. This model attributes rising obesity prevalence to inexpensive, convenient, energy-dense, "ultra-processed" foods high in fat and sugar. An alternative view, the carbohydrate-insulin model (CIM), proposes that hormonal responses to highly processed carbohydrates shift energy partitioning toward deposition in adipose tissue, leaving fewer calories available for the body's metabolic needs. Thus, increasing adiposity causes overeating to compensate for the sequestered calories. Here, we highlight robust contrasts in how the EBM and CIM view obesity pathophysiology and consider deficiencies in the EBM that impede paradigm testing and refinement. Rectifying these deficiencies should assume priority, as a constructive paradigm clash is needed to resolve long-standing scientific controversies and inform the design of new models to guide prevention and treatment. Nevertheless, public health action need not await resolution of this debate, as both models target processed carbohydrates as major drivers of obesity.