Effect of Isocaloric, Time-Restricted Eating on Body Weight in Adults With Obesity : A Randomized Controlled Trial.

BACKGROUND: Time-restricted eating (TRE) lowers body weight in many studies. Whether TRE induces weight loss independent of reductions in calorie intake, as seen in rodent studies, is unknown. OBJECTIVE: To determine the effect of TRE versus a usual eating pattern (UEP) on body weight in the setting of stable caloric intake. DESIGN: Randomized, isocaloric feeding study. (ClinicalTrials.gov: NCT03527368). SETTING: Clinical research unit. PARTICIPANTS: Adults with obesity and prediabetes or diet-controlled diabetes. INTERVENTION: Participants were randomly assigned 1:1 to TRE (10-hour eating window, 80% of calories before 1 p.m.) or UEP (≤16-hour window, ≥50% of calories after 5 p.m.) for 12 weeks. Both groups had the same nutrient content and were isocaloric with total calories determined at baseline. MEASUREMENTS: Primary outcome was change in body weight at 12 weeks. Secondary outcomes were fasting glucose, homeostatic model assessment for insulin resistance (HOMA-IR), glucose area under the curve by oral glucose tolerance test, and glycated albumin. We used linear mixed models to evaluate the effect of interventions on outcomes. RESULTS: All 41 randomly assigned participants (mean age, 59 years; 93% women; 93% Black race; mean BMI, 36 kg/m2) completed the intervention. Baseline weight was 95.6 kg (95% CI, 89.6 to 101.6 kg) in the TRE group and 103.7 kg (CI, 95.3 to 112.0 kg) in the UEP group. At 12 weeks, weight decreased by 2.3 kg (CI, 1.0 to 3.5 kg) in the TRE group and by 2.6 kg (CI, 1.5 to 3.7 kg) in the UEP group (average difference TRE vs. UEP, 0.3 kg [CI, -1.2 to 1.9 kg]). Change in glycemic measures did not differ between groups. LIMITATION: Small, single-site study; baseline differences in weight by group. CONCLUSION: In the setting of isocaloric eating, TRE did not decrease weight or improve glucose homeostasis relative to a UEP, suggesting that any effects of TRE on weight in prior studies may be due to reductions in caloric intake. PRIMARY FUNDING SOURCE: American Heart Association.

A whole-food, plant-based intensive lifestyle intervention improves glycaemic control and reduces medications in individuals with type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: We conducted the largest and longest clinical trial comparing a whole-food, plant-based intervention with standard medical care (SMC) in individuals with type 2 diabetes. METHODS: We randomised (parallel-arm; computerised 1:1 randomisation ratio) 169 adults aged 18-75 years with type 2 diabetes in the Marshall Islands to an intensive whole-food, plant-based intervention with moderate exercise (PB+Ex) or SMC for 24 weeks. The PB+Ex intervention included 12 weeks of meals, exercise sessions and group classes. Primary outcomes were glycaemic control (HbA1c, glucose, insulin and HOMA-IR) and glucose-lowering medication use. Secondary outcomes included lipids, blood pressure, heart rate and C-reactive protein. Only lab analysts were blinded. RESULTS: Compared with SMC (n=90 randomised; n=70 analysed), the PB+Ex (n=79 randomised; n=66 analysed) intervention decreased HbA1c by an additional 14 mmol/mol (1.3%) at week 12 (-22 vs -7 mmol/mol [-2.0% vs -0.7%]; p<0.0001) and 8 mmol/mol (0.7%) at week 24 (-16 vs -8 mmol/mol [-1.4% vs -0.7%]; p=0.01). Concomitantly, 63% of medicated PB+Ex participants reduced their glucose-lowering medications (vs 24%; p=0.006), and 23% of PB+Ex participants with a baseline HbA1c <75 mmol/mol (<9%) achieved remission. Additionally, the PB+Ex intervention reduced weight (-2.7 kg; p<0.0001), C-reactive protein (-11 nmol/l; p=0.005) and cardiovascular medication use compared with SMC. At intermediate timepoints, it improved glucose, insulin, HOMA-IR, cholesterol, triglycerides and heart rate, but not at week 24. CONCLUSIONS/INTERPRETATION: A whole-food, plant-based lifestyle intervention was more effective for improving glycaemic control than SMC. It also reduced the need for diabetes and cardiovascular medications and induced diabetes remission in some participants. Therefore, it is an effective, evidence-based lifestyle option for individuals with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03862963 FUNDING: This research was funded by the Department of the Army (W81XWH-05-1-0547). CJH received support through a National Institutes of Health Predoctoral T32 Obesity Fellowship (T32 HL105349).

Video chat technology to remotely quantify dietary, supplement and medication adherence in clinical trials.

We conducted two studies to test the validity, reliability, feasibility and acceptability of using video chat technology to quantify dietary and pill-taking (i.e. supplement and medication) adherence. In study 1, we investigated whether video chat technology can accurately quantify adherence to dietary and pill-taking interventions. Mock study participants ate food items and swallowed pills, while performing randomised scripted 'cheating' behaviours to mimic non-adherence. Monitoring was conducted in a cross-over design, with two monitors watching in-person and two watching remotely by Skype on a smartphone. For study 2, a twenty-two-item online survey was sent to a listserv with more than 20 000 unique email addresses of past and present study participants to assess the feasibility and acceptability of the technology. For the dietary adherence tests, monitors detected 86 % of non-adherent events (sensitivity) in-person v. 78 % of events via video chat monitoring (P=0·12), with comparable inter-rater agreement (0·88 v. 0·85; P=0·62). However, for pill-taking, non-adherence trended towards being more easily detected in-person than by video chat (77 v. 60 %; P=0·08), with non-significantly higher inter-rater agreement (0·85 v. 0·69; P=0·21). Survey results from study 2 (n 1076 respondents; ≥5 % response rate) indicated that 86·4 % of study participants had video chatting hardware, 73·3 % were comfortable using the technology and 79·8 % were willing to use it for clinical research. Given the capability of video chat technology to reduce participant burden and outperform other adherence monitoring methods such as dietary self-report and pill counts, video chatting is a novel and promising platform to quantify dietary and pill-taking adherence.

Scaling of adult regional body mass and body composition as a whole to height: Relevance to body shape and body mass index.

OBJECTIVES: Adult body mass (MB) empirically scales as height (Ht) squared (MB ∝ Ht(2) ), but does regional body mass and body composition as a whole also scale as Ht(2) ? This question is relevant to a wide range of biological topics, including interpretation of body mass index (BMI). METHODS: Dual-energy X-ray absorptiometry (DXA) was used to quantify regional body mass [head (MH), trunk, arms, and legs] and whole-body composition [fat, lean soft tissue (LST), and bone mineral content (BMC)] in non-Hispanic (NH) white, NH black, Mexican American, and Korean adults participating in the National Health and Nutrition Examination Survey (NHANES; n = 17,126) and Korean NHANES (n = 8,942). Regression models were developed to establish Ht scaling powers for each measured component with adjustments for age and adiposity. RESULTS: Exploratory analyses revealed a consistent scaling pattern across men and women of the four population groups: regional mass powers, head (∼0.8-1) < arms and trunk (∼1.8-2.3) < legs (∼2.3-2.6); and body composition, LST (∼2.0-2.3) < BMC (∼2.1-2.4). Small sex and population differences in scaling powers were also observed. As body mass scaled uniformly across the eight sex and population groups as Ht(∼2) , tall and short subjects differed in body shape (e.g., MH/MB ∝ Ht(-∼1) ) and composition. CONCLUSIONS: Adult human body shape and relative composition are a function of body size as represented by stature, a finding that reveals a previously unrecognized phenotypic heterogeneity as defined by BMI. These observations provide new pathways for exploring mechanisms governing the interrelations between adult stature, body morphology, biomechanics, and metabolism.

International consensus on fasting terminology.

Although fasting is increasingly applied for disease prevention and treatment, consensus on terminology is lacking. Using Delphi methodology, an international, multidisciplinary panel of researchers and clinicians standardized definitions of various fasting approaches in humans. Five online surveys and a live online conference were conducted with 38 experts, 25 of whom completed all 5 surveys. Consensus was achieved for the following terms: "fasting" (voluntary abstinence from some or all foods or foods and beverages), "modified fasting" (restriction of energy intake to max. 25% of energy needs), "fluid-only fasting," "alternate-day fasting," "short-term fasting" (lasting 2-3 days), "prolonged fasting" (≥4 consecutive days), and "religious fasting." "Intermittent fasting" (repetitive fasting periods lasting ≤48 h), "time-restricted eating," and "fasting-mimicking diet" were discussed most. This study provides expert recommendations on fasting terminology for future research and clinical applications, facilitating communication and cross-referencing in the field.

Impact of early time-restricted eating on diet quality, meal frequency, appetite, and eating behaviors: A randomized trial.

OBJECTIVE: Time-restricted eating (TRE) can reduce body weight, but it is unclear how it influences dietary patterns and behavior. Therefore, this study assessed the effects of TRE on diet quality, appetite, and several eating behaviors. METHODS: Adults with obesity were randomized to early TRE plus energy restriction (eTRE + ER; 8-hour eating window from 7:00 a.m. to 3:00 p.m.) or a control eating schedule plus energy restriction (CON + ER; ≥12-hour window) for 14 weeks. Food intake was assessed via the Remote Food Photography Method, while eating patterns, appetite, and eating behaviors were assessed via questionnaires. RESULTS: A total of 59 participants completed the trial, of whom 45 had valid food records. eTRE + ER did not affect eating frequency, eating restraint, emotional eating, or the consistency of mealtimes relative to CON + ER. eTRE + ER also did not affect overall diet quality. The intensity and frequency of hunger and fullness were similar between groups, although the eTRE + ER group was hungrier while fasting. CONCLUSIONS: When combined with a weight-loss program, eTRE does not affect diet quality, meal frequency, eating restraint, emotional eating, or other eating behaviors relative to eating over more than a 12-hour window. Rather, participants implement eTRE as a simple timing rule by condensing their normal eating patterns into a smaller eating window.

Early time-restricted eating affects weight, metabolic health, mood, and sleep in adherent completers: A secondary analysis.

OBJECTIVE: Data are mixed on whether intermittent fasting improves weight loss and cardiometabolic health. Here, the effects of time-restricted eating (TRE) in participants who consistently adhered ≥5 d/wk every week were analyzed. METHODS: Ninety patients aged 25 to 75 years old with obesity were randomized to early TRE (eTRE; 8-hour eating window from 07:00 to 15:00) or a control schedule (≥12-hour window) for 14 weeks. A per-protocol analysis of weight loss, body composition, cardiometabolic health, and other end points was performed. RESULTS: Participants who adhered to eTRE ≥5 d/wk every week had greater improvements in body weight (-3.7 ± 1.2 kg; p = 0.003), body fat (-2.8 ± 1.3 kg; p = 0.04), heart rate (-7 ± 3 beats/min; p = 0.02), insulin resistance (-2.80 ± 1.36; p = 0.047), and glucose (-9 ± 5 mg/dL; p = 0.047) relative to adherers in the control group. They also experienced greater improvements in mood, including fatigue and anger; however, they self-reported sleeping less and taking longer to fall asleep. CONCLUSIONS: For those who can consistently adhere at least 5 d/wk, eTRE is a valuable approach for improving body weight, body fat, cardiometabolic health, and mood. Further research is needed to determine whether eTRE's effects of shortening sleep but reducing fatigue are healthful or not.

Understanding heterogeneity of responses to, and optimizing clinical efficacy of, exercise training in older adults: NIH NIA Workshop summary.

Exercise is a cornerstone of preventive medicine and a promising strategy to intervene on the biology of aging. Variation in the response to exercise is a widely accepted concept that dates back to the 1980s with classic genetic studies identifying sequence variations as modifiers of the VO2max response to training. Since that time, the literature of exercise response variance has been populated with retrospective analyses of existing datasets that are limited by a lack of statistical power from technical error of the measurements and small sample sizes, as well as diffuse outcomes, very few of which have included older adults. Prospective studies that are appropriately designed to interrogate exercise response variation in key outcomes identified a priori and inclusive of individuals over the age of 70 are long overdue. Understanding the underlying intrinsic (e.g., genetics and epigenetics) and extrinsic (e.g., medication use, diet, chronic disease) factors that determine robust versus poor responses to various exercise factors will be used to improve exercise prescription to target the pillars of aging and optimize the clinical efficacy of exercise training in older adults. This review summarizes the proceedings of the NIA-sponsored workshop entitled, "Understanding Heterogeneity of Responses to, and Optimizing Clinical Efficacy of, Exercise Training in Older Adults" and highlights the importance and current state of exercise response variation research, particularly in older adults, prevailing challenges, and future directions.

Feasibility and acceptability of time-restricted eating in a group of adults with multiple sclerosis.

Introduction: Intermittent fasting (IF) has become a popular dietary pattern for adults with multiple sclerosis (MS), and initial studies in animal models and human trials indicate promising results for improving symptoms and slowing disease progression. Most studies published to date have focused on alternate day fasting or fasting mimicking diets including a 5:2 pattern, in which participants greatly restrict calorie intake on two non-consecutive days and eat regularly on other days; however, time restricted eating (TRE) may be equally effective for improving symptoms and may lead to better long term adherence due to its focus only on the time of day in which calories are consumed with no restriction on number of calories or types of food consumed. Methods: The purpose of this pilot study was to determine the feasibility and acceptability of a TRE intervention in adults with relapsing remitting MS (RRMS). Participants (n = 12) were instructed to eat all food within an 8-h window every day and fast the remaining 16 h for 8 weeks. Results: The eating pattern was determined to be feasible based on retention rates (n = 11; 92%) and acceptable based on participant feedback. Discussion: Exploratory results of changes in cognition, pain, and fatigue, indicate that further study of TRE in this population is warranted. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04389970; NCT04389970.

Nightshift Work and Nighttime Eating Are Associated With Higher Insulin and Leptin Levels in Hospital Nurses.

Background: Circadian misalignment between behaviors such as feeding and endogenous circadian rhythms, particularly in the context of shiftwork, is associated with poorer cardiometabolic health. We examined whether insulin and leptin levels differ between dayshift versus nightshift nurses, as well as explored whether the timing of food intake modulates these effects in nightshift workers. Methods: Female nurses (N=18; 8 dayshift and 10 nightshift) completed daily diet records for 8 consecutive days. The nurses then completed a 24-h inpatient stay, during which blood specimens were collected every 3 h (beginning at 09:00) and meals were consumed at regular 3-h intervals (09:00, 12:00, 15:00, and 18:00). Specimens were analyzed for insulin and leptin levels, and generalized additive models were used to examine differences in mean insulin and leptin levels. Results: Mean insulin and leptin levels were higher in nightshift nurses by 11.6 ± 3.8 mU/L (p=0.003) and 7.4 ± 3.4 ng/ml (p=0.03), respectively, compared to dayshift nurses. In an exploratory subgroup analysis of nightshift nurses, predominately eating at night (21:00 - 06:00) was associated with significantly higher insulin and leptin levels than consuming most calories during the daytime (06:00 - 21:00). Conclusions: In our study of hospital nurses, working the nightshift was associated with higher insulin and leptin levels, and these effects were driven by eating predominately at night. We conclude that although nightshift work may raise insulin and leptin levels, eating during the daytime may attenuate some of the negative effects of nightshift work on metabolic health.

Effectiveness of Early Time-Restricted Eating for Weight Loss, Fat Loss, and Cardiometabolic Health in Adults With Obesity: A Randomized Clinical Trial.

Importance: It is unclear how effective intermittent fasting is for losing weight and body fat, and the effects may depend on the timing of the eating window. This randomized trial compared time-restricted eating (TRE) with eating over a period of 12 or more hours while matching weight-loss counseling across groups. Objective: To determine whether practicing TRE by eating early in the day (eTRE) is more effective for weight loss, fat loss, and cardiometabolic health than eating over a period of 12 or more hours. Design, Setting, and Participants: The study was a 14-week, parallel-arm, randomized clinical trial conducted between August 2018 and April 2020. Participants were adults aged 25 to 75 years with obesity and who received weight-loss treatment through the Weight Loss Medicine Clinic at the University of Alabama at Birmingham Hospital. Interventions: All participants received weight-loss treatment (energy restriction [ER]) and were randomized to eTRE plus ER (8-hour eating window from 7:00 to 15:00) or control eating (CON) plus ER (≥12-hour window). Main Outcomes and Measures: The co-primary outcomes were weight loss and fat loss. Secondary outcomes included blood pressure, heart rate, glucose levels, insulin levels, and plasma lipid levels. Results: Ninety participants were enrolled (mean [SD] body mass index, 39.6 [6.7]; age, 43 [11] years; 72 [80%] female). The eTRE+ER group adhered 6.0 (0.8) days per week. The eTRE+ER intervention was more effective for losing weight (-2.3 kg; 95% CI, -3.7 to -0.9 kg; P = .002) but did not affect body fat (-1.4 kg; 95% CI, -2.9 to 0.2 kg; P = .09) or the ratio of fat loss to weight loss (-4.2%; 95% CI, -14.9 to 6.5%; P = .43). The effects of eTRE+ER were equivalent to reducing calorie intake by an additional 214 kcal/d. The eTRE+ER intervention also improved diastolic blood pressure (-4 mm Hg; 95% CI, -8 to 0 mm Hg; P = .04) and mood disturbances, including fatigue-inertia, vigor-activity, and depression-dejection. All other cardiometabolic risk factors, food intake, physical activity, and sleep outcomes were similar between groups. In a secondary analysis of 59 completers, eTRE+ER was also more effective for losing body fat and trunk fat than CON+ER. Conclusions and Relevance: In this randomized clinical trial, eTRE was more effective for losing weight and improving diastolic blood pressure and mood than eating over a window of 12 or more hours at 14 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT03459703.

Membrane Capacitance from a Bioimpedance Approach: Associations with Insulin Resistance in Relatively Healthy Adults.

OBJECTIVE: This study aimed to determine whether higher membrane capacitance (CM ), a bioelectrical measure of cell membrane function, is associated with insulin resistance (IR) and/or metabolic syndrome (MetS). METHODS: Cross-sectional analyses were performed on 2,191 relatively healthy adults from the National Health and Nutrition Examination Survey. The CM of those with low/no disease risk was compared with those with IR, MetS, or both IR and MetS using ANCOVA. The associations between CM and related clinical measures were assessed with multiple linear regression. RESULTS: Compared with those with low/no risk, women and men with IR (P < 0.001) and IR + MetS (P < 0.001) had higher CM , whereas CM was similar in women (P = 0.4526) and men (P = 0.1126) with MetS alone. Positive associations with CM were seen with waist circumference (women and men standardized beta [STD-ß] = 0.18, P < 0.0001) and fasting insulin (women STD-ß = 0.15, P < 0.0001; men STD-ß = 0.12, P < 0.0001). CONCLUSIONS: Higher CM was associated with IR in relatively healthy adults. In the absence of IR, higher CM was not associated with MetS as defined by its clinical diagnostic criteria. This study suggests that with further investigation, CM may be a potential tool to detect IR-related cell membrane dysfunction.

Resistant Starch Has No Effect on Appetite and Food Intake in Individuals with Prediabetes.

BACKGROUND: Type 2 resistant starch (RS2) has been shown to improve metabolic health outcomes and may increase satiety and suppress appetite and food intake in humans. OBJECTIVE: This study assessed whether 12 weeks of daily RS2 supplementation could influence appetite perception, food intake, and appetite-related gut hormones in adults with prediabetes, relative to the control (CTL) group. DESIGN: The study was a randomized controlled trial and analysis of secondary study end points. PARTICIPANTS/SETTING: Sixty-eight adults (body mass index ≥27) aged 35 to 75 years with prediabetes were enrolled in the study at Pennington Biomedical Research Center (2012 to 2016). Fifty-nine subjects were included in the analysis. INTERVENTION: Participants were randomized to consume 45 g/day of high-amylose maize (RS2) or an isocaloric amount of the rapidly digestible starch amylopectin (CTL) for 12 weeks. MAIN OUTCOME MEASURES: Subjective appetite measures were assessed via visual analogue scale and the Eating Inventory; appetite-related gut hormones (glucagon-like peptide 1, peptide YY, and ghrelin) were measured during a standard mixed-meal test; and energy and macronutrient intake were assessed by a laboratory food intake (buffet) test, the Remote Food Photography Method, and SmartIntake app. STATISTICAL ANALYSES PERFORMED: Data were analyzed using linear mixed models, adjusting for treatment group and time as fixed effects, with a significance level of α=.05. RESULTS: RS2 had no effect on subjective measures of appetite, as assessed by visual analogue scale (P>0.05) and the Eating Inventory (P≥0.24), relative to the CTL group. There were no effects of RS2 supplementation on appetite-related gut hormones, including glucagon-like peptide 1 (P=0.61), peptide YY (P=0.34), and both total (P=0.26) and active (P=0.47) ghrelin compared with the CTL. RS2 had no effect on total energy (P=0.30), carbohydrate (P=0.11), protein (P=0.64), or fat (P=0.37) consumption in response to a buffet meal test, relative to the CTL. In addition, total energy (P=0.40), carbohydrate (P=0.15), protein (P=0.46), and fat (P=0.53) intake, as quantified by the Remote Food Photography Method, were also unaffected by RS2, relative to the CTL. CONCLUSIONS: RS2 supplementation did not increase satiety or reduce appetite and food intake in adults with prediabetes.

Therapeutic Time-restricted Feeding Reduces Renal Tumor Bioluminescence in Mice but Fails to Improve Anti-CTLA-4 Efficacy.

BACKGROUND/AIM: Dietary interventions like time-restricted feeding (TRF) show promising anti-cancer properties. We examined whether therapeutic TRF alone or combined with immunotherapy would diminish renal tumor growth in mice of varying body weights. MATERIALS AND METHODS: Young (7 week) chow-fed or older (27 week) high-fat diet (HFD)-fed BALB/c mice were orthotopically injected with renal tumor cells expressing luciferase. After tumor establishment, mice were randomized to ad libitum feeding or TRF +/- anti-CTLA-4. Body composition, tumor viability and growth, and immune responses were quantified. RESULTS: TRF alone reduced renal tumor bioluminescence in older HFD-fed, but not young chow-fed mice. In the latter, TRF mitigated tumor-induced loss of lean- and fat-mass. However, TRF did not alter excised renal tumor weights or intratumoral immune responses and failed to improve anti-CTLA-4 outcomes in any mice. CONCLUSION: Therapeutic TRF exhibits modest anti-cancer properties but fails to improve anti-CTLA-4 immune checkpoint blockade in murine renal cancer.

Short-term time-restricted feeding is safe and feasible in non-obese healthy midlife and older adults.

Chronic calorie restriction (CR) improves cardiovascular function and several other physiological markers of healthspan. However, CR is impractical in non-obese older humans due to potential loss of lean mass and bone density, poor adherence, and risk of malnutrition. Time-restricted feeding (TRF), which limits the daily feeding period without requiring a reduction in calorie intake, may be a promising alternative healthspan-extending strategy for midlife and older adults; however, there is limited evidence for its feasibility and efficacy in humans. We conducted a randomized, controlled pilot study to assess the safety, tolerability, and overall feasibility of short-term TRF (eating <8 h day-1 for 6 weeks) without weight loss in healthy non-obese midlife and older adults, while gaining initial insight into potential efficacy for improving cardiovascular function and other indicators of healthspan. TRF was safe and well-tolerated, associated with excellent adherence and reduced hunger, and did not influence lean mass, bone density, or nutrient intake. Cardiovascular function was not enhanced by short-term TRF in this healthy cohort, but functional (endurance) capacity and glucose tolerance were modestly improved. These results provide a foundation for conducting larger clinical studies of TRF in midlife and older adults, including trials with a longer treatment duration.

Targeting Glucose Metabolism to Enhance Immunotherapy: Emerging Evidence on Intermittent Fasting and Calorie Restriction Mimetics.

There is growing interest in harnessing lifestyle and pharmaceutical interventions to boost immune function, reduce tumor growth, and improve cancer treatment efficacy while reducing treatment toxicity. Interventions targeting glucose metabolism are particularly promising, as they have the potential to directly inhibit tumor cell proliferation. However, because anti-tumor immune effector cells also rely on glycolysis to sustain their clonal expansion and function, it remains unclear whether glucose-modulating therapies will support or hinder anti-tumor immunity. In this perspective, we summarize a growing body of literature that evaluates the effects of intermittent fasting, calorie restriction mimetics, and anti-hyperglycemic agents on anti-tumor immunity and immunotherapy outcomes. Based on the limited data currently available, we contend that additional pre-clinical studies and clinical trials are warranted to address the effects of co-administration of anti-hyperglycemic agents or glucose-lowering lifestyle modifications on anti-tumor immunity and cancer treatment outcomes. We stress that there is currently insufficient evidence to provide recommendations regarding these interventions to cancer patients undergoing immunotherapy. However, if found to be safe and effective in clinical trials, interventions targeting glucose metabolism could act as low-cost combinatorial adjuvants for cancer patients receiving immune checkpoint blockade or other immunotherapies.

Early Time-Restricted Feeding Reduces Appetite and Increases Fat Oxidation But Does Not Affect Energy Expenditure in Humans.

OBJECTIVE: Eating earlier in the daytime to align with circadian rhythms in metabolism enhances weight loss. However, it is unknown whether these benefits are mediated through increased energy expenditure or decreased food intake. Therefore, this study performed the first randomized trial to determine how meal timing affects 24-hour energy metabolism when food intake and meal frequency are matched. METHODS: Eleven adults with overweight practiced both early time-restricted feeding (eTRF) (eating from 8 am to 2 pm) and a control schedule (eating from 8 am to 8 pm) for 4 days each. On the fourth day, 24-hour energy expenditure and substrate oxidation were measured by whole-room indirect calorimetry, in conjunction with appetite and metabolic hormones. RESULTS: eTRF did not affect 24-hour energy expenditure (Δ = 10 ± 16 kcal/d; P = 0.55). Despite the longer daily fast (intermittent fasting), eTRF decreased mean ghrelin levels by 32 ± 10 pg/mL (P = 0.006), made hunger more even-keeled (P = 0.006), and tended to increase fullness (P = 0.06-0.10) and decrease the desire to eat (P = 0.08). eTRF also increased metabolic flexibility (P = 0.0006) and decreased the 24-hour nonprotein respiratory quotient (Δ = -0.021 ± 0.010; P = 0.05). CONCLUSIONS: Meal-timing interventions facilitate weight loss primarily by decreasing appetite rather than by increasing energy expenditure. eTRF may also increase fat loss by increasing fat oxidation.

Illustration of Measurement Error Models for Reducing Bias in Nutrition and Obesity Research Using 2-D Body Composition Data.

OBJECTIVE: This study aimed to illustrate the use and value of measurement error models for reducing bias when evaluating associations between body fat and having type 2 diabetes (T2D) or being physically active. METHODS: Logistic regression models were used to evaluate T2D and physical activity among adults aged 19 to 80 years from the Photobody Study (n = 558). Self-reported T2D and physical activity were categorized as "yes" or "no." Body fat measured by two-dimensional photographs was adjusted for bias using dual-energy x-ray absorptiometry scans as a reference. Three approaches were applied: regression calibration (RC), simulation extrapolation (SIMEX), and multiple imputation (MI). RESULTS: Unadjusted two-dimensional measures of body fat had upward biases of 30% and 233% for physical activity and T2D, respectively. For the physical activity model, RC-adjusted values had a 13% upward bias, whereas MI and SIMEX decreased the bias to 9% and 91%, respectively. For the T2D model, MI reduced the bias to 0%, whereas RC and SIMEX increased the upward bias to > 300%. CONCLUSIONS: Of three statistical approaches to reducing bias due to measurement errors, MI performed best in comparison to RC and SIMEX. Measurement error methods can improve the reliability of analyses that look for relations between body fat measures and health outcomes.

Early Time-Restricted Feeding Improves 24-Hour Glucose Levels and Affects Markers of the Circadian Clock, Aging, and Autophagy in Humans.

Time-restricted feeding (TRF) is a form of intermittent fasting that involves having a longer daily fasting period. Preliminary studies report that TRF improves cardiometabolic health in rodents and humans. Here, we performed the first study to determine how TRF affects gene expression, circulating hormones, and diurnal patterns in cardiometabolic risk factors in humans. Eleven overweight adults participated in a 4-day randomized crossover study where they ate between 8 am and 2 pm (early TRF (eTRF)) and between 8 am and 8 pm (control schedule). Participants underwent continuous glucose monitoring, and blood was drawn to assess cardiometabolic risk factors, hormones, and gene expression in whole blood cells. Relative to the control schedule, eTRF decreased mean 24-hour glucose levels by 4 ± 1 mg/dl (p = 0.0003) and glycemic excursions by 12 ± 3 mg/dl (p = 0.001). In the morning before breakfast, eTRF increased ketones, cholesterol, and the expression of the stress response and aging gene SIRT1 and the autophagy gene LC3A (all p < 0.04), while in the evening, it tended to increase brain-derived neurotropic factor (BNDF; p = 0.10) and also increased the expression of MTOR (p = 0.007), a major nutrient-sensing protein that regulates cell growth. eTRF also altered the diurnal patterns in cortisol and the expression of several circadian clock genes (p < 0.05). eTRF improves 24-hour glucose levels, alters lipid metabolism and circadian clock gene expression, and may also increase autophagy and have anti-aging effects in humans.