Continuous Calorie Restriction Research Articles

The impact of continuous calorie restriction and fasting on cognition in adults without eating disorders.

Research into the effects of calorie restriction continues to intrigue those interested in whether it may allow humans to live longer and healthier lives. Animal studies of continuous calorie restriction (CCR) and fasting have demonstrated substantial advantages to health and longevity. However, concerns remain about the impact of restricting calorie intake on human health and cognition. Given the emerging evidence of cognitive impairments in eating disorders, studies investigating restricted calorie intake in healthy humans (in an ethical way) may also have implications for understanding restrictive eating disorders. In this review, the published literature on the impact of CCR and fasting on cognitive function in healthy human participants is synthesized. Of the 33 studies of CCR and fasting in humans identified, 23 demonstrated significant changes in cognition. Despite variation across the cognitive domains, results suggest CCR benefits inhibition, processing speed, and working memory, but may lead to impairments in cognitive flexibility. The results of fasting studies suggest fasting is associated with impairments in cognitive flexibility and psychomotor abilities. Overall, the results of these studies suggest the degree (ie, the severity) of calorie restriction is what most likely predicts cognitive improvements as opposed to impairments. For individuals engaging in sustained restriction, this may have serious, irreversible consequences. However, there are mixed findings regarding the impact of CCR and fasting on this aspect of human functioning, suggesting further research is required to understand the costs and benefits of different types of calorie restriction.

Intermittent Fasting versus Calorie Defect Approach in Losing Weight: A Systematic Review

Background: Calorie restriction (CR) is the gold standard of treatment for treating overweight and obesity. Although this method results in only moderate weight reduction, weight rebound is frequent and CR adherence gradually deteriorates over time. IMF, or intermittent fasting, is a different nutritional approach, reduces calorie consumption. The study's objective is to assess the efficacy of continuous calorie restriction (CCR) with intermittent fasting in treating overweight and obese individuals. Methods: To find the pertinent literature, PubMed, Web of Science, Science Direct, Cochrane Library, and Google Scholar were exhaustively searched. The Rayyan QRCI was applied throughout this methodical procedure. Results: our review included eight studies with parameters including body mass index (BMI), age, insulin resistance, eating behavior and sleep quality. The studies investigated the role of intermittent fasting compared to the role of calorie restriction in losing weight. Conclusion: Our findings imply that CR positively improves metabolic parameters, assisting individuals who are insulin resistant and pre-diabetic. Additionally, IMF can improve health and cellular resilience to illness without calorie restriction and without causing weight loss. In terms of BMI, there was no discernible difference between IMF and CR. These results imply that IMF could be effective like CR for weight reduction.

Effect of 12-week intermittent calorie restriction compared to standard of care in patients with nonalcoholic fatty liver disease: a randomized controlled trial

BackgroundNonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. NAFLD can result in various complications. Owing to the lack of effective pharmacological therapies, lifestyle modifications are the cornerstone treatment for NAFLD. However, there has been no recommendation for a specific dietary therapy. Because no significant effects have been observed in previous studies. Intermittent calorie restriction (ICR) consists of alternating phases of extreme energy restriction and regular energy intake. Recent studies have demonstrated a significantly higher reduction in liver fat content in the ICR group than in the standard of care (SOC) or continuous calorie restriction groups in patients with NAFLD. However, critical weaknesses limit the broader application of ICR in clinical practice; those are a lack of appropriate assessment tools, different cutoffs of body mass index (BMI) used to define obesity, and different food portions. Thus, we report a protocol for a prospective, randomized controlled trial. The trial will evaluate the effect of 12-week ICR on improving liver fat content in NAFLD patients (Nonalcoholic Fatty Liver Disease-Intermittent Calorie Restriction [FLICR]).MethodsWe will include adult (19–75 years) NAFLD patients. NAFLD will be diagnosed by histologic assessment or magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥ 8%. A total of 72 patients will be classified according to BMI (obese group: BMI ≥ 25 kg/m2 [n = 36] and non-obese group: BMI < 25 kg/m2 [n = 36]). Participants will be followed up for 24 weeks. Participants will be randomly assigned to one of the two groups: the SOC or ICR group. The primary objective will be the change in liver fat content measured using MRI-PDFF from baseline to 12 weeks.DiscussionThis FLICR study may provide clinical evidence on ICR in the treatment of NAFLD in both obese and non-obese patients. The use of ICR in patients with NAFLD will improve the clinical outcomes of patients facing a shortage of effective medical therapy.Trial registrationThis trial was registered at the United States National Library of Medicine (NLM) at the National Institutes of Health. ClinicalTrials.gov NCT05309642. Registered on April 4, 2022.

Intermittent Fasting versus Continuous Calorie Restriction: Which Is Better for Weight Loss?

We conducted a systematic review and meta-analysis of randomized clinical trials and pilot trial studies to compare the effectiveness of intermittent fasting (IF) and continuous calorie restriction (CCR) in overweight and obese people. The parameters included body mass index (BMI), body weight, and other metabolism-related indicators. A systematic search in PubMed, Embase, Cochrane Library, and Web of Science was conducted up to January 2022. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were used to measure the effectiveness. Publication bias was assessed using Egger’s test. The stability of the results was evaluated using sensitivity analyses. The significance of body weight change (SMD = −0.21, 95% CI (−0.40, −0.02) p = 0.028) was more significant after IF than CCR. There was no significant difference in BMI (SMD = 0.02, 95% CI (−0.16, 0.20) p = 0.848) between IF and CCR. These findings suggest that IF may be superior to CCR for weight loss in some respects.

Calorie restriction improves metabolic state independently of gut microbiome composition: a randomized dietary intervention trial

BackgroundThe gut microbiota has been suggested to play a significant role in the development of overweight and obesity. However, the effects of calorie restriction on gut microbiota of overweight and obese adults, especially over longer durations, are largely unexplored.MethodsHere, we longitudinally analyzed the effects of intermittent calorie restriction (ICR) operationalized as the 5:2 diet versus continuous calorie restriction (CCR) on fecal microbiota of 147 overweight or obese adults in a 50-week parallel-arm randomized controlled trial, the HELENA Trial. The primary outcome of the trial was the differential effects of ICR versus CCR on gene expression in subcutaneous adipose tissue. Changes in the gut microbiome, which are the focus of this publication, were defined as exploratory endpoint of the trial. The trial comprised a 12-week intervention period, a 12-week maintenance period, and a final follow-up period of 26 weeks.ResultsBoth diets resulted in ~5% weight loss. However, except for Lactobacillales being enriched after ICR, post-intervention microbiome composition did not significantly differ between groups. Overall weight loss was associated with significant metabolic improvements, but not with changes in the gut microbiome. Nonetheless, the abundance of the Dorea genus at baseline was moderately predictive of subsequent weight loss (AUROC of 0.74 for distinguishing the highest versus lowest weight loss quartiles). Despite the lack of consistent intervention effects on microbiome composition, significant study group-independent co-variation between gut bacterial families and metabolic biomarkers, anthropometric measures, and dietary composition was detectable. Our analysis in particular revealed associations between insulin sensitivity (HOMA-IR) and Akkermansiaceae, Christensenellaceae, and Tanerellaceae. It also suggests the possibility of a beneficial modulation of the latter two intestinal taxa by a diet high in vegetables and fiber, and low in processed meat.ConclusionsOverall, our results suggest that the gut microbiome remains stable and highly individual-specific under dietary calorie restriction.Trial registrationThe trial, including the present microbiome component, was prospectively registered at ClinicalTrials.govNCT02449148 on May 20, 2015.

Evidence-based information about intermittent fasting in diabetes patients: useful or harmful?

One of the most important components of treatment for diabetic patients is diet and healthy nutrition therapy. Calorie restriction is effective and without cost increases its appeal for both patients and physicians. Unfortunately, continuous calorie restriction is a difficult method. For this reason, alternative calorie restriction methods, such as intermittent fasting (IF), have been investigated by some researchers. IF refers to a wide range of diet programmes covering periods of eating and fasting, which vary according to the different regimens. In this article, first, some general information will enable us to understand the concept of IF, and then scientific evidence with respect to IF applications in diabetes will be discussed in detail. Thereafter our clinical experience will be summarised, finally, the author will try to answer the question "are the IF applications beneficial or harmful for diabetic patients?" Considering animal studies, epidemiological studies, pilot studies, clinical experiences and a small number of randomized controlled trials conducted so far, it seems possible to say that the beneficial effects of IF for diabetes patients are greater than potential harms. However, there are not yet enough studies with a high level of evidence to recommend IF as a routine part of the treatment in patients with diabetes. It is necessary to show which IF regimen is safe and effective, how often and for how long, for diabetic patients. This seems possible with well-designed randomized controlled trials focusing on long-term clinical outcomes and eliminating confounding factors. This will make the answer clearer.

Adherence and Dietary Composition during Intermittent vs. Continuous Calorie Restriction: Follow-Up Data from a Randomized Controlled Trial in Adults with Overweight or Obesity.

Although intermittent calorie restriction (ICR) has become popular as an alternative weight loss strategy to continuous calorie restriction (CCR), there is insufficient evidence on diet quality during ICR and on its feasibility over longer time periods. Thus, we compared dietary composition and adherence between ICR and CCR in a follow-up analysis of a randomized trial. A total of 98 participants with overweight or obesity [BMI (kg/m2) 25–39.9, 35–65 years, 49% females] were randomly assigned to ICR, operationalized as a “5:2 diet” (energy intake: ~100% on five non-restricted (NR) days, ~25% on two restricted (R) days), or CCR (daily energy intake: ~80%). The trial included a 12-week (wk) intervention phase, and follow-up assessments at wk24, wk50 and wk102. Apart from a higher proportion of energy intake from protein with ICR vs. CCR during the intervention (wk2: p < 0.001; wk12: p = 0.002), there were no significant differences with respect to changes in dietary composition over time between the groups, while overall adherence to the interventions appeared to be good. No significant difference between ICR and CCR regarding weight change at wk102 was observed (p = 0.63). However, self-reported adherence was worse for ICR than CCR, with 71.1% vs. 32.5% of the participants reporting not to or only rarely have followed the regimen to which they were assigned between wk50 and wk102. These results indicate that within a weight management setting, ICR and CCR were equivalent in achieving modest weight loss over two years while affecting dietary composition in a comparable manner.

Abstract 14607: Randomized Controlled Trial of Once-Per-Week Intermittent Fasting for the Reduction of Low-Density Lipoprotein Cholesterol

Introduction: High-frequency intermittent fasting (IF) diets reduce weight similarly to continuous calorie restriction (CR). In patients with type 2 diabetes, twice-weekly IF and CR equivalently reduced HbA1c. IF may improve chronic disease risk factors, but no controlled trial has evaluated whether IF reduces low-density lipoprotein cholesterol (LDL-C), regardless of weight loss, in patients with elevated LDL-C. Hypothesis: The Weekly ONe-Day watER-only Fasting interventionaL (WONDERFUL) randomized (1:1) controlled trial (NCT02770313) tested whether IF reduced LDL-C compared to ad libitum control over 6 months. Methods: Subjects (N=103) were ages 21-70 years, not taking a statin, had elevated baseline LDL-C (90-189 mg/dL for ages 21-39, 90-159 mg/dL for ages 40-70, ≥90 mg/dL for statin intolerant/contraindicated), and had diet-controlled type 2 diabetes or ≥1 metabolic syndrome feature but no anti-diabetes medication. The water-only IF regimen was 4 weeks of 2/week 24-hour IF followed by 22 weeks of 1/week 24-hour IF. Exclusions included pregnant, lactating, or chronic disease (e.g., CAD, MI, stroke/TIA, CKD, COPD, cancer, PE, PAD, DVT, dementia, type 1 diabetes). Results: At baseline, IF (n=50) and control (n=53) were, respectively, 49.3±12.0 and 47.0±9.8 years of age, 66.0% and 67.9% females, weight 103±24 and 100±21 kg, and LDL-C 124±19 and 128±20 mg/dL. Lost to follow-up (n=5 IF, n=4 control) and withdrawals (n=7 IF, n=16 control) gave a final sample of n=71 (n=38 IF, n=33 control). LDL-C change from baseline to 6 months was not different between IF and control (Table). HOMA-IR, one of 4 pre-specified secondary endpoints, was improved (-0.75 vs. -0.10) at p≤0.01 vs. control (Table). Conclusions: A once-per-week IF regimen did not reduce LDL-C compared to control, but HOMA-IR was significantly reduced. This more sustainable IF regimen may reduce some chronic cardiometabolic disease risks (e.g., HOMA-IR) with minimal effects on cholesterol and weight.

Effect of intermittent versus continuous calorie restriction on body weight and cardiometabolic risk markers in subjects with overweight or obesity and mild-to-moderate hypertriglyceridemia: a randomized trial

BackgroundIntermittent calorie restriction (ICR) is a novel method of dietary restriction for body weight control with the potential to improve obesity-related cardiometabolic markers, but the impact of this diet on subjects with hypertriglyceridemia (HTG) remains unknown.MethodsEighty-eight subjects with overweight or obesity and mild-to-moderate HTG were randomized to the continuous calorie restriction (CCR) group, or ICR group (a very low-calorie diet during 3 days of the week) for 8 weeks (44 patients in each group). Body composition, plasma lipids, glucose, insulin, adiponectin, and liver enzymes were measured at baseline and after 8 weeks. An intention-to-treat analysis was performed.ResultsThe body weight decreased in both groups (4.07 ± 1.83 kg in the CCR group and 4.57 ± 2.21 kg in the ICR group) with no significant difference between the groups. There was no significant difference between the two groups in the reduced amount of fat mass, fat-free mass, and waist circumference. Both groups achieved a significant reduction in plasma triglycerides after 8 weeks (by 15.6 and 6.3% in ICR and CCR groups, respectively) with no difference between treatment groups. HOMA-IR improved significantly in ICR compared to the CCR group (P = 0.03). Plasma glucose, insulin, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, liver enzyme, and adiponectin were not different between the two groups.ConclusionsThe results of this short-term study suggest that three-days a week of the ICR is comparable to a CCR diet for the reduction of triglycerides level in patients with HTG and in the short-term it appears to be more effective than continuous dieting in improving insulin resistance. However, longer-term studies are needed to confirm these findings.Trial registrationTrial registration number:NCT04143971.

Determining the Fasting Length in Time-Restricted Feeding: Analysis of Endocrine Function Among Young, Healthy, Normal Weight, European Men

Abstract Objectives Intermittent calorie restriction has emerged as an effective alternative to continuous calorie restriction to impart favorable health benefits. However, there remains a degree of uncertainty about the optimal fasting length to simultaneously improve metabolic flexibility and promote positive behavior-change. While a 16-hr fast is commonly employed, it is possible that a shorter fast could result in similar metabolic benefits and better longer term adherence. Thus, we compared changes in hormone response between two 4-hr time intervals of fasting – 11–15 hrs. vs. 15–19 hrs. Methods Secondary analyses were performed from a 38-hr fasting study that enrolled 24 healthy, European men (18–30 y) with normal body mass index. Participants initiated a fast at 2300, arrived to the laboratory at 0800, and continued fasting in individual rooms. Venous blood was sampled at 13 time-points to measure insulin, glucose, adrenocorticotropin (ACTH), C-peptide, cortisol, and adiponectin via immunoassays. Data were normally distributed without outliers or missing values. Within-group differences were analyzed with paired t-tests. Results Insulin (pmol/L) declined between 11–15 hrs. (7.00; CI = 0.97, 13.02; P = .025), but not 15–19 hrs. (5.67; CI = –0.65, 11.98; P = .076). The decline in C-peptide (nmol/L) was sharper between 11–15 hrs. (0.09; CI = 0.05, 0.13; P = &amp;lt; .001), compared to 15–19 hrs. (0.06; CI = 0.02, 0.09; P = .003). Cortisol (nmol/L) also steeply declined between 11–15 hrs. (60.09; CI = 30.58, 89.59; P = &amp;lt; .001), but slightly increased between 15–19 hrs. (10.75; CI = −33.15, 11.65; P = 0.331). The change in glucose (mmol/L) was not different between 11–15 hrs. (0.02 mmol/L; CI = −0.15, 0.19; P = 0.784), but sharply decreased between 15–19 hrs. (0.24; CI = 0.10, 0.39; P = 0.002). No differences were detected for ACTH or adiponectin. Conclusions Though substrate oxidation was not measured, changes in insulin, C-peptide, cortisol, and glucose were consistent with increased gluconeogenesis during 11–15 hrs. and lipid oxidation during 15–19 hrs. of fasting. Whereas cortisol often declines throughout the day, a slight increase was noted between 15–19 hrs. – evidence of a heightened sympathetic activity. Further study of hormone response during intermittent fasting will inform optimal length to promote health benefits and longer term adherence. Funding Sources None

From the Literature

From the Literature

The Effectiveness of Intermittent Fasting to Reduce Body Mass Index and Glucose Metabolism: A Systematic Review and Meta-Analysis.

The effects of an intermittent fasting diet (IFD) in the general population are still controversial. In this study, we aimed to systematically evaluate the effectiveness of an IFD to reduce body mass index and glucose metabolism in the general population without diabetes mellitus. Cochrane, PubMed, and Embase databases were searched to identify randomized controlled trials and controlled clinical trials that compared an IFD with a regular diet or a continuous calorie restriction diet. The effectiveness of an IFD was estimated by the weighted mean difference (WMD) for several variables associated with glucometabolic parameters including body mass index (BMI) and fasting glucose. The pooled mean differences of outcomes were calculated using a random effects model. From 2814 studies identified through a literature search, we finally selected 12 articles (545 participants). Compared with a control diet, an IFD was associated with a significant decline in BMI (WMD, −0.75 kg/m2; 95% CI, −1.44 to −0.06), fasting glucose level (WMD, −4.16 mg/dL; 95% CI, −6.92 to −1.40), and homeostatic model assessment of insulin resistance (WMD, −0.54; 95% CI, −1.05 to −0.03). Fat mass (WMD, −0.98 kg; 95% CI, −2.32 to 0.36) tended to decrease in the IFD group with a significant increase in adiponectin (WMD, 1008.9 ng/mL; 95% CI, 140.5 to 1877.3) and a decrease in leptin (WMD, −0.51 ng/mL; 95% CI, −0.77 to −0.24) levels. An IFD may provide a significant metabolic benefit by improving glycemic control, insulin resistance, and adipokine concentration with a reduction of BMI in adults.

Comparison of glycemic improvement between intermittent calorie restriction and continuous calorie restriction in diabetic mice

BackgroundCalorie restriction (CR) has been well proved to be a powerful tool to improve metabolic health associated with aging; and many types of CR have been proposed. Intermittent CR has become a trend in recent years due to its better compliance than continuous CR every day. However, there are few studies that directly compare the interventional activity of intermittent CR vs continuous CR in metabolic disorders such as diabetes.MethodsIn this study, we analyzed two protocols of intermittent CR with the calorie-matched continuous CR in two diabetic mouse models including db/db and streptozotocin-treated mice. Intermittent CR was carried out by a fasting-mimicking diet (FMD, with 30% calorie intake of the control per day) for 2 days or 5 days (i.e., 2–5 or 5–9 regimes followed by free eating for 5 or 9 days respectively).ResultsIn the two diabetic mouse models, both intermittent CR and continuous CR significantly reduced fasting blood glucose level and improved insulin sensitivity. However, intermittent CR performed significantly better than continuous CR in improving glycemic control and insulin sensitivity in db/db mice. In addition, intermittent CR improved the glucose homeostasis of the db/db mice without causing loss of body weight. Analyses with the pancreatic islets reveal that intermittent CR profoundly elevated the number of insulin-positive cells in both diabetic mouse models.ConclusionsOur study indicated that both intermittent CR and continuous CR can lower fasting blood glucose level in the diabetic mice, while intermittent CR is better than the latter in improving glucose homeostasis in db/db mice.

Comparison of Glycemic Improvement Between Intermittent Calorie Restriction and Continuous Calorie Restriction in Diabetic Mice

Calorie restriction (CR) has been well proved to be a powerful tool to improve metabolic health associated with aging; and many types of CR have been proposed. Intermittent CR has become a trend in recent years due to its better compliance than continuous CR every day. However, there are few studies that directly compare the interventional efficacy of intermittent CR to continuous CR in metabolic disorders such as diabetes. In this study, we analyzed two regimes of intermittent CR with the calorie-matched continuous CR in two diabetic mouse models including db/db and streptozotocin-treated mice. Intermittent CR was carried out by a fasting-mimicking diet (FMD, with 30% calorie intake of the control per day) for 2 days or 5 days (i.e., 2-5 or 5-9 regimes followed by free eating for 5 or 9 days respectively). In the two diabetic mouse models, both intermittent CR and continuous CR significantly reduced fasting blood glucose level and improved insulin sensitivity. However, intermittent CR performed significantly better than continuous CR in improving glycemic control and insulin sensitivity in db/db mice. In addition, intermittent CR improved the glucose homeostasis of the db/db mice without causing loss of body weight. Analyses with the pancreatic islets reveal that intermittent CR profoundly elevated the number of insulin-positive cells in both diabetic mouse models. In conclusion, our study indicated that both intermittent CR and continuous CR can lower fasting blood glucose level in the diabetic mice, while intermittent CR is better than the latter in improving insulin sensitivity. Funding Statement: This study was supported by research grants from the National Natural Science Foundation of China (31630036 to Y.C.), the Ministry of Science and Technology of China (2016YFA0500103 to Y.C.), and the Chinese Academy of Sciences (XDA12010102, QYZDJ-SSW-SMC008, ZDRW-ZS-2016-8, and Y817X11141 to Y.C Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The animal experiments were conducted in accordance with the guidelines of the Institutional Animal Care and Use Committee of the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) with an approval number 2010-AN-8.

Key Genes of Lipid Metabolism and WNT-Signaling Are Downregulated in Subcutaneous Adipose Tissue with Moderate Weight Loss.

Smaller cross-sectional studies and bariatric surgery trials suggest that weight loss may change the expression of genes in adipose tissue that have been implicated in the development of metabolic diseases, but well-powered intervention trials are lacking. In post hoc analyses of data from a 12-week dietary intervention trial initially designed to compare metabolic effects of intermittent vs. continuous calorie restriction, we analyzed the effects of overall weight loss on the subcutaneous adipose tissue (SAT) transcriptome. Changes in the transcriptome were measured by microarray using SAT samples of 138 overweight or obese individuals (age range: 35–65 years, BMI range: 25–40, non-smokers, non-diabetics). Participants were grouped post hoc according to the degree of their weight loss by quartiles (average weight loss in quartiles 1 to 4: 0%, −3.2%, −5.9%, and −10.7%). Candidate genes showing differential expression with weight loss according to microarray analyses were validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR), and fold changes (FCs) were calculated to quantify differences in gene expression. A comparison of individuals in the highest vs. the lowest weight loss quartile revealed 681 genes to be differentially expressed (corrected p < 0.05), with 40 showing FCs of at least 0.4. Out of these, expression changes in secreted frizzled-related protein 2 (SFRP2, FC = 0.65, p = 0.006), stearoyl-CoA desaturase (SCD, FC = −1.00, p < 0.001), and hypoxia inducible lipid droplet-associated (HILPDA, FC = −0.45, p = 0.001) with weight loss were confirmed by RT-qPCR. Dietary weight loss induces significant changes in the expression of genes implicated in lipid metabolism (SCD and HILPDA) and WNT-signaling (SFRP2) in SAT.

Exercise is the Key to Keeping Weight Off, but What is the Key to Consistently Exercising?

In this issue of Obesity, Ostendorf et al. (1) employs modern measurement techniques and a creative cross-sectional design to expand findings from the landmark National Weight Control Registry study (2). Utilizing doubly labeled water, calorimetry, and physical activity monitoring devices, the authors examined the relative contributions of metabolism, physical activity, and caloric intake in long-term weight loss maintenance. To our knowledge, there are no available randomized studies that have a priori examined the contribution of physical activity in weight loss maintenance, leaving us with cross-sectional and nonrandomized study designs. The available data are consistent, however, in suggesting that physical activity plays a critical role in successful weight loss maintenance. Ostendorf et al. went one step further in attempting to determine the amount of activity required to maintain weight loss. They reported that successful weight loss maintainers achieve more than 12,000 steps per day and 800 kcal of total physical activity per day, and that they have a physical activity level (PAL) of 1.75 compared with approximately 9,000 steps per day, 600 kcal per day expended in activity, and a PAL of 1.6 in normal weight controls. The level of activity achieved by the weight loss maintainers is associated with 60 to 90 minutes of moderate-intensity physical activity or 30 to 40 minutes of vigorous-intensity activity. Regardless of the way it is quantified, the physical activity dose associated with weight loss maintenance is large and daunting. In addition and critically, the Ostendorf results are striking in that the weight loss maintainers did not appear to maintain their weight loss via continuous calorie restriction. Rather, the weight loss maintainers ate approximately the same number of calories per day as the control participants with overweight/obesity but had much higher energy burn from exercise. These findings beg the question, who are these individuals who can achieve large amounts of exercise on a consistent basis and what drives this behavior? Is their psychology or physiology different, or both? Does the energy flux or high amount of energy in and energy out affect their bodies in unique ways? Achieving the activity level observed in the weight loss maintainers is a significant time commitment; therefore, it is logical to conclude that this group of people may have tremendous discipline or willpower (e.g., type A exercisers), or they are driven to exercise for reasons other than weight management and weight loss maintenance is essentially a by-product of exercise. For example, we consistently hear people convey that they “exercise for their head, not the scale,” and it is well documented that regular exercise can lower stress, moderate anxiety, and improve overall quality of life (3) but with great individual variation in magnitude of response. Are the individuals who stick with their exercise program the same ones who receive substantial psychological benefit from exercising, and could this be a benefit that they become dependent on? The time required to maintain such high doses of exercise also suggests that these individuals may benefit from a supportive environment, which could include a supportive family and workplace, access to facilities/programs and available time to dedicate to them, and peers who support exercise and/or are exercise partners. The extent to which such environmental factors contribute to the success of these individuals is unclear, however, and it is also unclear to what extent these factors are malleable. This highlights the need for further research to identify the physiological, psychological, and environmental factors that help people successfully maintain weight loss through large amounts of exercise, as such research will help shape future weight loss maintenance strategies.

Effects of intermittent and continuous calorie restriction on body weight and metabolism over 50 wk: a randomized controlled trial

Although preliminary evidence suggests that intermittent calorie restriction (ICR) exerts stronger effects on metabolic parameters, which may link obesity and major chronic diseases, compared with continuous calorie restriction (CCR), there is a lack of well-powered intervention studies. We conducted a randomized controlled trial to test whether ICR, operationalized as the "5:2 diet," has stronger effects on adipose tissue gene expression, anthropometric and body composition measures, and circulating metabolic biomarkers than CCR and a control regimen. One hundred and fifty overweight and obese nonsmokers [body mass index (kg/m2) ≥25 to <40, 50% women], aged 35-65 y, were randomly assigned to an ICR group (5 d without energy restriction and 2 d with 75% energy deficit, net weekly energy deficit ∼20%), a CCR group (daily energy deficit ∼20%), or a control group (no advice to restrict energy) and participated in a 12-wk intervention phase, a 12-wk maintenance phase, and a 26-wk follow-up phase. Loge relative weight change over the intervention phase was -7.1%±0.7% (mean±SEM) with ICR, -5.2%±0.6% with CCR, and -3.3%±0.6% with the control regimen (Poverall<0.001, PICR vs. CCR=0.053). Despite slightly greater weight loss with ICR than with CCR, there were no significant differences between the groups in the expression of 82 preselected genes in adipose tissue implicated in pathways linking obesity to chronic diseases. At the final follow-up assessment (week 50), weight loss was -5.2%±1.2% with ICR, -4.9%±1.1% with CCR, and -1.7%±0.8% with the control regimen (Poverall=0.01, PICR vs. CCR=0.89). These effects were paralleled by proportional changes in visceral and subcutaneous adipose tissue volumes. There were no significant differences between ICR and CCR regarding various circulating metabolic biomarkers. Our results on the effects of the "5:2 diet" indicate that ICR may be equivalent but not superior to CCR for weight reduction and prevention of metabolic diseases. This trial was registered at clinicaltrials.gov as NCT02449148.

Intermittent calorie restriction enhances epithelial-mesenchymal transition through the alteration of energy metabolism in a mouse tumor model

The effect of intermittent calorie restriction (ICR) on cancer is controversial. In this study, we examined the effects of ICR and food content in syngeneic BALB/c mice injected with CT26 mouse colon cancer cells. Mice were subjected to 24-h fasting once a week for 4 weeks, and then provided with a control, high-calorie, or trans fatty acid-rich diet. While ICR resulted in increases in tumor weights, metastasis and in the number of cancer stem cells (CSCs) in the tumors or blood of mice fed the control and high-fat diets, it had no effect on body weight after 4 weeks. In particular, we detected increases in the numbers of CSCs in the tumor or blood on the day after starvation, when food overconsumption was detected. Conversely, continuous calorie restriction had no effect on tumor weight, metastasis, or the number of CSCs in tumors or blood. In the post-starvation period, energy metabolism in the tumor was altered from oxidative phosphorylation to glycolysis/lactate fermentation, with the acquisition of the epithelial-mesenchymal transition (EMT) phenotype. Hyperglycemia at the post-starvation period induced the expression of insulin-like growth factor-1, hypoxia-induced factor-1α and Nanog, as well as the phosphorylation of Stat3. Taken together, these findings suggest that ICR induces an increase in the number of CSCs and enhances EMT by promoting the Warburg/Crabtree effect following post-fasting food overconsumption.

The effects of intermittent calorie restriction on metabolic health: Rationale and study design of the HELENA Trial

Mechanistic studies suggest benefits of intermittent calorie restriction (ICR) in chronic disease prevention that may exceed those of continuous calorie restriction (CCR), even at equal net calorie intake. Despite promising results from first trials, it remains largely unknown whether ICR-induced metabolic alterations reported from experimental studies can also be observed in humans, and whether ICR diets are practicable and effective in real life situations. Thus, we initiated the HELENA Trial to test the effects of ICR (eu-caloric diet on five days and very low energy intake on two days per week) on metabolic parameters and body composition over one year. We will assess the effectiveness of ICR compared to CCR and a control diet over a 12-week intervention, 12-week maintenance phase and 24-week follow-up in 150 overweight or obese non-smoking adults (50 per group, 50% women). Our primary endpoint is the difference between ICR and CCR with respect to fold-changes in expression levels of 82 candidate genes in abdominal subcutaneous adipose tissue biopsies (SATb) during the intervention phase. The candidate genes represent pathways, which may link obesity-related metabolic alterations with the risk for major chronic diseases. In secondary and exploratory analyses, changes in metabolic, hormonal, inflammatory and metagenomic parameters measured in different biospecimens (SATb, blood, urine, stool) are investigated and effects of ICR/CCR/control on imaging-based measures of subcutaneous, visceral and hepatic fat are evaluated. Our study is the first randomized trial over one year testing the effects of ICR on metabolism, body composition and psychosocial factors in humans.

Proteome adaptation of Saccharomyces cerevisiae to severe calorie restriction in Retentostat cultures.

Stationary-phase, carbon-starved shake-flask cultures of Saccharomyces cerevisiae are popular models for studying eukaryotic chronological aging. However, their nutrient-starved physiological status differs substantially from that of postmitotic metazoan cells. Retentostat cultures offer an attractive alternative model system in which yeast cells, maintained under continuous calorie restriction, hardly divide but retain high metabolic activity and viability for prolonged periods of time. Using TMT labeling and UHPLC-MS/MS, the present study explores the proteome of yeast cultures during transition from exponential growth to near-zero growth in severely calorie-restricted retentostats. This transition elicited protein level changes in 20% of the yeast proteome. Increased abundance of heat shock-related proteins correlated with increased transcript levels of the corresponding genes and was consistent with a strongly increased heat shock tolerance of retentostat-grown cells. A sizable fraction (43%) of the proteins with increased abundance under calorie restriction was involved in oxidative phosphorylation and in various mitochondrial functions that, under the anaerobic, nongrowing conditions used, have a very limited role. Although it may seem surprising that yeast cells confronted with severe calorie restriction invest in the synthesis of proteins that, under those conditions, do not contribute to fitness, these responses may confer metabolic flexibility and thereby a selective advantage in fluctuating natural habitats.