Effects Of Intermittent Calorie Restriction Research Articles

Effects of Intermittent Calorie Restriction in Nondiabetic Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease

Background & AimsWe compared the effects of a 12-week intermittent calorie restriction (ICR) and standard of care (SOC) diet on liver fat content (LFC) in metabolic dysfunction-associated steatotic liver disease (MASLD) patients. MethodsThis randomized controlled trial included patients with MRI-proton density fat fraction (PDFF) ≥8%. Patients were randomly assigned to the ICR (5:2 diet) or SOC (80% of the recommended calorie intake) groups and stratified according to the body mass index (≥ or <25 kg/m2). The primary outcome was the proportion of patients who achieved a relative LFC reduction as measured by MRI-PDFF ≥30%. ResultsSeventy-two participants underwent randomization (36 patients with and 36 without obesity), and 63 (34 patients with and 29 without obesity) completed the trial. At week 12, a higher proportion of patients in the ICR arm achieved a relative LFC reduction of ≥30% compared to the SOC arm (72.2% vs. 44.4%; P=0.033), which was more prominent in the group with obesity (61.1% vs. 27.7%; P=0.033) than in the group without obesity (83.3% vs. 61.1%; P=0.352). The relative weight reduction was insignificant between the ICR and SOC arms (-5.3% vs. -4.2%; P=0.273); however, it was higher in the ICR arm compared to the SOC arm (-5.5% vs. -2.9%; P=0.039) in the group with obesity. Changes in fibrosis, muscle and fat mass, and liver enzyme levels were similar between the two groups (all P>0.05). ConclusionsThe ICR diet reduced LFC more effectively than SOC in patients with MASLD, particularly in patients with obesity. Additional studies are warranted in larger and more diverse cohorts.

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.

Intermittent administration of a fasting-mimicking diet reduces intestinal inflammation and promotes repair to ameliorate inflammatory bowel disease in mice

Recent studies have revealed that calorie restriction is able to modulate immune system and aid in intervention of immune disorders. Inflammatory bowel disease (IBD) is an immune disease in the intestine caused by interplay between genetic susceptibility and environmental factors such as diets. Here we analyzed the therapeutic effect of intermittent calorie restriction with a fasting-mimicking diet (FMD) on dextran sodium sulfate (DSS)-induced chronic IBD model in mice. Two cycles of FMD was administered after IBD symptoms occurred in the mice. FMD administration significantly reduced the score of disease activity index. FMD reversed DSS-mediated shortening of colon length, infiltration of lymphocytes in the crypt of colon, and accumulation of CD4+ cells in the colon and small intestine. The expression of an inflammation marker NLRP3 was also reduced by FMD administration. The percentage of CD4+ T cells in both peripheral blood and spleen was also reduced by FMD. In addition, FMD application reversed DSS-mediated reduction in intestinal stem cell marker Lgr5, while the cell proliferation markers Ki67 and PCNA were increased by FMD. Taken together, these results indicate that in the mouse model of IBD, application of the FMD can effectively ameliorate the symptoms and pathogenesis of IBD through reducing the inflammation of intestine and promoting the regeneration and repair of the damaged intestinal epithelium.

Treatment of NAFLD with intermittent calorie restriction or low-carb high-fat diet – a randomised controlled trial

Background & AimsThe first-line treatment for non-alcoholic fatty liver disease (NAFLD) is weight reduction. Several diets have been proposed, with various effects specifically on liver steatosis. This trial compared the effects of intermittent calorie restriction (the 5:2 diet) and a low-carb high-fat diet (LCHF) on reduction of hepatic steatosis.MethodsWe conducted an open-label randomised controlled trial that included 74 patients with NAFLD randomised in a 1:1:1 ratio to 12 weeks’ treatment with either a LCHF or 5:2 diet, or general lifestyle advice from a hepatologist (standard of care; SoC). The primary outcome was reduction of hepatic steatosis as measured by magnetic resonance spectroscopy. Secondary outcomes included transient elastography, insulin resistance, blood lipids, and anthropometrics.ResultsThe LCHF and 5:2 diets were both superior to SoC treatment in reducing steatosis (absolute reduction: LCHF: −7.2% [95% CI = −9.3 to −5.1], 5:2: −6.1% [95% CI = −8.1 to −4.2], SoC: −3.6% [95% CI = −5.8 to −1.5]) and body weight (LCHF: −7.3 kg [95% CI = −9.6 to −5.0]; 5:2: −7.4 kg [95% CI = −8.7 to −6.0]; SoC: −2.5 kg [95% CI =−3.5 to −1.5]. There was no difference between 5:2 and LCHF (p = 0.41 for steatosis and 0.78 for weight). Liver stiffness improved in the 5:2 and SoC but not in the LCHF group. The 5:2 diet was associated with reduced LDL levels and was tolerated to a higher degree than LCHF.ConclusionsThe LCHF and 5:2 diets were more effective in reducing steatosis and body weight in patients with NAFLD than SoC, suggesting dietary advice can be tailored to meet individual preferences.Lay summaryFor a person with obesity who suffers from fatty liver, weight loss through diet can be an effective treatment to improve the condition of the liver. Many popular diets that are recommended for weight reduction, such as high-fat diets and diets based on intermittent fasting, have not had their effects on the liver directly evaluated. This study shows that both a low-carb high-fat and the 5:2 diet are effective in treating fatty liver caused by obesity.Clinical Trials RegistrationThis study is registered at Clinicaltrials.gov (NCT03118310).

Intermittent Administration of a Modified Fasting-Mimicking Diet Reduces Intestinal Inflammation and Promotes Repair to Ameliorate Inflammatory Bowel Disease in Mice

Recent studies have revealed that calorie restriction is able to modulate immune system and aid in intervention of immune disorders. Inflammatory bowel disease (IBD) is an immune disease in the intestine caused by interplay between genetic susceptibility and environmental factors such as diets. Here we analyzed the therapeutic effect of intermittent calorie restriction with a modified fasting-mimicking diet (FMD) on dextran sodium sulfate (DSS)-induced chronic IBD model in mice. Two cycles of FMD was administered after IBD symptoms occurred in the mice. FMD administration significantly reduced the score of disease activity index (DAI). FMD reversed DSS-mediated shortening of colon length, infiltration of lymphocytes in the crypt of colon, and accumulation of CD4+ cells in the colon and small intestine. The expression of an inflammation marker NLRP3 was also reduced by FMD administration. The percentage of CD4+ T cells in both peripheral blood and spleen was also reduced by FMD. In addition, FMD application reversed DSS-mediated reduction in intestinal stem cell marker Lgr5, while the cell proliferation markers Ki67 and PCNA were increased by FMD. Taken together, these results indicate that in the mouse model of IBD, application of a modified FMD can effectively ameliorate the symptoms and pathogenesis of IBD through reducing the inflammation of intestine and promoting the regeneration and repair of the damaged intestinal epithelium. 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 CAS Interdisciplinary Innovation Team to Y.C.). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: All animal experimental procedures were reviewed and authorized under the Institutional Animal Care and Use Committee (IACUC) guidelines of Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences with an approval number 2010-AN-8.

Effect of Intermittent Calorie Restriction on NAFLD Patients With Disorders of Glucose Metabolism

Effect of Intermittent Calorie Restriction on NAFLD Patients With Disorders of Glucose Metabolism

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.

Effects of intermittent calorie restriction on weight, fat mass, lean mass, visceral adipose tissue: Results from a pilot controlled-feeding study in multiple sclerosis patients (P3.390)

Effects of intermittent calorie restriction on weight, fat mass, lean mass, visceral adipose tissue: Results from a pilot controlled-feeding study in multiple sclerosis patients (P3.390)

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.

Abstract 1873: Effect of intermittent calorie restriction on cancer stem cells.

Abstract Effect of intermittent calorie restriction (ICR) on cancer is controversial. We then examined the effect of ICR and food contents on cancer using mouse model. CT26 mouse colon cancer cells were inoculated into the back of syngeneic BALB/c mouse. A 24 hours-fasting was performed once a week for 4 weeks. A control diet and a high calorie diet were used for feeding. The body weight at week 4 of mice was not different among control diet (Group C), control diet+ICR (Group CI) and high fat diet+ICR (Group FI). The tumor weight, nodal metastasis and CD133-positive cancer stem cells (CSC) in the tumor were more pronounced in Group CI and FI than those in Group C and F. Blood CD133 mRNA levels after fasting breakage were increased in Group CI and FI. We have reported the prometastatic effect of trans fatty acids in colorectal cancer. Here effect of oral intake of trans fatty acids on tumor stem cells with ICR was examined using the same model. Mice fed with 10% elaidic acid diet with ICR- (Group E) or ICR+ (Group EI) were compared with Group C and CI. The tumor weight and tumor MIB1 index was Group EI, Group E, Group CI and Group C in high order. In Group EI, nucleostemin (NS)-positive tumor cells were transiently increased on the next day of ICR. During 12 ICR cycle, NS-positive CSCs were gradually increased in Group EI. These findings suggest that ICR might enhance cancer stem cell-activating factors. Citation Format: Yi Luo, Yasuhiko Kitadai, Yoshitomo Chihara, Rina Fujiwara, Kiyohide Fujimoto, Hiroki Kuniyasu. Effect of intermittent calorie restriction on cancer stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1873. doi:10.1158/1538-7445.AM2013-1873

The protective effect of intermittent calorie restriction on mammary tumorigenesis is not compromised by consumption of a high fat diet during refeeding

Previously we reported that intermittent calorie restriction (ICR) provided greater prevention of mammary tumors (MTs) than chronic calorie restriction (CCR). Here the impact of increased fat intake during refeeding in an ICR protocol was evaluated. MMTV-TGF-α female mice were assigned to one of three groups: ad libitum (AL) fed (n=45) with free access to a moderately high fat diet (22% fat calories); ICR (n=45) 50% calorie restricted for 3-week intervals followed by 3 weeks of 100% of AL intake; and CCR (n=45) fed 75% of AL mice, matching each 6-week cycle of ICR mice. ICR mice were further designated as ICR-Restricted or ICR-Refed for data obtained during these intervals. All mice consumed the same absolute amount of dietary fat. Mice were followed to assess MT incidence, body weight and serum IGF-1, IGFBP3, leptin and adiponectin levels until 79 (end of final 3-week restriction) or 82 (end of final 3-weeks refeeding) weeks of age. Age of MT detection was significantly extended for CCR (74weeks) and ICR (82weeks) mice, compared to 57.5weeks for AL mice. MT incidence for AL, ICR and CCR mice was 66.7, 4.4, and 52.3%, respectively. Mammary and fat pad weights were reduced significantly following 50% calorie restriction in ICR-Restricted mice compared to AL, CCR and ICR-Refed mice. IGF-1 and leptin levels also tended to be reduced in ICR-Restricted mice over the course of the study while adiponectin was not compared to AL, CCR, and ICR-Refed mice. The adiponectin:leptin ratio was consistently higher following 50% restriction in ICR-Restricted mice. There was no relationship of IGF-1, leptin, or adiponectin with the presence of MTs in any groups. Thus the manner in which calories are restricted impacts the protective effect of calorie restriction independently of high fat intake.

Effect of Chronic and Intermittent Calorie Restriction on Serum Adiponectin and Leptin and Mammary Tumorigenesis

The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum adiponectin and leptin levels was investigated in relation to mammary tumorigenesis. 10-wks old MMTV-TGF-α female mice were assigned to ad libitum fed (AL; AIN-93M diet), ICR (3-week 50% caloric restriction, AIN-93M-mod diet, 2× protein, fat, vitamins, and minerals followed by 3-wks 100% AL consumption of AIN-93M), and CCR (calorie and nutrient intake matched for each 6-wks ICR cycle, ∼ 75% of AL) groups. Mice were sacrificed at 79 (end of restriction) or 82 (end of refeeding) wks of age. Serum was obtained in cycles 1, 3, 5, 8, 11, and terminal. Mammary tumor incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice, respectively. Serum adiponectin levels were similar among groups with no impact of either CCR or ICR. Serum leptin level rose in AL mice with increasing age but was significantly reduced by long-term CCR and ICR. The ICR protocol was also associated with an elevated adiponectin/leptin ratio. In addition, ICR-restricted mice had increased mammary tissue AdipoR1 expression and decreased leptin and ObRb expression compared with AL mice. Mammary fat pads from tumor-free ICR-mice had higher adiponectin expression than AL and CCR mice whereas all tumor-bearing mice had weak adiponectin signal in mammary fat pad. Although we did not show an association of either adiponectin or leptin with individual mice in relation to mammary tumorigenesis, we did find that reduced serum leptin and elevated adiponectin/leptin ratio were associated with the protective effect of intermittent calorie restriction.

Abstract A110: Protective effect of intermittent calorie restriction on mammary tumor development despite high-fat feeding

Abstract Intermittent caloric restriction (ICR) provides greater prevention of mammary tumor (MT) development than chronic caloric restriction (CCR). Here we assessed the impact of a high-fat diet on this protective effect in relation to serum IGF-I, leptin and adiponectin. At 10 wk of age MMTV-TGF-α female mice were assigned to AL (ad libitum 23% fat calories), ICR (3-wk of 50% caloric restriction with 2× protein, fat, vitamins and minerals followed by 3-wk of 100%AL mice's consumption) and CCR (calorie/nutrient intake matched to ICR for each 6-wk cycle) groups (n=45/group). Food intakes were determined daily. Body weights, MT palpation and MT measurements were done weekly. Mice were followed until MT burden necessitated euthanasia or they reached 79 (end of restriction) or 82 (end of refeeding) weeks of age. Serum samples were obtained at baseline, euthanasia and cycles 5, 8, and 11 during restriction and refeeding for ICR mice. Food intakes for ICR and CCR mice were 24.2% and 24.3% lower than AL mice (p&amp;lt;0.05). Body weights of ICR mice fluctuated in response to their calorie intake resulting in a significant difference among the groups. Final body, mammary and internal fat pad weights of AL mice were heaviest, followed by CCR and ICR-refed mice. ICR-restricted mice weights were the lowest. 66.7% of AL mice developed 1–5 MTs/mouse (grade 1–4). 52.3% of CCR mice had 1–3 MTs/mouse (grade 1–4). Only 4.4% of ICR mice developed 1 MT/mouse (grade 2). ICR-Restricted mice had significantly higher terminal serum IGFBP-3 and lower IGF-I and IGF-1/IGFBP-3 ratio than AL mice. There were no differences for CCR and ICR-Refed mice compared to either AL or ICR-Restricted groups. ICR-Restricted mice had significantly lower serum leptin and significantly higher terminal adiponectin and adiponectin/leptin ratio compared to AL, CCR and ICR-Refed mice. There were no differences in terminal serum measurements between mice with MTs versus those without MTs. IGF-I of AL and CCR mice did not change with age whereas for ICR mice IGF-1 was reduced during restriction periods. AL mice had the highest leptin levels across the study follow by CCR. For ICR mice leptin fluctuated in response to calorie intake, higher in refeeding vs restriction. Adiponectin levels for AL and CCR mice over time were similar. ICR mice had higher adiponectin levels when restricted vs refed. The adiponectin/leptin ratio of AL, CCR and ICR-refed mice was dramatically lower across the study compared with baseline but for ICR-restricted mice it was similar. These results indicate that ICR provides greater protection compared to CCR to prevent MT development even when a high fat diet is fed during refeeding. This was reflected by decreased MT incidence and MT burden and aggressiveness. Serum IGF-I, adiponectin and leptin were significantly affected by periods of 50% restriction providing a milieu conducive to reduced MT development. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A110.