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[The below paper is pdf-availed.]

Significant Improvement in Cardiometabolic Health in Healthy Non-Obese Individuals during Caloric Restriction-induced Weight Loss and Weight Loss Maintenance.

Most J, Gilmore LA, Smith SR, Han H, Ravussin E, Redman LM.

Am J Physiol Endocrinol Metab. 2017 Dec 12. doi: 10.1152/ajpendo.00261.2017. [Epub ahead of print]

PMID: 29351490

Abstract

Caloric restriction (CR) triggers benefits for healthspan including decreased risk of cardiometabolic disease. In an ancillary study to CALERIE 2, a 24-month 25% CR study, we assessed the cardiometabolic effects of CR in 53 non-obese (BMI: 22-28 kg/m2) men (n=17) and women (n=36). According to the energy-balance method (doubly labeled water and changes in body energy stores), the 25% CR intervention (n=34) produced 17{plus minus}1% (mean{plus minus}SE) and 14{plus minus}1% CR after 12 and 24 months (M12, M24), resulting in significant weight loss (M12: -9{plus minus}0.5; M24: -9{plus minus}0.5, kg; P<0.001). Weight was maintained in the control group whom continued their habitual diet ad libitum (AL, n=19). In comparison to AL, 24 months of CR resulted in a decrease in visceral (-0.5{plus minus}0.01 kg; P<0.0001) and subcutaneous abdominal fat depots (-1.9{plus minus}0.2kg; P<0.001) as well as intramyocellular lipid content (-0.11{plus minus}0.05%; P=0.031). Furthermore, CR decreased blood pressure (SBP: -8{plus minus}3 mmHg; P=0.005 and DBP: -6{plus minus}2 mmHg; P<0.001), total cholesterol (-13.6{plus minus}5.3 mg/dL; P=0.001) and LDL-cholesterol (-12.9{plus minus}4.4 mg/dL; P=0.005). HOMA-IR decreased during weight loss in the CR group (-0.46{plus minus}0.15, P=0.003), but this decrease was not maintained during weight maintenance (-0.11{plus minus}0.15, P=0.458). In conclusion, CR in normal weight and healthy individuals is beneficial in improving risk factors for cardiovascular and metabolic disease such as visceral adipose tissue mass, ectopic lipid accumulation, blood pressure, lipid profile, whereas improvements in insulin sensitivity were only transient.

KEYWORDS:

Caloric Restriction; Cardiometabolic Health; Ectopic Fat Accumulation; Physical Fitness; Visceral Adipose Tissue

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Erythrocytes and Skeletal Muscle Unsaturated and Omega-6 Fatty Acids Are Positively Correlated after Caloric Restriction and Exercise.

Martorell M, Pons V, Domingo JC, Capó X, Sureda A, Drobnic F, Tur JA, Pons A.

Ann Nutr Metab. 2018 Jan 19;72(2):126-133. doi: 10.1159/000486553. [Epub ahead of print]

PMID: 29353271

Abstract

BACKGROUND:

Nutritional intervention studies with fatty acid (FA) supplements assess the efficacy of the intervention by measuring the changes in erythrocyte membrane lipid profiles reflected in tissue composition changes. The aim was to determine the effects of caloric restriction (CR) on erythrocytes lipid composition and to compare and correlate these changes with skeletal muscle acid profiles after CR.

METHODS:

Erythrocytes were obtained from 11 healthy men before and after 4 weeks of 33% CR in post-exercise conditions; muscle biopsies were obtained from the same athletes after 4 weeks of 33% CR in post-exercise conditions. Samples were used for FA determination by chromatography.

RESULTS:

CR significantly modified erythrocyte FAs composition. Skeletal muscle FA profile was significantly different from that for the erythrocytes. The erythrocyte FA profile was more saturated (52.1 ± 1.5% and 32.8 ± 0.9%, respectively) and less monounsaturated (21.0 ± 0.8% and 39.0 ± 2.0%, respectively) than the skeletal muscle FA profile and similarly polyunsaturated.

CONCLUSIONS:

CR modifies erythrocyte lipid composition, mainly omega-6 FAs. Erythrocyte monounsaturated, polyunsaturated and omega-6 FAs, but not the saturated and omega-3 FAs, were significantly positively correlated with skeletal muscle FAs. There is a discordance between saturated and omega-3 FAs from erythrocyte and from muscle, but monounsaturated, polyunsaturated and omega-6 fatty acids are positively correlated.

KEYWORDS:

Calorie restriction; Erythrocyte; Exercise; Fatty acids; Humans; Skeletal muscle

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Caloric restriction ameliorates acrolein-induced neurotoxicity in rats.

Huang YJ, Zhang L, Shi LY, Wang YY, Yang YB, Ke B, Zhang TY, Qin J.

Neurotoxicology. 2018 Jan 17. pii: S0161-813X(18)30022-6. doi: 10.1016/j.neuro.2018.01.003. [Epub ahead of print]

PMID: 29355571

Abstract

OBJECTIVE:

Acrolein, a highly reactive unsaturated aldehyde, is a ubiquitous environmental pollutant and oxidative damage induced by acrolein is hypothesized to involve in the etiology of Alzheimer's disease (AD). Calorie restriction (CR) is the only non-genetic intervention that has consistently been verified to retard aging by ameliorating oxidative stress. Therefore, we investigated the effects of CR on acrolein-induced neurotoxicity in Sprague-Dawley (SD) rats.

METHODS:

A total of 45 weaned and specific-pathogen-free SD rats (male, weighing 180-220 g) were gavage-fed with acrolein (2.5 mg/kg/day) and fed ab libitum of 10 g/day or 7 g/day (representing 30% CR regimen), or gavage-fed with same volume of tap water and fed al libitum as vehicle control for 12 weeks. After behavioral test conducted by Morris Water Maze, SD rats were sacrificed and brain tissues were prepared for histochemical evaluation and Western blotting to detect alterations in oxidative stress, BDNF/TrkB pathway and key enzymes involved in amyloid precursor protein (APP) metabolism.

RESULTS:

Treatment with 30% CR in SD rats significantly attenuated acrolein-induced cognitive impairment. Oxidative damage including deletion of glutathione and superoxide dismutase and sharp rise in malondialdehyde were notably improved by 30% CR. Further study suggested that 30% CR showed protective effects against acrolein by modulating BDNF/TrkB signaling pathways. Moreover, 30% CR restored acrolein-induced changes of APP, β-secretase, α-secretase and receptor for advanced glycation end products.

CONCLUSION:

These findings suggest that CR may provide a promising approach for the treatment of AD, targeting acrolein.

KEYWORDS:

Acrolein; Alzheimer’s disease; BDNF/TrkB; Calorie restriction; Oxidative stress

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Is there a role of H<sub>2</sub>S in mediating health span benefits of caloric restriction?

Ng LT, Gruber J, Moore PK.

Biochem Pharmacol. 2018 Jan 19. pii: S0006-2952(18)30030-3. doi: 10.1016/j.bcp.2018.01.030. [Epub ahead of print] Review.

PMID: 29360438

Abstract

Caloric restriction (CR) is a dietary regimen that aims to reduce the intake of total calories while maintaining adequate supply of key nutrients so as to avoid malnutrition. CR is one of only a small number of interventions that show promising outcomes on health span and lifespan across different species. There is growing interest in the development of compounds that might replicate CR-related benefits without actually restricting food intake. Hydrogen sulfide (H2S) is produced inside the bodies of many animals, including humans, by evolutionarily conserved H2S synthesizing enzymes. Endogenous H2S is increasingly recognized as an important gaseous signalling molecule involved in diverse cellular and molecular processes. However, the specific role of H2S in diverse biological processes remains to be elucidated and not all its biological effects are beneficial. Nonetheless, recent evidence suggests that the biological functions of H2S intersect with the network of evolutionarily conserved nutrient sensing and stress response pathways that govern organismal responses to CR. Induction of H2S synthesizing enzymes appears to be a conserved and essential feature of the CR response in evolutionarily distant organisms, including nematodes and mice. Here we review the evidence for a role of H2S in CR and lifespan modulation. H2S releasing drugs, capable of controlled delivery of exogenous H2S, are currently in clinical development. These findings suggest such H2S releasing drugs as a promising novel avenue for the development of CR mimetic compounds.

KEYWORDS:

Ageing; Caloric restriction; Healthspan; Hydrogen sulfide; Lifespan

 

The 3 types of intermittent fasting, compared

Here’s exactly what it takes to lose fat and maintain muscle without having to track calories.

by Rachael Schultz

https://www.mensfitness.com/weight-loss/burn-fat-fast/3-types-intermittent-fasting-compared

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Effects of calorie restriction plus fish oil supplementation on abnormal metabolic characteristics and the iron status of middle-aged obese women.

Utami FA, Lee HC, Su CT, Guo YR, Tung YT, Huang SY.

Food Funct. 2018 Jan 24. doi: 10.1039/c7fo01787a. [Epub ahead of print]

PMID: 29362766

Abstract

The increasing prevalence of obesity and sedentary lifestyles has led to a higher incidence of metabolic syndrome (MetS) worldwide as well as in Taiwan. Middle-aged women are at a greater risk of MetS, type 2 diabetes, and cardiovascular disease than men because they have more subcutaneous fat and larger waist circumferences compared with men with equal visceral fat levels. In this study, we investigated the effects of calorie restriction (CR) and fish oil supplementation (CRF) on middle-aged Taiwanese women with MetS. An open-label, parallel-arm, controlled trial was conducted for 12 weeks. A total of 75 eligible participants were randomly assigned to the CR or CRF group. Both the dietary intervention groups were further divided into two age groups: ≤45 and >45 years. Changes in MetS severity, inflammatory status, iron status, and red blood cell fatty acid profile were evaluated. A total of 71 participants completed the trial. Both dietary interventions significantly ameliorated MetS and improved the participants' inflammatory status. CR significantly increased the total iron-binding capacity (TIBC) whereas CRF increased hepcidin levels in women aged >45 years. Furthermore, CRF significantly increased the n-6/n-3 and arachidonic acid/docosahexaenoic acid ratios. Both interventions improved the anthropometric and MetS characteristics, including body weight, blood glucose and triglyceride levels, and the score of the homeostasis model assessment of insulin resistance and quantitative insulin sensitivity check index. In conclusion, the 12-week dietary interventions improved the abnormal metabolic status of middle-aged obese women. CRF was demonstrated to be more effective in ameliorating postprandial glucose level and TIBC in women aged >45 years than in those aged ≤45 years.

 

Lessons from animal nutritionists: dietary amino acid requirement studies and considerations for healthy aging studies.

Shoveller AK, McKnight LM, Wood KM, Cant JP.

Ann N Y Acad Sci. 2018 Jan 24. doi: 10.1111/nyas.13546. [Epub ahead of print] Review.

PMID: 29363772

Abstract

Dietary restriction (DR) increases median life span and protects against age-related disease. Improved longevity can be achieved by restriction of dietary energy, protein, or amino acids (AAs), such as methionine (Met). Met requirements have been defined using methodologies that measure the dose response to Met when all other dietary variables are held constant and with outcomes focused on protein turnover. Here, we cover protein and sulfur AA requirements and discuss the terms "deficient," "optimal," and "excess" and how these need to be considered. We additionally discuss the effect of methyl-donating compounds on sulfur AA metabolism and outcomes. We will discuss how the mechanistic target of rapamycin complex 1 (mTORC1) signaling network regulates protein turnover, lipogenesis and cell growth, proliferation, differentiation, and metabolism in response to hormones, AAs, and cellular energy status. Inhibition of mTORC1 signaling with rapamycin or genetic mutation increases median life span in model organisms, and mTORC1 inhibition may be responsible for some of the life span-extending effects of DR. Finally, we discuss how the sulfur AAs may regulate aspects of reactive oxygen species (ROS) mitigation. Overall, we suggest that approaches evaluating AA intake need to consider whole-body protein synthesis and measures related to tissue-specific and whole-body metabolism that have been associated with longevity.

KEYWORDS:

amino acid requirements; cysteine; dietary restriction; methionine; methionine restriction

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Sex-dependent Differences in Liver and Gut Metabolomic Profiles With Acarbose and Calorie Restriction in C57BL/6 Mice.

Gibbs VK, Brewer RA, Miyasaki ND, Patki A, Smith DL Jr.

J Gerontol A Biol Sci Med Sci. 2018 Jan 16;73(2):157-165. doi: 10.1093/gerona/glx127.

PMID: 28651373

https://academic.oup.com/biomedgerontology/article/73/2/157/3885832

Abstract

Acarbose, an alpha-glucosidase inhibitor used in treating type 2 diabetes, impairs complex carbohydrate digestion and absorption and extends life span in mice (without a requisite reduction in food intake). To assess sex-differential effects coincident with calorie restriction versus a nonrestricted longevity enhancing intervention, we evaluated the metabolite profiles (by liquid chromatography-mass spectroscopy) from livers and cecal contents of C57BL/6J mice (n = 4/sex/group), which were maintained for 10 months under one of the three diet treatments: ad libitum control diet (CON), ad libitum control diet containing 0.1% acarbose (ACA), or 40% calorie restriction using the control diet (CR). Principal component analysis revealed sex-differential profiles with ACA in livers. Of the identified metabolites (n = 621) in liver, CR significantly altered ~44% (males:187↑/131↓, females:74↑/148↓) compared with CON, in contrast with ACA (M:165↑/61↓, F:52↑/60↓). Dissimilarity in ACA-F liver metabolites was observed for ~50% of common metabolites from ACA-M and CR-M/F. CR resulted in fewer significant cecal metabolite differences (n = 615 metabolites; M:86↑/66↓, F:51↑/48↓ vs CON), relative to ACA treatment (M:32↑/189↓, F:36↑/137↓). Metabolomic profiling identifies sex-differential and tissue-specific effects with amino acid metabolism sub-pathways including those involving tryptophan, branch-chain and sulfur amino acids, and the urea cycle, as well as bile acid, porphyrin, and cofactor metabolism pathways.

KEYWORDS:

Calorie restriction mimetic; Glucose; Glucosidase

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DNA methylation is not involved in dietary restriction induced lifespan extension in adult Drosophila.

Lian T, Gaur U, Wu QI, Tu J, Sun B, Yang D, Fan X, Mao X, Yang M.

Genet Res (Camb). 2018 Feb 1;100:e1. doi: 10.1017/S0016672317000064.

PMID: 29386085

Abstract

Dietary restriction (DR) is widely regarded as a viable intervention to extend lifespan and healthspan in diverse organisms. The precise molecular regulatory mechanisms are largely unknown. Epigenetic modifications are not stable upon DR and also keep changing with age. Here, we employed whole genome bisulfite sequencing to determine the DNA methylation changes upon DR in adult Drosophila. Our results indicate that although a low level of DNA methylation exists in the adult Drosophila genome, there is no significant difference in DNA methylation levels upon DR when compared to unrestricted flies. This suggests that other epigenetic components such as histone modifications might be altered by DR.

 

Caloric Restriction and Diet-Induced Weight Loss Do Not Induce Browning of Human Subcutaneous White Adipose Tissue in Women and Men with Obesity.

Barquissau V, Léger B, Beuzelin D, Martins F, Amri EZ, Pisani DF, Saris WHM, Astrup A, Maoret JJ, Iacovoni J, Déjean S, Moro C, Viguerie N, Langin D.

Cell Rep. 2018 Jan 23;22(4):1079-1089. doi: 10.1016/j.celrep.2017.12.102. Epub 2018 Jan 28.

PMID: 29386128

Abstract

Caloric restriction (CR) is standard lifestyle therapy in obesity management. CR-induced weight loss improves the metabolic profile of individuals with obesity. In mice, occurrence of beige fat cells in white fat depots favors a metabolically healthy phenotype, and CR promotes browning of white adipose tissue (WAT). Here, human subcutaneous abdominal WAT samples were analyzed in 289 individuals with obesity following a two-phase dietary intervention consisting of an 8 week very low calorie diet and a 6-month weight-maintenance phase. Before the intervention, we show sex differences and seasonal variation, with higher expression of brown and beige markers in women with obesity and during winter, respectively. The very low calorie diet resulted in decreased browning of subcutaneous abdominal WAT. During the whole dietary intervention, evolution of body fat and insulin resistance was independent of changes in brown and beige fat markers. These data suggest that diet-induced effects on body fat and insulin resistance are independent of subcutaneous abdominal WAT browning in people with obesity.

KEYWORDS:

browning of white fat; caloric restriction; dietary intervention; human obesity; insulin resistance; sex difference; subcutaneous abdominal white adipose tissue; uncoupling protein 1

 

Energy Scarcity Promotes a Brain-wide Sleep State Modulated by Insulin Signaling in C. elegans.

Skora S, Mende F, Zimmer M.

Cell Rep. 2018 Jan 23;22(4):953-966. doi: 10.1016/j.celrep.2017.12.091. Epub 2018 Jan 28.

PMID: 29386137

Abstract

Neural information processing entails a high energetic cost, but its maintenance is crucial for animal survival. However, the brain's energy conservation strategies are incompletely understood. Employing functional brain-wide imaging and quantitative behavioral assays, we describe a neuronal strategy in Caenorhabditis elegans that balances energy availability and expenditure. Upon acute food deprivation, animals exhibit a transiently elevated state of arousal, indicated by foraging behaviors and increased responsiveness to food-related cues. In contrast, long-term starvation suppresses these behaviors and biases animals to intermittent sleep episodes. Brain-wide neuronal population dynamics, which are likely energetically costly but important for behavior, are robust to starvation while animals are awake. However, during starvation-induced sleep, brain dynamics are systemically downregulated. Neuromodulation via insulin-like signaling is required to transiently maintain the animals' arousal state upon acute food deprivation. Our data suggest that the regulation of sleep and wakefulness supports optimal energy allocation.

KEYWORDS:

Caenorhabditis elegans; arousal; behavior; daf-2; energy homeostasis; insulin signaling; neuronal population dynamics; sleep; starvation; whole-brain imaging

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Differential response to caloric restriction of retroperitoneal, epididymal, and subcutaneous adipose tissue depots in rats.

Narita T, Kobayashi M, Itakura K, Itagawa R, Kabaya R, Sudo Y, Okita N, Higami Y.

Exp Gerontol. 2018 Feb 1. pii: S0531-5565(17)30547-8. doi: 10.1016/j.exger.2018.01.016. [Epub ahead of print]

PMID: 29410017

Abstract

The beneficial actions of caloric restriction (CR) are partially mediated by metabolic remodeling of white adipose tissue (WAT). Recently, we showed that CR enhances de novo fatty acid (FA) biosynthesis and mitochondrial biogenesis, particularly in WAT. Here, to better understand the response of WAT to CR, we compare the effects of CR on three WAT depots in rats: retroperitoneal (rWAT), epididymal (eWAT) and subcutaneous (sWAT). Computed tomography and histological analysis showed that CR reduced the volume and average size of rWAT adipocytes. In all WAT depots, CR markedly upregulated the expression of proteins involved in FA biosynthesis in fed rats. In visceral WAT (rWAT and eWAT), hormone-sensitive lipase (lipolytic form) phosphorylation was increased by CR under fed conditions, and decreased by CR under fasted conditions. Conversely, in sWAT, hormone-sensitive lipase phosphorylation was increased by CR under fasted conditions. CR enhanced the effect of feeding on AKT activity in sWAT (indicative of a positive effect on insulin sensitivity) but not in rWAT or eWAT. These data suggest that CR improves lipid metabolism in an insulin signaling-dependent manner in sWAT only. The effects of CR on adipokine (adiponectin and leptin) expression were also different among rWAT, eWAT and sWAT, and CR reduced the gene expression of M2 macrophage markers in rWAT and sWAT, but not in eWAT. We conclude that CR differentially affects the characteristics of WAT depots in rats, including adipocyte size, lipid metabolism, insulin signaling, adipocytokine profile and macrophage infiltration.

KEYWORDS:

Caloric restriction; Insulin signaling; Lipid metabolism; Macrophage; White adipose tissue

 

The type of dietary fat and dietary energy restriction affects the activity of the desaturases in the liver microsomes.

Stawarska A, Białek A, Tokarz A.

Prostaglandins Leukot Essent Fatty Acids. 2018 Jan;128:62-66. doi: 10.1016/j.plefa.2017.12.001. Epub 2017 Dec 8.

PMID: 29413362

Abstract

The aim of present study was to investigate the effect of different dietary oils and the dietary energy restriction on the activity of enzymes participating in the process of arachidonic acid synthesis and on fatty acid profile in serum. It was also evaluated how diet modification affects the weight of animals and weight of the specific organs: liver, kidney and spleen. Wistar male rats were divided into 6 groups according to the diet fed (control, sunflower oil, olive oil, rapeseed oil, fish oil and a group of dietary energy restriction - DER group). The enzyme activities were established indirectly in liver microsomes. To this aim the method of high performance liquid chromatography with UV/VIS detection was used. In addition, the indices of ∆6-desaturase (D6D) and ∆5-desaturase (D5D) were determined. Significant differences in the concentrations of fatty acids and enzyme activity were observed. The results concerning desaturases show the negative correlation between n-3 polyunsaturated fatty acids intake and enzymes activity. The highest D6D activity was observed in microsomes obtained from sunflower oil fed rats and the lowest D6D activity was in the DER group. D5D index did not differ much depending on the diet. Among groups supplemented with oils the higher mean values of the weight of liver were observed in the group supplemented with rapeseed oil. Consumption of diets supplemented with edible oils of different fatty acid profile influence both serum fatty acid composition and the activity of ∆6- and Δ5-desaturase.

KEYWORDS:

Arachidonic acid; Dietary energy restriction; Oils; ∆(5)-desaturase; ∆(6)-desaturase

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Intermittent energy restriction improves weight loss efficiency in obese men: the MATADOR study.

Byrne NM, Sainsbury A, King NA, Hills AP, Wood RE.

Int J Obes (Lond). 2018 Feb;42(2):129-138. doi: 10.1038/ijo.2017.206. Epub 2017 Aug 17.

PMID: 28925405

https://www.nature.com/articles/ijo2017206

Abstract

BACKGROUND/OBJECTIVES:

The MATADOR (Minimising Adaptive Thermogenesis And Deactivating Obesity Rebound) study examined whether intermittent energy restriction (ER) improved weight loss efficiency compared with continuous ER and, if so, whether intermittent ER attenuated compensatory responses associated with ER.

SUBJECTS/METHODS:

Fifty-one men with obesity were randomised to 16 weeks of either: (1) continuous (CON), or (2) intermittent (INT) ER completed as 8 × 2-week blocks of ER alternating with 7 × 2-week blocks of energy balance (30 weeks total). Forty-seven participants completed a 4-week baseline phase and commenced the intervention (CON: N=23, 39.4±6.8 years, 111.1±9.1 kg, 34.3±3.0 kg m-2; INT: N=24, 39.8±9.5 years, 110.2±13.8 kg, 34.1±4.0 kg m-2). During ER, energy intake was equivalent to 67% of weight maintenance requirements in both groups. Body weight, fat mass (FM), fat-free mass (FFM) and resting energy expenditure (REE) were measured throughout the study.

RESULTS:

For the N=19 CON and N=17 INT who completed the intervention per protocol, weight loss was greater for INT (14.1±5.6 vs 9.1±2.9 kg; P<0.001). INT had greater FM loss (12.3±4.8 vs 8.0±4.2 kg; P<0.01), but FFM loss was similar (INT: 1.8±1.6 vs CON: 1.2±2.5 kg; P=0.4). Mean weight change during the 7 × 2-week INT energy balance blocks was minimal (0.0±0.3 kg). While reduction in absolute REE did not differ between groups (INT: -502±481 vs CON: -624±557 kJ d-1; P=0.5), after adjusting for changes in body composition, it was significantly lower in INT (INT: -360±502 vs CON: -749±498 kJ d-1; P<0.05).

CONCLUSIONS:

Greater weight and fat loss was achieved with intermittent ER. Interrupting ER with energy balance 'rest periods' may reduce compensatory metabolic responses and, in turn, improve weight loss efficiency.

 

Intermittent fasting interventions for treatment of overweight and obesity in adults: a systematic review and meta-analysis.

Harris L, Hamilton S, Azevedo LB, Olajide J, De Brún C, Waller G, Whittaker V, Sharp T, Lean M, Hankey C, Ells L.

JBI Database System Rev Implement Rep. 2018 Feb;16(2):507-547. doi: 10.11124/JBISRIR-2016-003248.

PMID: 29419624

Abstract

OBJECTIVE:

To examine the effectiveness of intermittent energy restriction in the treatment for overweight and obesity in adults, when compared to usual care treatment or no treatment.

INTRODUCTION:

Intermittent energy restriction encompasses dietary approaches including intermittent fasting, alternate day fasting, and fasting for two days per week. Despite the recent popularity of intermittent energy restriction and associated weight loss claims, the supporting evidence base is limited.

INCLUSION CRITERIA:

This review included overweight or obese (BMI ≥25 kg/m) adults (≥18 years). Intermittent energy restriction was defined as consumption of ≤800 kcal on at least one day, but no more than six days per week. Intermittent energy restriction interventions were compared to no treatment (ad libitum diet) or usual care (continuous energy restriction ∼25% of recommended energy intake). Included interventions had a minimum duration of 12 weeks from baseline to post outcome measurements. The types of studies included were randomized and pseudo-randomized controlled trials. The primary outcome of this review was change in body weight. Secondary outcomes included: i) anthropometric outcomes (change in BMI, waist circumference, fat mass, fat free mass); ii) cardio-metabolic outcomes (change in blood glucose and insulin, lipoprotein profiles and blood pressure); and iii) lifestyle outcomes: diet, physical activity, quality of life and adverse events.

METHODS:

A systematic search was conducted from database inception to November 2015. The following electronic databases were searched: MEDLINE, Embase, CINAHL, Cochrane Library, ClinicalTrials.gov, ISRCTN registry, and anzctr.org.au for English language published studies, protocols and trials. Two independent reviewers evaluated the methodological quality of included studies using the standardized critical appraisal instruments from the Joanna Briggs Institute. Data were extracted from papers included in the review by two independent reviewers using the standardized data extraction tool from the Joanna Briggs Institute. Effect sizes were expressed as weighted mean differences and their 95% confidence intervals were calculated for meta-analyses.

RESULTS:

Six studies were included in this review. The intermittent energy restriction regimens varied across studies and included alternate day fasting, fasting for two days, and up to four days per week. The duration of studies ranged from three to 12 months. Four studies included continuous energy restriction as a comparator intervention and two studies included a no treatment control intervention. Meta-analyses showed that intermittent energy restriction was more effective than no treatment for weight loss (-4.14 kg; 95% CI -6.30 kg to -1.99 kg; p ≤ 0.001). Although both treatment interventions achieved similar changes in body weight (approximately 7 kg), the pooled estimate for studies that investigated the effect of intermittent energy restriction in comparison to continuous energy restriction revealed no significant difference in weight loss (-1.03 kg; 95% CI -2.46 kg to 0.40 kg; p = 0.156).

CONCLUSIONS:

Intermittent energy restriction may be an effective strategy for the treatment of overweight and obesity. Intermittent energy restriction was comparable to continuous energy restriction for short term weight loss in overweight and obese adults. Intermittent energy restriction was shown to be more effective than no treatment, however, this should be interpreted cautiously due to the small number of studies and future research is warranted to confirm the findings of this review.

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Effects of 2 years of caloric restriction on oxidative status assessed by urinary F2-isoprostanes: The CALERIE 2 randomized clinical trial.

Il'yasova D, Fontana L, Bhapkar M, Pieper CF, Spasojevic I, Redman LM, Das SK, Huffman KM, Kraus WE; CALERIE Study Investigators.

Aging Cell. 2018 Feb 9. doi: 10.1111/acel.12719. [Epub ahead of print]

PMID: 29424490

Abstract

Calorie restriction (CR) without malnutrition slows aging in animal models. Oxidative stress reduction was proposed to mediate CR effects. CR effect on urinary F2-isoprostanes, validated oxidative stress markers, was assessed in CALERIE, a two-year randomized controlled trial. Healthy volunteers (n = 218) were randomized to prescribed 25% CR (n = 143) or ad libitum control (AL, n = 75) stratifying the randomization schedule by site, sex, and BMI. F2-isoprostanes were quantified using LC-MS/MS in morning, fasted urine specimens at baseline, at 12 and 24 months. The primary measure of oxidative status was creatinine-adjusted 2,3-dinor-iPF(2α)-III concentration, additional measured included iPF(2α)-III, iPF2a-VI, and 8,12-iso-iPF2a-VI. Intention-to-treat analyses assessed change in 2,3-dinor-iPF(2α)-III using mixed models assessing treatment, time, and treatment-by-time interaction effects, adjusted for blocking variables and baseline F2-isoprostane value. Exploratory analyses examined changes in iPF(2α)-III, iPF(2α)-VI, and 8,12-iso-iPF(2α)-VI. A factor analysis used aggregate information on F2-isoprostane values. In CR group, 2,3-dinor-iPF(2α)-III concentrations were reduced from baseline by 17% and 13% at 12 and 24 months, respectively; these changes were significantly different from AL group (p < .01). CR reduced iPF(2α)-III concentrations by 20% and 27% at 12 and 24 months, respectively (p < .05). The effects were weaker on the VI-species. CR caused statistically significant reduction in isoprostane factor at both time points, and mean (se) changes were -0.36 (0.06) and -0.31 (0.06). No significant changes in isoprostane factor were at either time point in AL group (p < .01 between-group difference). We conclude that two-year CR intervention in healthy, nonobese men and women reduced whole body oxidative stress as assessed by urinary concentrations of F2-isoprostanes.

KEYWORDS:

caloric restriction; oxidative stress; randomized controlled trial

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Metabolic effects of short-term caloric restriction in mice with reduced insulin gene dosage.

Dommerholt MB, Dionne DA, Hutchinson DF, Kruit JK, Johnson JD.

J Endocrinol. 2018 Feb 9. pii: JOE-17-0505. doi: 10.1530/JOE-17-0505. [Epub ahead of print]

PMID: 29439088

Abstract

Caloric restriction (CR) is the only environmental intervention with robust evidence that it extends lifespan and delays the symptoms of ageing, but its mechanisms are incompletely understood. Based on the prolonged longevity of knockout models, it was hypothesized that the insulin-IGF pathway could be a target for developing a CR mimic. This study aimed to test whether CR has additive effects on glucose homeostasis and beta-cell function in mice with reduced insulin gene dosage. To study models with a range of basal insulin levels, wildtype C57BL/6J and mice on an Ins2-/- background, were put on 8 weeks of 40% CR. Both male and female mice rapidly lost weight due to a reduced WAT mass. Interestingly, absolute BAT mass was increased in female Ins2-/- mice, suggesting the possibility of increased thermogenic capacity. Glucose tolerance was improved and fasting glucose levels were reduced by CR in both wildtype and 45 and 70 week-old Ins2-/- mice. The effects of CR and reduced insulin on glucose tolerance were non-additive in 20 week-old mice. Interestingly, mice on CR generally exhibited an inability to further depress blood glucose after insulin injection, pointing to possible alterations in insulin sensitivity. In conclusion, our results demonstrate that CR can cause weight loss in the context of reduced insulin production, but that CR-improved glucose homeostasis does not occur near the 'insulin floor' in young mice. Collectively, these data shed further light on the relationships between caloric restriction, insulin and glucose homeostasis.

 

Association of the Gly482Ser PPARGC1A gene variant with different cholesterol outcomes in response to two energy-restricted diets in subjects with excessive weight.

Ramos-Lopez O, Riezu-Boj JI, Milagro FI, Goni L, Cuervo M, Martinez JA.

Nutrition. 2018 Mar;47:83-89. doi: 10.1016/j.nut.2017.10.008. Epub 2018 Jan 4.

PMID: 29429541

Abstract

OBJECTIVES:

The aim of this study was to investigate the influence of two PPARGC1A gene polymorphisms on metabolic outcomes in response to two energy-restricted diets.

METHODS:

A 4-mo nutritional intervention was conducted that involved two different hypo-energetic diets based on low-fat (LF) and moderately high-protein (MHP) dietary patterns. Unrelated subjects with excessive weight were genotyped for two PPARGC1A polymorphisms: Rs8192678 (Gly482Ser) and rs3755863 (G > A). Genotyping was performed by next-generation sequencing and haplotypes were screened. Anthropometric measurements and biochemical tests were assessed with standardized methods.

RESULTS:

Different cholesterol outcomes were observed by diet and Gly482Ser genotype. The Gly482 Gly homozygotes after an LF diet had lower reductions in total cholesterol (-9 mg/dL vs. -27 mg/dL; P = 0.017) and low-density lipoprotein cholesterol levels (-5 mg/dL vs. -18 mg/dL; P = 0.016) than the subjects who were carriers of 482 Ser allele. However, this finding was not recorded in the MHP group where Gly482 Gly homozygotes underwent similar cholesterol decreases as the 482 Ser allele carriers. Likewise, all genotype carriers had significant reductions in the frequencies of hypercholesterolemia (total cholesterol ≥200 mg/dL) except for Gly482 Gly homozygotes in the LF group. Meanwhile, the rs3755863 polymorphism and PPARGC1A haplotypes showed borderline effects with regard to cholesterol decreases.

CONCLUSIONS:

An energy-restricted MHP diet might be more beneficial than an LF diet to reduce serum cholesterol among subjects who are carriers of the PPARGC1A Gly482Gly genotype. The analysis of this genetic variant might be the basis for a precise, nutrigenetic management of hypercholesterolemia based on genetic makeup.

KEYWORDS:

Cholesterol; Diet; Genetics; Nutrigenetics; Obesity; Overweight; PPARGC1A

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Caloric Restriction Dramatically Stalls Lesion Growth in Mice With Induced Endometriosis.

Yin B, Liu X, Guo SW.

Reprod Sci. 2018 Jan 1:1933719118756755. doi: 10.1177/1933719118756755. [Epub ahead of print]

PMID: 29439622

Abstract

Caloric restriction (CR) has been demonstrated to have many health-beneficial effects in many species, but whether CR can impede the development of endometriosis is unknown. To test the hypothesis that CR can impede the growth of endometriotic lesions and fibrogenesis, we conducted 2 experiments. In experiment 1, 20 female Balb/C mice were randomly assigned to either ad libitum (AL) group that was fed AL or to CR group that was fed 30% less calories than that of AL mice. Two weeks after the implementation of the dietary intervention, endometriosis was induced by intraperitoneal injection of endometrial fragments. Two weeks after the induction, all mice were sacrificed and their lesion samples were evaluated. In experiment 2, another 20 mice were used and CR was implemented 2 weeks after induction of endometriosis and lasted for 4 weeks. Caloric restriction instituted before the induction of endometriosis reduced the lesion weight by 88.5%, whereas CR implemented well after lesions were established reduced the lesion weight by 93.0%. In both cases, CR significantly increased staining levels of markers of autophagy but reduced proliferation, angiogenesis, steroidogenesis, and fibrosis in lesions as compared with the AL group. Consequently, CR, instituted either before or after the induction of endometriosis, dramatically curbs the growth of endometriotic lesions and fibrogenesis through multiple mechanisms. Caloric restriction and CR mimetics, a family of compounds mimicking the beneficial effect of CR, even when instituted well after lesions are established, may stall the development of endometriosis. Given the scarcity in research on how lifestyle can impact on the development of endometriosis, our study should hopefully stimulate more research in this area.

KEYWORDS:

autophagy; caloric restriction; endometriosis; fibrogenesis; mouse

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Curcumin and piperine supplementation of obese mice under caloric restriction modulates body fat and interleukin-1β.

Miyazawa T, Nakagawa K, Kim SH, Thomas MJ, Paul L, Zingg JM, Dolnikowski GG, Roberts SB, Kimura F, Miyazawa T, Azzi A, Meydani M.

Nutr Metab (Lond). 2018 Feb 6;15:12. doi: 10.1186/s12986-018-0250-6. eCollection 2018.

PMID: 29445415

https://nutritionandmetabolism.biomedcentral.com/track/pdf/10.1186/s12986-018-0250-6?site=nutritionandmetabolism.biomedcentral.com

Abstract

BACKGROUND:

Dietary bioactive compounds capable of improving metabolic profiles would be of great value, especially for overweight individuals undergoing a caloric restriction (CR) regimen. Curcumin (Cur), a possible anti-obesity compound, and piperine (Pip), a plausible enhancer of Cur's bioavailability and efficacy, may be candidate agents for controlling body fat, metabolism and low grade inflammation.

METHODS:

47 eight-week-old male C57BL/6 mice were fed a high fat diet (HFD) for 23 weeks to induce obesity. Then, mice were divided into 5 groups. Group 1 continued on HFD ad libitum. The other 4 groups underwent CR (reduced 10% HFD intake for 10 weeks, 20% for 20 weeks) with Cur, Pip, Cur + Pip or none of these. Percent body fat, plasma inflammatory markers associated with obesity (interferon (IFN)-γ, interleukin (IL)-10, IL-12 p70, IL-1β, IL-6 and KC/GRO), plasma Cur metabolites and liver telomere length were measured.

RESULTS:

Compared to the other groups, obese mice who underwent CR and received Cur + Pip in their diet lost more fat and had significantly lower IL-1β and KC/GRO. Tandem mass spectrometry analysis of plasma from obese mice under CR showed no difference in Cur metabolite levels between groups supplemented with Cur alone or combined with Pip. However, plasma IL-1β levels were inversely correlated with curcumin glucuronide. Minor modulation of telomere length were observed.

CONCLUSIONS:

It is plausible that supplementing the high fat diet of CR mice with Cur + Pip may increase loss of body fat and suppresses HFD induced inflammation. Combination of Cur and Pip has potential to enhance CR effects for the prevention of metabolic syndrome.

KEYWORDS:

Caloric restriction; Curcumin; Glucuronide; High fat diet; Inflammation; Meso scale discovery; Metabolic syndrome; Obesity; Piperine; Tandem mass spectrometry

 

Transcriptome Analysis Reveals Intermittent Fasting-Induced Genetic Changes in Ischemic Stroke.

Kim J, Kang SW, Mallilankaraman K, Baik SH, Lim JC, Balaganapathy P, She DT, Lok KZ, Fann DY, Thambiayah U, Tang SC, Stranahan AM, Dheen ST, Gelderblom M, Seet RC, Karamyan VT, Vemuganti R, Sobey CG, Mattson MP, Jo DG, Arumugam TV.

Hum Mol Genet. 2018 Feb 13. doi: 10.1093/hmg/ddy057. [Epub ahead of print]

PMID: 29447348

Abstract

Genetic changes due to dietary intervention in the form of either calorie restriction (CR) or intermittent fasting (IF) are not reported in detail until now. However, it is well established that both CR and IF extend the lifespan and protect against neurodegenerative diseases and stroke. The current research aims were first to describe the transcriptomic changes in brains of IF mice and, second, to determine whether IF induces extensive transcriptomic changes following ischemic stroke to protect the brain from injury. Mice were randomly assigned to ad libitum feeding (AL), 12 (IF12) or 16 (IF16) hours daily fasting. Each diet group was then subjected to sham surgery or middle cerebral artery occlusion and consecutive reperfusion. Mid-coronal sections of ipsilateral cerebral tissue were harvested at the end of the 1 hour ischemic period or at 3, 12, 24 or 72 hours of reperfusion, and genome-wide mRNA expression was quantified by RNA sequencing. The cerebral transcriptome of mice in AL group exhibited robust, sustained up-regulation of detrimental genetic pathways under ischemic stroke, but activation of these pathways was suppressed in IF16 group. Interestingly, the cerebral transcriptome of AL mice was largely unchanged during the 1 hour of ischemia, whereas mice in IF16 group exhibited extensive up-regulation of genetic pathways involved in neuroplasticity and down-regulation of protein synthesis. Our data provide a genetic molecular framework for understanding how IF protects brain cells against damage caused by ischemic stroke, and reveal cellular signaling and bioenergetic pathways to target in the development of clinical interventions.

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Exercise counteracts the homeostatic decrease in thermogenesis caused by caloric restriction in sheep.

Fuller-Jackson JP, Clarke IJ, Rao A, Henry BA.

FASEB J. 2018 Feb 13:fj201701504R. doi: 10.1096/fj.201701504R. [Epub ahead of print]

PMID: 29455575

Abstract

Caloric restriction causes a homeostatic reduction in thermogenesis. We aimed to determine whether exercise could counteract this. We studied four groups of normal-weight ewes ( n = 5), including control sedentary fed ad libitum, exercise fed ad libitum (30 min/d, 5 d/wk), diet-restricted (70% of ad libitum food intake), and combined diet and exercise. Temperature probes implanted in sternal and retroperitoneal adipose tissue and skeletal muscle measured thermogenesis. After the 4-wk intervention, hypothalami were collected for in situ hybridization, and fat and muscle biopsies were collected for real-time PCR and Western blotting. Combined diet and exercise reduced adiposity ( P < 0.05). Caloric restriction alone reduced overnight temperatures in sternal and retroperitoneal fat ( P < 0.05), which was counteracted by exercise ( P < 0.05). Exercise did not induce expression of cellular markers of browning in adipose tissue. There was no effect of diet or exercise on skeletal muscle thermogenesis. Combined diet and exercise increased the expression of neuropeptide Y and agouti-related protein in the hypothalamic arcuate nucleus ( P < 0.05), consistent with reduced adiposity. Gene expressions of key hypothalamic appetite-regulating peptides were not associated with altered thermogenesis. We demonstrate that exercise counteracts the inhibitory effect of caloric restriction to restore thermogenesis in adipose tissue of sheep.

KEYWORDS:

brown adipose tissue; diet; hypothalamic appetite-regulating peptides; physical activity

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Inhibition of corticosterone synthesis and its effect on acute phase proteins, heat shock protein 70, and interleukin-6 in broiler chickens subjected to feed restriction.

Najafi P, Zulkifli I, Soleimani AF.

Poult Sci. 2018 Feb 14. doi: 10.3382/ps/pex364. [Epub ahead of print]

PMID: 29462352

Abstract

The aim of the current study was to elucidate whether inhibition of corticosterone (CORT) synthesis could modify stress response to feed deprivation and its possible interactions with feed restriction in the neonatal period in broiler chickens. Equal numbers of broiler chicks were subjected to either 60% feed restriction (60FR) or ad libitum (AL) on d 4, 5, and 6. On day 7, blood CORT, acute phase proteins (APP), interleukin-6 (IL-6) levels, and brain heat shock protein 70 (HSP70) expression were determined. On d 35, chickens in each early age feeding regimen were subjected to one of the following treatments: (i) ad libitum feeding (ALF), (ii) 24 h feed deprivation (SFR), or (iii) 24 h feed deprivation with intramuscular injection of 1,1-bis(4-chlorophenyl)-2,2,2-trichloroethane (DDT) at 100 mg/kg BW (SFR+DDT). The effect of SFR on CORT, APP, IL-6, and HSP 70 were determined on d 36. The results showed that subjecting chicks to 60FR significantly elevated CORT and brain HSP70 concentration compared to the AL group on d 7. The early feeding regimen had no significant effect on CORT, alpha-1 acid glycoprotein (AGP), ovotransferrin (OVT), ceruoplasmin (CP), IL-6, or brain HSP70 on d 36. The CORT, AGP, OVT, CP, IL-6, and brain HSP70 expression of SFR birds following 24 h of feed deprivation (d 36) were significantly higher than their ALF and SFR+DDT counterparts. Both ALF and SFR+DDT birds had similar values. Stress attributed to feed deprivation without concurrent increase in CORT had a negligible effect on serum levels of APP and IL-6 and brain HSP70 expression.

Edited by AlPater

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The involvement of serum exosomal miR-500-3p and miR-770-3p in aging: modulation by calorie restriction.

Lee EK, Jeong HO, Bang EJ, Kim CH, Mun JY, Noh S, Gim JA, Kim DH, Chung KW, Yu BP, Chung HY.

Oncotarget. 2017 Dec 24;9(5):5578-5587. doi: 10.18632/oncotarget.23651. eCollection 2018 Jan 19.

PMID: 29464019

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814159/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814159/pdf/oncotarget-09-5578.pdf

Abstract

Recent studies have shown a role for miRNAs in aging and age-related diseases, and the modulation of miRNA expression by diet attracts attention as a new therapeutic strategy. Here, we focused on identifying specific exosomal miRNAs derived from serum of aged rats and the effect of short-term calorie restriction (CR) on their expression. Exosomes from serum of young (7-month), old (22-month), and old-CR Sprague Dawley rats were isolated and characterized by transmission electron microscopy analyses, dynamic light scattering measurements, and Western blotting. A total of 12 significantly expressed miRNAs in serum exosomes of young and old rats were identified by next generation sequencing. After analysis of qRT-PCR, we found that miR-500-3p and miR-770-3p expression was significantly upregulated by aging and downregulated by CR. Furthermore, receiver operating characteristic (ROC) curve revealed that the selected miRNAs represented high accuracy in discriminating old rats from young rats. Finally, PANTHER analysis predicted selected miRNAs targets genes involved in Wnt/chemokines and cytokines -related inflammatory signaling pathway and function as transcription factor. In conclusion, our results suggest that the expression of serum exosomal miR-500-3p and miR-770-3p was significantly increased with aging, whereas these were decreased by CR, and age-/CR-modulated exosomal miR-500-3p and miR-770-3p could potentially be used as informative biomarkers candidates for aging.

KEYWORDS:

Gerotarget; aging; calorie restriction; exosome; miR-500-3p; miR-770-3p

 

Effect of caloric restriction on depression.

Manchishi SM, Cui RJ, Zou XH, Cheng ZQ, Li BJ.

J Cell Mol Med. 2018 Feb 21. doi: 10.1111/jcmm.13418. [Epub ahead of print] Review.

PMID: 29465826

http://onlinelibrary.wiley.com/doi/10.1111/jcmm.13418/full

http://onlinelibrary.wiley.com/doi/10.1111/jcmm.13418/epdf

Abstract

Recently, most of evidence shows that caloric restriction could induce antidepressant-like effects in animal model of depression. Based on studies of the brain-gut axis, some signal pathways were common between the control of caloric restriction and depression. However, the specific mechanism of the antidepressant-like effects induced by caloric restriction remains unclear. Therefore, in this article, we summarized clinical and experimental studies of caloric restriction on depression. This review may provide a new therapeutic strategy for depression.

KEYWORDS:

BDNF ; antidepressant; calorie restriction; fasting

 

Resting metabolic rate of obese patients under very low calorie ketogenic diet.

Gomez-Arbelaez D, Crujeiras AB, Castro AI, Martinez-Olmos MA, Canton A, Ordoñez-Mayan L, Sajoux I, Galban C, Bellido D, Casanueva FF.

Nutr Metab (Lond). 2018 Feb 17;15:18. doi: 10.1186/s12986-018-0249-z. eCollection 2018.

PMID: 29467800

Abstract

BACKGROUND:

The resting metabolic rate (RMR) decrease, observed after an obesity reduction therapy is a determinant of a short-time weight regain. Thus, the objective of this study was to evaluate changes in RMR, and the associated hormonal alterations in obese patients with a very low-calorie ketogenic (VLCK)-diet induced severe body weight (BW) loss.

METHOD:

From 20 obese patients who lost 20.2 kg of BW after a 4-months VLCK-diet, blood samples and body composition analysis, determined by DXA and MF-Bioimpedance, and RMR by indirect calorimetry, were obtained on four subsequent visits: visit C-1, basal, initial fat mass (FM) and free fat mass (FFM); visit C-2, - 7.2 kg in FM, - 4.3 kg in FFM, maximal ketosis; visit C-3, - 14.4 kg FM, - 4.5 kg FFM, low ketosis; visit C-4, - 16.5 kg FM, - 3.8 kg FFM, no ketosis. Each subject acted as his own control.

RESULTS:

Despite the large BW reduction, measured RMR varied from basal visit C-1 to visit C-2, - 1.0%; visit C-3, - 2.4% and visit C-4, - 8.0%, without statistical significance. No metabolic adaptation was observed. The absent reduction in RMR was not due to increased sympathetic tone, as thyroid hormones, catecholamines, and leptin were reduced at any visit from baseline. Under regression analysis FFM, adjusted by levels of ketonic bodies, was the only predictor of the RMR changes (R2 = 0.36; p < 0.001).

CONCLUSION:

The rapid and sustained weight and FM loss induced by VLCK-diet in obese subjects did not induce the expected reduction in RMR, probably due to the preservation of lean mass.

KEYWORDS:

DXA; Energy expenditure; Indirect calorimetry; Ketogenic diet; Metabolic adaptation; Multifrequency BIA; Obesity; Pronokal method; Protein diet; Very low-energy diet

 

Daily pattern of energy distribution and weight loss.

Raynor HA, Li F, Cardoso C.

Physiol Behav. 2018 Feb 19. pii: S0031-9384(18)30097-0. doi: 10.1016/j.physbeh.2018.02.036. [Epub ahead of print]

PMID: 29471076

Abstract

Timing of energy intake, a temporal dietary pattern, may enhance health. Eating a greater amount of energy earlier and a smaller amount of energy later in the day, a behavioral circadian rhythm, may assist with chronoenhancement. Chronoenhancement seeks to enhance entrainment (synchronization) of biological and behavioral circadian rhythms. In humans, research reports that eating a greater amount of energy early and a smaller amount of energy later in the day increases dietary induced thermogenesis, improves cardiometabolic outcomes, and enhances weight loss. However, little human research has examined if this eating pattern enhances regularity of biological circadian rhythm. In a randomized controlled 8-week pilot study, the influence of energy distribution timing on weight loss and regularity of sleep onset and wake times (marker for biological circadian rhythm) was examined. Within an hypocaloric, three-meal prescription, participants (n = 8) were assigned to either: 1) Morning: 50%, 30%, and 20% of kcal at breakfast, lunch, and dinner, respectively; or 2) Evening: 20%, 30%, and 50% of kcal at breakfast, lunch, and dinner, respectively. Percent weight loss and regularity of sleep onset and wake times were significantly (p < 0.05) greater for Morning than Evening. To enhance understanding of the influence of energy distribution timing on health, longer studies conducted in free-living participants, with dietary intake assessed using time-stamped methods, that include measures of the circadian timing system are needed.

KEYWORDS:

Circadian; Distribution; Energy; Pattern; Temporal; Weight loss

 

Starvation, Stress Resistance, and Cancer.

Buono R, Longo VD.

Trends Endocrinol Metab. 2018 Feb 17. pii: S1043-2760(18)30017-1. doi: 10.1016/j.tem.2018.01.008. [Epub ahead of print] Review.

PMID: 29463451

Abstract

Cancer cells are characterized by dysregulation in signal transduction and metabolic pathways leading to increased glucose uptake, altered mitochondrial function, and the evasion of antigrowth signals. Fasting and fasting-mimicking diets (FMDs) provide a particularly promising intervention to promote differential effects in normal and malignant cells. These effects are caused in part by the reduction in IGF-1, insulin, and glucose and the increase in IGFBP1 and ketone bodies, which generate conditions that force cancer cells to rely more on metabolites and factors that are limited in the blood, thus resulting in cell death. Here we discuss the cellular and animal experiments demonstrating the differential effects of fasting on normal and cancer cells and the mechanisms responsible for these effects.

KEYWORDS:

IGF-1; cancer; differential stress resistance; differential stress sensitization; fasting-mimicking diet; starvation

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Effect of weight loss on circulating fatty acid profiles in overweight subjects with high visceral fat area: a 12-week randomized controlled trial.

Lee YJ, Lee A, Yoo HJ, Kim M, Kim M, Jee SH, Shin DY, Lee JH.

Nutr J. 2018 Feb 22;17(1):28. doi: 10.1186/s12937-018-0323-4.

PMID: 29471812

https://nutritionj.biomedcentral.com/articles/10.1186/s12937-018-0323-4

Abstract

BACKGROUND:

Significant associations between visceral fat and alterations in plasma fatty acids have been identified in overweight individuals. However, there are scant data regarding the relationships of the visceral fat area (VFA) with the plasma fatty acid profiles and desaturase activities following weight loss. We investigated the effect of weight loss with mild calorie restriction on the circulating fatty acid profiles and desaturase activities in nondiabetic overweight subjects with high VFA.

METHODS:

Eighty overweight subjects with high VFA (L4 VFA ≥100 cm2) were randomized into the 12-week mild-calorie-restriction (300 kcal/day) or control groups.

RESULTS:

Comparison of the percent of body weight changes between groups revealed that the weight-loss group had greater reductions in body weight. The VFA decreased by 17.7 cm2 from baseline in the weight-loss group (P < 0.001). At follow-up, the weight-loss group showed greater reductions in serum triglycerides, insulin, and HOMA-IR than the control group. Significantly greater reductions in total saturated fatty acids, palmitic acid, stearic acid, total monounsaturated fatty acids, palmitoleic acid, oleic acid, eicosadienoic acid, and dihomo-γ-linolenic acid levels were detected in the weight-loss group compared with the control group after adjusting for baseline values. Following weight loss, C16 Δ9-desaturase activity was significantly decreased and Δ5-desaturase activity was significantly increased, and the changes were greater in the weight-loss group than in the control group.

CONCLUSIONS:

The results suggest that mild weight loss improves abdominal obesity, overall fatty acid profiles, and desaturase activities; therefore, mild calorie restriction has potential health benefits related to obesity-related diseases in overweight subjects with high VFA.

KEYWORDS:

Fatty acid; Fatty acid desaturase; Obesity-related disease; Visceral fat; Weight loss

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Calorie Restriction Governs Intestinal Epithelial Regeneration through Cell-Autonomous Regulation of mTORC1 in Reserve Stem Cells.

Yousefi M, Nakauka-Ddamba A, Berry CT, Li N, Schoenberger J, Simeonov KP, Cedeno RJ, Yu Z, Lengner CJ.

Stem Cell Reports. 2018 Feb 15. pii: S2213-6711(18)30052-3. doi: 10.1016/j.stemcr.2018.01.026. [Epub ahead of print]

PMID: 29478893

Abstract

Aging is a complex process associated with a decline in functionality of adult stem cells affecting tissue homeostasis and regeneration. Calorie restriction (CR) is the only experimental manipulation known to extend lifespan and reduce the incidence of age-related disorders across numerous species. These benefits are likely mediated, at least in part, through the preservation of stem cell function. Here, we show that CR enhances the regenerative capacity of the intestinal epithelium through preservation of an injury-resistant reserve intestinal stem cell (ISC) pool. Cell-autonomous activity of mechanistic target of rapamycin complex 1 (mTORC1) governs the sensitivity of reserve ISCs to injury. CR inhibits mTORC1 in these cells, protecting them against DNA damage, while mTORC1 stimulation, either genetically or through nutrient sensing, sensitizes reserve ISCs to injury, thus compromising regeneration of the epithelium. These data delineate a critical role for mTORC1 in epithelial regeneration and inform clinical strategies based on nutrient modulation.

KEYWORDS:

calorie restriction; intestine; mTORC1 signaling; radiation injury; radiosensitivity; regeneration; reserve intestinal stem cells; stem cells

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Metabolic and molecular framework for the enhancement of endurance by intermittent food deprivation.

Marosi K, Moehl K, Navas-Enamorado I, Mitchell SJ, Zhang Y, Lehrmann E, Aon MA, Cortassa S, Becker KG, Mattson MP.

FASEB J. 2018 Feb 27:fj201701378RR. doi: 10.1096/fj.201701378RR. [Epub ahead of print]

PMID: 29485903

Abstract

Evolutionary considerations suggest that the body has been optimized to perform at a high level in the food-deprived state when fatty acids and their ketone metabolites are a major fuel source for muscle cells. Because controlled food deprivation in laboratory animals and intermittent energy restriction in humans is a potent physiologic stimulus for ketosis, we designed a study to determine the impact of intermittent food deprivation during endurance training on performance and to elucidate the underlying cellular and molecular mechanisms. Male mice were randomly assigned to either ad libitum feeding or alternate-day food deprivation (ADF) groups, and half of the mice in each diet group were trained daily on a treadmill for 1 mo. A run to exhaustion endurance test performed at the end of the training period revealed superior performance in the mice maintained on ADF during training compared to mice fed ad libitum during training. Maximal O2 consumption was increased similarly by treadmill training in mice on ADF or ad libitum diets, whereas respiratory exchange ratio was reduced in ADF mice on food-deprivation days and during running. Analyses of gene expression in liver and soleus tissues, and metabolomics analysis of blood suggest that the metabolic switch invoked by ADF and potentiated by exercise strongly modulates molecular pathways involved in mitochondrial biogenesis, metabolism, and cellular plasticity. Our findings demonstrate that ADF engages metabolic and cellular signaling pathways that result in increased metabolic efficiency and endurance capacity.

KEYWORDS:

exercise; intermittent fasting; ketone; mitochondrial biogenesis; muscle

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Intermittent v. continuous energy restriction: differential effects on postprandial glucose and lipid metabolism following matched weight loss in overweight/obese participants.

Antoni R, Johnston KL, Collins AL, Robertson MD.

Br J Nutr. 2018 Mar;119(5):507-516. doi: 10.1017/S0007114517003890.

PMID: 29508693

Abstract

The intermittent energy restriction (IER) approach to weight loss involves short periods of substantial (>70 %) energy restriction (ER) interspersed with normal eating. Studies to date comparing IER to continuous energy restriction (CER) have predominantly measured fasting indices of cardiometabolic risk. This study aimed to compare the effects of IER and CER on postprandial glucose and lipid metabolism following matched weight loss. In all, twenty-seven (thirteen male) overweight/obese participants (46 (sem 3) years, 30·1 (sem 1·0) kg/m2) who were randomised to either an IER intervention (2638 kJ for 2 d/week with an overall ER of 22 (sem 0·3) %, n 15) or a CER intervention (2510 kJ below requirements with overall ER of 23 (sem 0·8) %) completed the study. Postprandial responses to a test meal (over 360 min) and changes in anthropometry (fat mass, fat-free mass, circumferences) were assessed at baseline and upon attainment of 5 % weight loss, following a 7-d period of weight stabilisation. The study found no statistically significant difference in the time to attain a 5 % weight loss between groups (median 59 d (interquartile range (IQR) 41-80) and 73 d (IQR 48-128), respectively, P=0·246), or in body composition (P≥0·437). For postprandial measures, neither diet significantly altered glycaemia (P=0·266), whereas insulinaemia was reduced comparatively (P=0·903). The reduction in C-peptide tended (P=0·057) to be greater following IER (309 128 (sem23 268) to 247781 (sem20 709) pmol×360 min/l) v. CER (297 204 (sem25 112) to 301 655 (sem32 714) pmol×360 min/l). The relative reduction in TAG responses was greater (P=0·045) following IER (106 (sem30) to 68 (sem 15) mmol×360 min/l) compared with CER (117 (sem 43) to 130 (sem 31) mmol×360 min/l). In conclusion, these preliminary findings highlight underlying differences between IER and CER, including a superiority of IER in reducing postprandial lipaemia, which now warrant targeted mechanistic evaluation within larger study cohorts.

KEYWORDS:

3-OHB 3-hydroxybutyrate; CER continuous energy restriction; ER energy restriction; IER intermittent energy restriction; REE resting energy expenditure; Glucose; Humans; Intermittent fasting; Lipids; TAG

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Transcriptome Analysis of the Thymus in Short-Term Calorie-Restricted Mice Using RNA-seq.

Omeroğlu Ulu Z, Ulu S, Dogan S, Guvenc Tuna B, Ozdemir Ozgenturk N.

Int J Genomics. 2018 Feb 4;2018:7647980. doi: 10.1155/2018/7647980. eCollection 2018.

PMID: 29511668

Abstract

Calorie restriction (CR), which is a factor that expands lifespan and an important player in immune response, is an effective protective method against cancer development. Thymus, which plays a critical role in the development of the immune system, reacts to nutrition deficiency quickly. RNA-seq-based transcriptome sequencing was performed to thymus tissues of MMTV-TGF-α mice subjected to ad libitum (AL), chronic calorie restriction (CCR), and intermittent calorie restriction (ICR) diets in this study. Three cDNA libraries were sequenced using Illumina HiSeq™ 4000 to produce 100 base pair-end reads. On average, 105 million clean reads were mapped and in total 6091 significantly differentially expressed genes (DEGs) were identified (p < 0.05). These DEGs were clustered into Gene Ontology (GO) categories. The expression pattern revealed by RNA-seq was validated by quantitative real-time PCR (qPCR) analysis of four important genes, which are leptin, ghrelin, Igf1, and adinopectin. RNA-seq data has been deposited in NCBI Gene Expression Omnibus (GEO) database (GSE95371). We report the use of RNA sequencing to find DEGs that are affected by different feeding regimes in the thymus.

 

Caloric Restriction Engages Hepatic RNA Processing Mechanisms in Rhesus Monkeys.

Rhoads TW, Burhans MS, Chen VB, Hutchins PD, Rush MJP, Clark JP, Stark JL, McIlwain SJ, Eghbalnia HR, Pavelec DM, Ong IM, Denu JM, Markley JL, Coon JJ, Colman RJ, Anderson RM.

Cell Metab. 2018 Mar 6;27(3):677-688.e5. doi: 10.1016/j.cmet.2018.01.014.

PMID: 29514073

Abstract

Caloric restriction (CR) extends lifespan and delays the onset of age-related disorders in diverse species. Metabolic regulatory pathways have been implicated in the mechanisms of CR, but the molecular details have not been elucidated. Here, we show that CR engages RNA processing of genes associated with a highly integrated reprogramming of hepatic metabolism. We conducted molecular profiling of liver biopsies collected from adult male rhesus monkeys (Macaca mulatta) at baseline and after 2 years on control or CR (30% restricted) diet. Quantitation of over 20,000 molecules from the hepatic transcriptome, proteome, and metabolome indicated that metabolism and RNA processing are major features of the response to CR. Predictive models identified lipid, branched-chain amino acid, and short-chain carbon metabolic pathways, with alternate transcript use for over half of the genes in the CR network. We conclude that RNA-based mechanisms are central to the CR response and integral in metabolic reprogramming.

KEYWORDS:

RNA processing; aging; caloric restriction; lipid metabolism; metabolism; rhesus macaque

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Effects of polymorphism rs3123554 in the cannabinoid receptor gene type 2 (CB2R) on metabolic and adiposity parameters after weight loss with two hypocaloric diets.

de Luis DA, Primo D, Izaola O, Aller R.

Diabetes Res Clin Pract. 2018 Mar 5. pii: S0168-8227(18)30143-8. doi: 10.1016/j.diabres.2018.02.030. [Epub ahead of print]

PMID: 29518488

Abstract

BACKGROUND:

The role of CB2R gene variants on weight loss after a dietary intervention remained unclear.

OBJECTIVE:

Our aim was to analyze the effects of rs3123554 of CB2R receptor gene on metabolic and adiposity parameters after two different hypocaloric diets in obese subjects DESIGN: A Caucasian population of 280 obese patients was enrolled. Patients were randomly allocated during 3 months to one of two diets (Diet I - moderate in carbohydrate. Vs Diet II -normal in carbohydrate).

RESULTS:

In both genotype groups (GG vs GA+AA), body weight, body mass index (BMI), fat mass, waist circumference and systolic blood pressure decreased after diet I and II. The decrease of these parameters was higher in non A allele carriers than A allele carriers. Pre- and post-dietary intervention, body weight, BMI, fat mass and waist circumference were higher in A allele carriers than non A allele carriers. In non A allele carriers, the decrease of glucose, insulin, HOMA-IR and Interleukin-6 levels was higher than A allele carriers after both diets.

CONCLUSION:

Carriers of the minor allele of rs3123554 variant of CB2R gene loose less body weight during two different hypocaloric diets. The improvement of metabolic parameters was better in no A allele carriers than A allele carriers.

KEYWORDS:

ADIPOKINES; CANNABINOID RECEPTOR GENE TYPE 2; OBESITY; hypocaloric DIET; rs3123554

 

The Effects of Diet on the Proportion of Intramuscular Fat in Human Muscle: A Systematic Review and Meta-analysis.

Ahmed S, Singh D, Khattab S, Babineau J, Kumbhare D.

Front Nutr. 2018 Feb 20;5:7. doi: 10.3389/fnut.2018.00007. eCollection 2018. Review.

PMID: 29516003

Abstract

BACKGROUND:

There is an increasing trend in the consumption of poor-quality diets worldwide, contributing to the increase of non-communicable diseases. Diet directly influences physiological composition and subsequently physical health. Studies have shown that dietary macronutrient and energy content can influence the proportion of intramuscular fat (IMF), which mediates various metabolic and endocrine dysfunction. The purpose of this systematic review was to identify evidence in the literature assessing the association between different dietary interventions on the proportion of IMF in humans.

METHODS:

Three medical databases were investigated (Medline, EMBASE, and Cochrane) to identify studies assessing changes in IMF after dietary interventions. The primary outcome measure was the change in IMF proportions after a dietary intervention. The effects of high-fat, high-carbohydrate, low-calorie, and starvation diets were assessed qualitatively. A meta-analysis assessing the effect of high-fat diets was conducted. Follow-up sensitivity and subgroup analyses were also conducted.

RESULTS:

One thousand eight hundred and sixty-six articles were identified for review. Of these articles, 13 were eligible for inclusion after a full screening. High-fat diets increased IMF proportions, standardized mean difference = 1.24 (95% confidence interval, 0.43-2.05) and a significant overall effect size (P = 0.003). Diets with an increased proportion of carbohydrates decreased IMF proportions; however, increasing caloric intake with carbohydrates increased IMF. Starvation diets increased IMF stores, and hypocaloric diets did not result in any IMF proportion changes.

CONCLUSION:

This systematic review suggests that high-fat diets and diets with caloric intake increased above the amount required to maintain BMI with carbohydrates, and short-term starvation diets are associated with increases in IMF content. Further studies are needed to assess the effects of macronutrient combinations on IMF and the influence of diet-induced IMF alterations on health outcomes. In addition, IMF poses a possibly effective clinical marker of health.

KEYWORDS:

diet; energy; high-fat diets; intramuscular fat; review

 

Effect of caloric restriction on liver function in young and old ApoE/LDLr-/- mice

Kostogrys RB, Franczyk-Żarów M, Manterys A, Wybrańska I.

Rocz Panstw Zakl Hig. 2018;69(1):37-43.

PMID: 29517190

Abstract

BACKGROUND:

Caloric restriction (CR) leads to decrease metabolic intensity, which results in a reduction of oxygen consumption and the amount of free radicals. This can affect the function of the liver. Studies show that caloric restriction does not alter or significantly increase the enzyme activity associated with gluconeogenesis, but the effect was different according to the age of the model animals.

OBJECTIVE:

The aim of the study was to determine the effect of caloric restriction on liver function in young and old ApoE/ LDLr-/- mice.

MATERIAL AND METHODS:

Dietary experiments were performed on 2 and 5 month old male ApoE/LDLr-/- mice. Animals were divided into 3 experimental groups (n=6) and fed AIN’93G diet for 8 and 5 weeks, respectively. Control animals were fed ad libitum (AL) and housed in a colony cages. These animals were checked for dietary intake. The second group were also fed ad libitum but the animals were kept individually in cages (stress AL- sAL). Similarly to sAL group, the animals from the CR group were kept individually but received a 30% less diet compared to AL group. At the end of the experiment animals were euthanized and the blood, liver and adipose tissue have been collected. Alanine aminotransferase (ALT) as well as aspartate aminotransferase (AST) were measured in plasma. Fatty acid profile was evaluated (relative %) in adipose tissue (GC-MS). Liver’s stetosis was assessed. Results were analyzed statistically (ANOVA, STATISTICA v.10.0).

RESULTS:

CR ApoE/LDLr-/- mice showed significantly lower body weight compared to animals, both AL and sAL. There were no significant differences between ALT and AST in both younger and older animals. However, negative tendencies were more pronounced in younger animals. In young animals CR significantly increased liver weight compared to AL (4.14 vs 3.73g/100g). In adipose tissue fatty acid profile differed in CR mice compared to control in young animals.

CONCLUSIONS:

Caloric restriction did not affect liver enzymes in mice. Caloric restriction showed similar but not identical metabolic activity in young and old mice.

KEYWORDS:

caloric restriction; liver; ApoE/LDLr-/- mice

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Caloric Restriction and Its Effect on Blood Pressure, Heart Rate Variability and Arterial Stiffness and Dilatation: A Review of the Evidence.

Nicoll R, Henein MY.

Int J Mol Sci. 2018 Mar 7;19(3). pii: E751. doi: 10.3390/ijms19030751. Review.

PMID: 29518898

http://www.mdpi.com/1422-0067/19/3/751/htm

Abstract

Essential hypertension, fast heart rate, low heart rate variability, sympathetic nervous system dominance over parasympathetic, arterial stiffness, endothelial dysfunction and poor flow-mediated arterial dilatation are all associated with cardiovascular mortality and morbidity. This review of randomised controlled trials and other studies demonstrates that caloric restriction (CR) is capable of significantly improving all these parameters, normalising blood pressure (BP) and allowing patients to discontinue antihypertensive medication, while never becoming hypotensive. CR appears to be effective regardless of age, gender, ethnicity, weight, body mass index (BMI) or a diagnosis of metabolic syndrome or type 2 diabetes, but the greatest benefit is usually observed in the sickest subjects and BP may continue to improve during the refeeding period. Exercise enhances the effects of CR only in hypertensive subjects. There is as yet no consensus on the mechanism of effect of CR and it may be multifactorial. Several studies have suggested that improvement in BP is related to improvement in insulin sensitivity, as well as increased nitric oxide production through improved endothelial function. In addition, CR is known to induce SIRT1, a nutrient sensor, which is linked to a number of beneficial effects in the body.

KEYWORDS:

arterial stiffness; blood pressure; caloric restriction fasting; flow-mediated dilatation; heart rate variability

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Effect of resistance training and protein intake pattern on myofibrillar protein synthesis and proteome kinetics in older men in energy restriction.

Murphy CH, Shankaran M, Churchward-Venne TA, Mitchell CJ, Kolar NM, Burke LM, Hawley JA, Kassis A, Karagounis LG, Li K, King C, Hellerstein M, Phillips SM.

J Physiol. 2018 Mar 12. doi: 10.1113/JP275246. [Epub ahead of print]

PMID: 29532476

Abstract

We determined how the pattern of protein intake and resistance training (RT) influenced longer-term (2-wk) integrated myofibrillar protein synthesis (MyoPS) during energy restriction (ER). MyoPS and proteome kinetics were measured during 2-wk of ER alone and 2-wk of ER plus RT (ER + RT) in overweight/obese older men. Participants were randomized to consume dietary protein in a balanced (BAL: 25% daily protein/meal x 4 meals) or skewed (SKEW: 7:17:72:4% daily protein/meal) pattern (n = 10/group). Participants ingested D2 O during the consecutive 2-wk periods, and skeletal muscle biopsies and serum were obtained at the beginning and conclusion of ER and ER + RT. Bulk MyoPS (i.e. synthesis of the myofibrillar protein sub-fraction) and the synthetic rates of numerous individual skeletal muscle proteins were quantified. Bulk MyoPS was not affected by protein distribution during ER or ER + RT (ER: BAL = 1.24 ± 0.31%/d, SKEW = 1.26 ± 0.37%/d; ER+RT: BAL = 1.64 ± 0.48%/d, SKEW = 1.52 ± 0.66%/d) but was ∼26% higher during ER+RT than ER (P = 0.023). The synthetic rates of 175 of 190 contractile, cytosolic and mitochondrial skeletal muscle proteins, as well as synthesis of muscle-derived proteins measured in serum, creatine kinase M-type (CK-M) and carbonic anhydrase 3 (CA-3), were higher during ER+RT than ER (P < 0.05). In addition, the synthetic rates of CK-M and CA-3 measured in serum correlated with the synthetic rates of proteins obtained via muscle sampling (P < 0.05). This study provides novel data on the skeletal muscle adaptations to RT and dietary protein distribution.

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Long-Term Caloric Restriction Improves Cardiac Function, Remodeling, Adrenergic Responsiveness, and Sympathetic Innervation in a Model of Postischemic Heart Failure.

de Lucia C, Gambino G, Petraglia L, Elia A, Komici K, Femminella GD, D'Amico ML, Formisano R, Borghetti G, Liccardo D, Nolano M, Houser SR, Leosco D, Ferrara N, Koch WJ, Rengo G.

Circ Heart Fail. 2018 Mar;11(3):e004153. doi: 10.1161/CIRCHEARTFAILURE.117.004153.

PMID: 29535114

Abstract

BACKGROUND:

Caloric restriction (CR) has been described to have cardioprotective effects and improve functional outcomes in animal models and humans. Chronic ischemic heart failure (HF) is associated with reduced cardiac sympathetic innervation, dysfunctional β-adrenergic receptor signaling, and decreased cardiac inotropic reserve. We tested the effects of a long-term CR diet, started late after myocardial infarction on cardiac function, sympathetic innervation, and β-adrenergic receptor responsiveness in a rat model of postischemic HF.

METHODS AND RESULTS:

Adult male rats were randomly assigned to myocardial infarction or sham operation and 4 weeks later were further randomized to a 1-year CR or normal diet. One year of CR resulted in a significant reduction in body weight, heart weight, and heart weight/tibia length ratio when compared with normal diet in HF groups. At the end of the study period, echocardiography and histology revealed that HF animals under the CR diet had ameliorated left ventricular remodeling compared with HF rats fed with normal diet. Invasive hemodynamic showed a significant improvement of cardiac inotropic reserve in CR HF rats compared with HF-normal diet animals. Importantly, CR dietary regimen was associated with a significant increase of cardiac sympathetic innervation and with normalized cardiac β-adrenergic receptor levels in HF rats when compared with HF rats on the standard diet.

CONCLUSIONS:

We demonstrate, for the first time, that chronic CR, when started after HF established, can ameliorate cardiac dysfunction and improve inotropic reserve. At the molecular level, we find that chronic CR diet significantly improves sympathetic cardiac innervation and β-adrenergic receptor levels in failing myocardium.

KEYWORDS:

; caloric restriction; heart failure; myocardial infarction; receptors, adrenergic; sympathetic nervous system

Edited by AlPater

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