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      Short‐term very low caloric intake causes endothelial dysfunction and increased susceptibility to cardiac arrhythmias and pathology in male rats

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          Abstract

          New Findings

          • What is the central question of this study?

            What are the effects of a 2 week period of severe food restriction on vascular reactivity of resistance arteries and on cardiac structure and function?

          • What is the main finding and its importance?

            This study showed, for the first time, that a 2 week period of severe food restriction in adult male Fischer rats caused endothelial dysfunction in mesenteric arteries and increased the susceptibility to ischaemia–reperfusion‐induced arrhythmias and cardiac pathology. Our findings might have ramifications for cardiovascular risk in people who experience periods of inadequate caloric intake.

          Abstract

          Severe food restriction (sFR) is a common dieting strategy for rapid weight loss. Male Fischer rats were maintained on a control (CT) or sFR (40% of CT food intake) diet for 14 days to mimic low‐calorie crash diets. The sFR diet reduced body weight by 16%. Haematocrits were elevated by 10% in the sFR rats, which was consistent with the reduced plasma volume. Mesenteric arteries from sFR rats had increased sensitivity to vasoconstrictors, including angiotensin II [maximum (%): CT, 1.30 ± 0.46 versus sFR, 11.5 ± 1.6; P < 0.0001; n = 7] and phenylephrine [maximum (%): CT, 78.5 ± 2.8 versus sFR, 94.5 ± 1.7; P < 0.001; n = 7] and reduced sensitivity to the vasodilator acetylcholine [EC 50 (n m): CT, 49.2 ± 5.2 versus sFR, 71.6 ± 6.8; P < 0.05; n = 7]. Isolated hearts from sFR rats had a 1.7‐fold increase in the rate of cardiac arrhythmias in response to ischaemia–reperfusion and more cardiac pathology, including myofibrillar disarray with contractions and cardiomyocyte lysis, than hearts from CT rats. The sFR dietary regimen is similar to very low‐calorie commercial and self‐help weight‐loss programmes, which provide ∼800–1000 kcal day −1. Therefore, these findings in rats warrant the study of cardiovascular function in individuals who engage in extreme dieting or are subjected to bouts of very low caloric intake for other reasons, such as socioeconomic factors and natural disasters.

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          Most cited references51

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          Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study.

          Calorie restriction (CR), a reduction of 10–40% in intake of a nutritious diet, is often reported as the most robust non-genetic mechanism to extend lifespan and healthspan. CR is frequently used as a tool to understand mechanisms behind ageing and age-associated diseases. In addition to and independently of increasing lifespan, CR has been reported to delay or prevent the occurrence of many chronic diseases in a variety of animals. Beneficial effects of CR on outcomes such as immune function, motor coordination and resistance to sarcopenia in rhesus monkeys have recently been reported. We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. Our findings contrast with an ongoing study at the Wisconsin National Primate Research Center (WNPRC), which reported improved survival associated with 30% CR initiated in adult rhesus monkeys (7–14 years) and a preliminary report with a small number of CR monkeys. Over the years, both NIA and WNPRC have extensively documented beneficial health effects of CR in these two apparently parallel studies. The implications of the WNPRC findings were important as they extended CR findings beyond the laboratory rodent and to a long-lived primate. Our study suggests a separation between health effects, morbidity and mortality, and similar to what has been shown in rodents, study design, husbandry and diet composition may strongly affect the life-prolonging effect of CR in a long-lived nonhuman primate.
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            The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women.

            The problems of adherence to energy restriction in humans are well known. To compare the feasibility and effectiveness of intermittent continuous energy (IER) with continuous energy restriction (CER) for weight loss, insulin sensitivity and other metabolic disease risk markers. Randomized comparison of a 25% energy restriction as IER (∼ 2710 kJ/day for 2 days/week) or CER (∼ 6276 kJ/day for 7 days/week) in 107 overweight or obese (mean (± s.d.) body mass index 30.6 (± 5.1) kg m(-2)) premenopausal women observed over a period of 6 months. Weight, anthropometry, biomarkers for breast cancer, diabetes, cardiovascular disease and dementia risk; insulin resistance (HOMA), oxidative stress markers, leptin, adiponectin, insulin-like growth factor (IGF)-1 and IGF binding proteins 1 and 2, androgens, prolactin, inflammatory markers (high sensitivity C-reactive protein and sialic acid), lipids, blood pressure and brain-derived neurotrophic factor were assessed at baseline and after 1, 3 and 6 months. Last observation carried forward analysis showed that IER and CER are equally effective for weight loss: mean (95% confidence interval ) weight change for IER was -6.4 (-7.9 to -4.8) kg vs -5.6 (-6.9 to -4.4) kg for CER (P-value for difference between groups = 0.4). Both groups experienced comparable reductions in leptin, free androgen index, high-sensitivity C-reactive protein, total and LDL cholesterol, triglycerides, blood pressure and increases in sex hormone binding globulin, IGF binding proteins 1 and 2. Reductions in fasting insulin and insulin resistance were modest in both groups, but greater with IER than with CER; difference between groups for fasting insulin was -1.2 (-1.4 to -1.0) μU ml(-1) and for insulin resistance was -1.2 (-1.5 to -1.0) μU mmol(-1) l(-1) (both P = 0.04). IER is as effective as CER with regard to weight loss, insulin sensitivity and other health biomarkers, and may be offered as an alternative equivalent to CER for weight loss and reducing disease risk.
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              Deacetylation of FoxO by Sirt1 Plays an Essential Role in Mediating Starvation-Induced Autophagy in Cardiac Myocytes.

              autophagy, a bulk degradation process of cytosolic proteins and organelles, is protective during nutrient starvation in cardiomyocytes (CMs). However, the underlying signaling mechanism mediating autophagy is not well understood. we investigated the role of FoxOs and its posttranslational modification in mediating starvation-induced autophagy. glucose deprivation (GD) increased autophagic flux in cultured CMs, as evidenced by increased mRFP-GFP-LC3 puncta and decreases in p62, which was accompanied by upregulation of Sirt1 and FoxO1. Overexpression of either Sirt1 or FoxO1 was sufficient for inducing autophagic flux, whereas both Sirt1 and FoxO1 were required for GD-induced autophagy. GD increased deacetylation of FoxO1, and Sirt1 was required for GD-induced deacetylation of FoxO1. Overexpression of FoxO1(3A/LXXAA), which cannot interact with Sirt1, or p300, a histone acetylase, increased acetylation of FoxO1 and inhibited GD-induced autophagy. FoxO1 increased expression of Rab7, a small GTP-binding protein that mediates late autophagosome-lysosome fusion, which was both necessary and sufficient for mediating FoxO1-induced increases in autophagic flux. Although cardiac function was maintained in control mice after 48 hours of food starvation, it was significantly deteriorated in mice with cardiac-specific overexpression of FoxO1(3A/LXXAA), those with cardiac-specific homozygous deletion of FoxO1 (c-FoxO1(-/-)), and beclin1(+/-) mice, in which autophagy is significantly inhibited. these results suggest that Sirt1-mediated deacetylation of FoxO1 and upregulation of Rab7 play an important role in mediating starvation-induced increases in autophagic flux, which in turn plays an essential role in maintaining left ventricular function during starvation.
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                Author and article information

                Contributors
                sandberg@georgetown.edu
                Journal
                Exp Physiol
                Exp. Physiol
                10.1111/(ISSN)1469-445X
                EPH
                expphysiol
                Experimental Physiology
                John Wiley and Sons Inc. (Hoboken )
                0958-0670
                1469-445X
                08 June 2020
                01 July 2020
                : 105
                : 7 ( doiID: 10.1113/eph.v105.7 )
                : 1172-1184
                Affiliations
                [ 1 ] Department of Medicine Georgetown University Washington DC USA
                [ 2 ] Department of Pharmacology & Physiology Georgetown University Washington DC USA
                [ 3 ] Department of Biostatistics Bioinformatics and Biomathematics Georgetown University Washington DC USA
                Author notes
                [*] [* ] Correspondence

                Kathryn Sandberg, Suite 232 Building D, 4000 Reservoir Road, NW, Washington, DC 20057, USA.

                Email: sandberg@ 123456georgetown.edu

                Author information
                https://orcid.org/0000-0003-2967-8336
                Article
                EPH12761
                10.1113/EP088434
                7496402
                31e206cd-f190-41a4-9be0-409288edaa49
                © 2020 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 09 January 2020
                : 05 May 2020
                Page count
                Figures: 8, Tables: 2, Pages: 13, Words: 8528
                Funding
                Funded by: Conselho Nacional de Desenvolvimento Científico e Tecnológico , open-funder-registry 10.13039/501100003593;
                Award ID: Predoctoral Student Award
                Funded by: Georgetown University Partners‐in‐Research
                Funded by: American Heart Association , open-funder-registry 10.13039/100000968;
                Award ID: Postdoctoral Fellowship Award
                Funded by: National Heart, Lung, and Blood Institute , open-funder-registry 10.13039/100000050;
                Award ID: R01‐HL121456
                Funded by: National Institute on Aging , open-funder-registry 10.13039/100000049;
                Award ID: R21‐AG060730
                Categories
                Research Paper
                Research Papers
                Vascular
                Custom metadata
                2.0
                1 July 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.0 mode:remove_FC converted:11.09.2020

                Anatomy & Physiology
                inadequate food intake,langendorff,vascular reactivity
                Anatomy & Physiology
                inadequate food intake, langendorff, vascular reactivity

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