Calorie restriction anti-hypertrophic effects are associated with improved mitochondrial content, blockage of Ca2+-induced mitochondrial damage, and lower reverse electron transport-mediated oxidative stress.

Calorie restriction is a nutritional intervention that reproducibly protects against the maladaptive consequences of cardiovascular diseases. Pathological cardiac hypertrophy leads to cellular growth, dysfunction (with mitochondrial dysregulation), and oxidative stress. The mechanisms behind the cardiovascular protective effects of calorie restriction are still under investigation. In this study, we show that this dietetic intervention prevents cardiac protein elevation, avoids fetal gene reprogramming (atrial natriuretic peptide), and blocks the increase in heart weight per tibia length index (HW/TL) seen in isoproterenol-induced cardiac hypertrophy. Our findings suggest that calorie restriction inhibits cardiac pathological growth while also lowering mitochondrial reverse electron transport-induced hydrogen peroxide formation and improving mitochondrial content. Calorie restriction also attenuated the opening of the Ca2+-induced mitochondrial permeability transition pore. We also found that calorie restriction blocked the negative correlation of antioxidant enzymes (superoxide dimutase and glutatione peroxidase activity) and HW/TL, leading to the maintenance of protein sulphydryls and glutathione levels. Given the nature of isoproterenol-induced cardiac hypertrophy, we investigated whether calorie restriction could alter cardiac beta-adrenergic sensitivity. Using isolated rat hearts in a Langendorff system, we found that calorie restricted hearts have preserved beta-adrenergic signaling. In contrast, hypertrophic hearts (treated for seven days with isoproterenol) were insensitive to beta-adrenergic activation using isoproterenol (50 nM). Despite protecting against cardiac hypertrophy, calorie restriction did not alter the lack of responsiveness to isoproterenol in isolated hearts harvested from isoproterenol-treated rats. These results suggest (through a series of mitochondrial, oxidative stress, and cardiac hemodynamic studies) that calorie restriction possesses beneficial effects against hypertrophic cardiomyopathy.

Calorie Restriction and Time-Restricted Feeding: Effective Interventions in Overweight or Obese Patients Undergoing Radiotherapy Treatment with Curative Intent for Cancer.

This study assesses the feasibility of calorie restriction (CR) and time-restricted feeding (TRF) in overweight and obese cancer patients who realized little to no physical activity undergoing curative radiotherapy, structured as a prospective, interventional, non-randomized open-label clinical trial. Of the 27 participants initially enrolled, 21 patients with breast cancer were selected for analysis. The participants self-selected into two dietary interventions: TRF, comprising a sugar and saturated fat-free diet calibrated to individual energy needs consumed within an 8 h eating window followed by a 16 h fast, or CR, involving a 25% reduction in total caloric intake from energy expenditure distributed across 4 meals and 1 snack with 55% carbohydrates, 15% protein, and 30% fats, excluding sugars and saturated fats. The primary goal was to evaluate the feasibility of these diets in the specific patient group. The results indicate that both interventions are effective and statistically significant for weight loss and reducing one's waist circumference, with TRF showing a potentially stronger impact and better adherence. Changes in the LDL, HDL, total cholesterol, triglycerides, glucose and insulin were not statistically significant.

Sirtuin 1 and Vascular Function in Healthy Women and Men: A Randomized Clinical Trial Comparing the Effects of Energy Restriction and Resveratrol.

Background: Sirtuin 1 (SIRT1) has been associated with longevity and protection against cardiometabolic diseases, but little is known about how it influences human vascular function. Therefore, this study evaluated the effects of SIRT1 activation by resveratrol and energy restriction on vascular reactivity in adults. Methods: A randomized trial allocated 48 healthy adults (24 women and 24 men), aged 55 to 65 years, to resveratrol supplementation or energy restriction for 30 days. Blood lipids, glucose, insulin, C-reactive protein, noradrenaline, SIRT1 (circulating and gene expression), and flow-mediated vasodilation (FMD) and nitrate-mediated vasodilation (NMD) were measured. Results: Both interventions increased circulating SIRT1 (p < 0.001). Pre- and post-tests changes of plasma noradrenaline were significant for both groups (resveratrol: p = 0.037; energy restriction: p = 0.008). Baseline circulating SIRT1 was inversely correlated with noradrenaline (r = -0.508; p < 0.01), and post-treatment circulating SIRT1 was correlated with NMD (r = 0.433; p < 0.01). Circulating SIRT1 was a predictor of FMD in men (p = 0.045), but not in women. SIRT1 was an independent predictor of NMD (p = 0.026) only in the energy restriction group. Conclusions: Energy restriction and resveratrol increased circulating SIRT1 and reduced sympathetic activity similarly in healthy adults. SIRT1 was independently associated with NMD only in the energy restriction group.

Adiponectin reverses ß-Cell damage and impaired insulin secretion induced by obesity.

Obesity significantly decreases life expectancy and increases the incidence of age-related dysfunctions, including ß-cell dysregulation leading to inadequate insulin secretion. Here, we show that diluted plasma from obese human donors acutely impairs ß-cell integrity and insulin secretion relative to plasma from lean subjects. Similar results were observed with diluted sera from obese rats fed ad libitum, when compared to sera from lean, calorically restricted, animals. The damaging effects of obese circulating factors on ß-cells occurs in the absence of nutrient overload, and mechanistically involves mitochondrial dysfunction, limiting glucose-supported oxidative phosphorylation and ATP production. We demonstrate that increased levels of adiponectin, as found in lean plasma, are the protective characteristic preserving ß-cell function; indeed, sera from adiponectin knockout mice limits ß-cell metabolic fluxes relative to controls. Furthermore, oxidative phosphorylation and glucose-sensitive insulin secretion, which are completely abrogated in the absence of this hormone, are restored by the presence of adiponectin alone, surprisingly even in the absence of other serological components, for both the insulin-secreting INS1 cell line and primary islets. The addition of adiponectin to cells treated with plasma from obese donors completely restored ß-cell functional integrity, indicating the lack of this hormone was causative of the dysfunction. Overall, our results demonstrate that low circulating adiponectin is a key damaging element for ß-cells, and suggest strong therapeutic potential for the modulation of the adiponectin signaling pathway in the prevention of age-related ß-cell dysfunction.

Fasting and prolonged food restriction differentially affect GH secretion independently of GH receptor signaling in AgRP neurons.

Growth hormone (GH) receptor (GHR) is abundantly expressed in neurons that co-release the agouti-related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARH). Since ARHAgRP/NPY neurons regulate several hypothalamic-pituitary-endocrine axes, this neuronal population possibly modulates GH secretion via a negative feedback loop, particularly during food restriction, when ARHAgRP/NPY neurons are highly active. The present study aims to determine the importance of GHR signaling in ARHAgRP/NPY neurons on the pattern of GH secretion in fed and food-deprived male mice. Additionally, we compared the effect of two distinct situations of food deprivation: 16 h of fasting or four days of food restriction (40% of usual food intake). Overnight fasting strongly suppressed both basal and pulsatile GH secretion. Animals lacking GHR in ARHAgRP/NPY neurons (AgRP∆GHR mice) did not exhibit differences in GH secretion either in the fed or fasted state, compared to control mice. In contrast, four days of food restriction increased GH pulse frequency, basal GH secretion, and pulse irregularity/complexity (measured by sample entropy), whereas pulsatile GH secretion was not affected in both control and AgRP∆GHR mice. Hypothalamic Ghrh mRNA levels were unaffected by fasting or food restriction, but Sst expression increased in acutely fasted mice, but decreased after prolonged food restriction in both control and AgRP∆GHR mice. Our findings indicate that short-term fasting and prolonged food restriction differentially affect the pattern of GH secretion, independently of GHR signaling in ARHAgRP/NPY neurons.

Intermittent fasting for health care, a review / El ayuno intermitente, ¿un éxito o una desventaja para el cuidado de la salud?

The incidence of obesity and overweight in the world has been increasing in recent years due to poor diet and lack of physical activity; people suffering obesity and overweight, related with malnutrition due to excess, often resort to calorie restriction diets that are usually not very effective. In this context, intermittent fasting (IF) has become popular due to the possibilities for weight loss that it offers. This diet consists of alternating periods of fasting with unrestricted eating; however, its effectiveness and consequences are unknown to most users. This narrative review analyzes whether intermittent fasting contributes to the improvement of body and metabolic composition. The purpose of the review was to examine the available data on the contribution of intermittent fasting to the improvement of body and metabolic composition, in order to provide information and to define the parameters that condition safe achievement of its benefits. IF dieting triggers adaptive cell responses that cause a decrease in lipid oxidative stress markers in individuals with obesity and prediabetes. Metabolic alterations have been found to go hand in hand with the alteration of circadian rhythms; if IF contributes to this effect, it may assist in treating and preventing obesity and associated diseases. However, there are also disadvantages, such as the loss of lean muscle mass by wasting, and increased hypoglycemia(AU)

La incidencia de obesidad y sobrepeso en el mundo ha ido en aumento en los últimos años debido a la mala alimentación y la falta de actividad física; Las personas que padecen obesidad y sobrepeso, relacionadas con la desnutrición por exceso, suelen recurrir a dietas de restricción calórica que suelen ser poco efectivas. En este contexto, el ayuno intermitente (AI) se ha popularizado debido a las posibilidades de pérdida de peso que ofrece. Esta dieta consiste en alternar períodos de ayuno con alimentación sin restricciones; sin embargo, su eficacia y consecuencias son desconocidas para la mayoría de los usuarios. Esta revisión narrativa analiza si el ayuno intermitente contribuye a la mejora de la composición corporal y metabólica. El objetivo de la revisión fue examinar los datos disponibles sobre la contribución del ayuno intermitente a la mejora de la composición corporal y metabólica, con el fin de aportar información y definir los parámetros que condicionan la consecución segura de sus beneficios. Se ha encontrado que las alteraciones metabólicas van de la mano con la alteración de los ritmos circadianos; si AI contribuye a este efecto, puede ayudar a tratar y prevenir la obesidad y las enfermedades asociadas. Sin embargo, también existen desventajas, como la pérdida de masa muscular magra por atrofia y el aumento de la hipoglucemia(AU)

Effects of whey protein supplementation on adiposity, body weight, and glycemic parameters: A synthesis of evidence.

AIMS: The aim of this review was to analyze the evidence of whey protein supplementation on body weight, fat mass, lean mass and glycemic parameters in subjects with overweight or type 2 diabetes mellitus (T2DM) undergoing calorie restriction or with ad libitum intake. DATA SYNTHESIS: Overweight and obesity are considered risk factors for the development of chronic noncommunicable diseases such as T2DM. Calorie restriction is a dietary therapy that reduces weight and fat mass, promotes the improvement of glycemic parameters, and decreases muscle mass. The maintenance of muscle mass during weight loss is necessary in view of its implication in preventing chronic diseases and improving functional capacity and quality of life. The effects of increased protein consumption on attenuating muscle loss and reducing body fat during calorie restriction or ad libitum intake in overweight individuals are discussed. Some studies have demonstrated the positive effects of whey protein supplementation on improving satiety and postprandial glycemic control in short term; however, it remains unclear whether long-term whey protein supplementation can positively affect glycemic parameters. CONCLUSIONS: Although whey protein is considered to have a high nutritional quality, its effects in the treatment of overweight, obese individuals and those with T2DM undergoing calorie restriction or ad libitum intake are still inconclusive.

The Interplay of Sirtuin-1, LDL-Cholesterol, and HDL Function: A Randomized Controlled Trial Comparing the Effects of Energy Restriction and Atorvastatin on Women with Premature Coronary Artery Disease.

INTRODUCTION: HDL function has gained prominence in the literature as there is a greater predictive capacity for risk in early coronary artery disease when compared to the traditional parameters. However, it is unclear how dietary energy restriction and atorvastatin influence HDL function. METHODS: A randomized controlled trial with 39 women with early CAD divided into three groups (n = 13): energy restriction (30% of VET), atorvastatin (80 mg), and control. Analyses of traditional biochemical markers (lipid and glucose profile), circulating Sirt-1, and HDL function (lipid composition, lipid transfer, and antioxidant capacity). RESULTS: Participants' mean age was 50.5 ± 3.8 years. Energy restriction increased Sirt-1 by 63.6 pg/mL (95%CI: 1.5-125.7; p = 0.045) and reduced BMI by 0.8 kg/m2 (95%CI: -1.349--0.273; p = 0.004) in a manner independent of other cardiometabolic factors. Atorvastatin reduced LDL-c by 40.0 mg/dL (95%CI: -69.910--10.1; p = 0.010). Increased Sirt-1 and reduced BMI were independently associated with reduced phospholipid composition of HDL (respectively, ß = -0.071; CI95%:-0.136--0.006; p = 0.033; ß = 7.486; CI95%:0.350-14.622; p = 0.040). Reduction in BMI was associated with lower HDL-free cholesterol (ß = 0.818; CI95%:0.044-1.593; p = 0.039). LDL-c reduction by statins was associated with reduced maximal lipid peroxide production rate of HDL (ß = 0.002; CI95%:0.000-0.003; p = 0.022) and total conjugated diene generation (ß = 0.001; CI95%:0.000-0.001; p = 0.029). CONCLUSION: This study showed that energy restriction and atorvastatin administration were associated with changes in lipid profile, serum Sirt-1 concentrations, and HDL function.

Regulation of kidney mitochondrial function by caloric restriction.

Caloric restriction (CR) prevents obesity and increases resilience against pathological stimuli in laboratory rodents. At the mitochondrial level, protection promoted by CR in the brain and liver is related to higher Ca2+ uptake rates and capacities, avoiding Ca2+-induced mitochondrial permeability transition. Dietary restriction has also been shown to increase kidney resistance against damaging stimuli; if these effects are related to similar mitochondrial adaptations has not been uncovered. Here, we characterized changes in mitochondrial function in response to 6 mo of CR in rats and measured bioenergetic parameters, redox balance, and Ca2+ homeostasis. CR promoted an increase in succinate-supported mitochondrial oxygen consumption rates. Although CR prevents mitochondrial reactive oxygen species production in many tissues, in kidney, we found that mitochondrial H2O2 release was enhanced in a succinate-dependent manner. Surprisingly, and opposite to the effects observed in the brain and liver, mitochondria from CR animals were more prone to Ca2+-induced mitochondrial permeability transition, in a manner reversed by the antioxidant dithiothreitol. CR mitochondria also displayed higher Ca2+ uptake rates, which were not accompanied by changes in Ca2+ efflux rates or related to altered inner mitochondrial membrane potentials or amounts of the mitochondrial Ca2+ uniporter. Instead, increased mitochondrial Ca2+ uptake rates in CR kidneys correlated with loss of mitochondrial Ca2+ uptake protein 2 (MICU2), a mitochondrial Ca2+ uniporter modulator. Interestingly, MICU2 is also modulated by CR in the liver, suggesting that it has a broader diet-sensitive regulatory role controlling mitochondrial Ca2+ homeostasis. Together, our results highlight the organ-specific bioenergetic, redox, and ionic transport results of CR, with some unexpected deleterious effects in the kidney.NEW & NOTEWORTHY Prevention of obesity through caloric restriction (CR) is well known to protect many tissues but has been poorly studied in kidneys. Here, we determined the effects of long-term CR in rat kidney mitochondria, which are central players in energy metabolism and aging. Surprisingly, we found that the diet increased mitochondrial reactive oxygen production and permeability transition. This suggests that the kidneys respond differently to restricted diets and may be more susceptible under CR.

Effect of Chronic Moderate Caloric Restriction on the Reproductive Function in Aged Male Wistar Rats.

Caloric restriction (CR) has been shown to be an effective nutritional intervention for increasing longevity in some animal species. The objective of this study was to evaluate CR's effects on metabolic and reproductive parameters in 12-month-old male Wistar rats. The rats were distributed in three groups: control, CR at 15%, and CR at 35% for 6 (up to 18 months of age) and 12 months (up to 24 months of age). At the end of CR treatment, we evaluated reproductive (male sexual behavior (MSB), sperm quality) and biochemical parameters (plasma glucose, glucose-regulating hormone, and sex steroid levels), and quantified annexin V in the seminiferous epithelium. Results showed that MSB and sperm quality were improved after 6 months of CR associated with increases in plasma testosterone and decrease annexin V in the seminiferous epithelium of the testicles compared to their control group. The metabolic profile of the CR rats also improved compared to controls. However, these effects of CR on reproductive parameters were not maintained after 12 months of CR. Findings suggest that beginning CR at the age of maturity reestablishes the behavioral sexual response and reproductive function in older animals after 6 months of CR and improves endocrine functioning during aging.

Calorie restriction changes lipidomic profiles and maintains mitochondrial function and redox balance during isoproterenol-induced cardiac hypertrophy.

Typically, healthy cardiac tissue utilizes more fat than any other organ. Cardiac hypertrophy induces a metabolic shift leading to a preferential consumption of glucose over fatty acids to support the high energetic demand. Calorie restriction is a dietary procedure that induces health benefits and lifespan extension in many organisms. Given the beneficial effects of calorie restriction, we hypothesized that calorie restriction prevents cardiac hypertrophy, lipid content changes, mitochondrial and redox dysregulation. Strikingly, calorie restriction reversed isoproterenol-induced cardiac hypertrophy. Isolated mitochondria from hypertrophic hearts produced significantly higher levels of succinate-driven H2O2 production, which was blocked by calorie restriction. Cardiac hypertrophy lowered mitochondrial respiratory control ratios, and decreased superoxide dismutase and glutathione peroxidase levels. These effects were also prevented by calorie restriction. We performed lipidomic profiling to gain insights into how calorie restriction could interfere with the metabolic changes induced by cardiac hypertrophy. Calorie restriction protected against the consumption of several triglycerides (TGs) linked to unsaturated fatty acids. Also, this dietary procedure protected against the accumulation of TGs containing saturated fatty acids observed in hypertrophic samples. Cardiac hypertrophy induced an increase in ceramides, phosphoethanolamines, and acylcarnitines (12:0, 14:0, 16:0, and 18:0). These were all reversed by calorie restriction. Altogether, our data demonstrate that hypertrophy changes the cardiac lipidome, causes mitochondrial disturbances, and oxidative stress. These changes are prevented (at least partially) by calorie restriction intervention in vivo. This study uncovers the potential for calorie restriction to become a new therapeutic intervention against cardiac hypertrophy, and mechanisms in which it acts.

Comparison of Resveratrol Supplementation and Energy Restriction Effects on Sympathetic Nervous System Activity and Vascular Reactivity: A Randomized Clinical Trial.

Background: Chronic sympathetic nervous system activation is associated with endothelial dysfunction and cardiometabolic disease, which may be modulated by resveratrol (RSV) and energy restriction (ER). This study aimed to examine the effects of RSV and ER on plasma noradrenaline (NA), flow-mediated vasodilation (ed-FMD), and endothelium-independent nitrate-mediated vasodilation (ei-NMD). Methods: The study included 48 healthy adults randomized to 30-days intervention of RSV or ER. Results: Waist circumference, total cholesterol, HDL-c, LDL-c, apoA-I, and plasma NA decreased in the ER group, whilst RSV increased apoB and total cholesterol, without changing plasma NA. No effects on vascular reactivity were observed in both groups. Plasma NA change was positively correlated with total cholesterol (r = 0.443; p = 0.002), triglycerides (r = 0.438; p = 0.002), apoA-I (r = 0.467; p = 0.001), apoB (r = 0.318; p = 0.032) changes, and ei-NMD (OR = 1.294; 95%CI: 1.021-1.640). Conclusions: RSV does not improve cardiometabolic risk factors, sympathetic activity, and endothelial function. ER decreases plasma NA and waist circumference as well as improves blood lipids, but does not modify endothelial function. Finally, plasma NA was associated with ei-NMD, which could be attributed to a higher response to nitrate in patients with greater resting sympathetic vasoconstriction.

Cardioprotective effects of severe calorie restriction from birth in adult ovariectomized rats.

AIMS: Menopause is a female condition induced by a reduction of ovarian hormone and is related to an increase in cardiovascular diseases in women. We have shown that severe calorie restriction (SCR) from birth reduces the cardiometabolic risk in adult male Wistar rats. In this study, we investigated the effects of SCR from birth to adulthood on cardiovascular function of ovariectomized rats. MAIN METHODS: From birth to adulthood, rats were daily fed ad libitum (control group - C) or with 50% of the amount consumed by the control group (calorie-restricted group - R). At 90 days, half of the rats in each group underwent bilateral ovariectomy (OVX), totaling 4 groups: C-Sham, C-OVX, R-Sham, R-OVX. Systolic blood pressure (SBP), heart rate (HR) and, double product (DP) index were recorded by tail-cuff plethysmography. Cardiac function was analyzed by the Langendorff technique and cardiomyocyte diameter was accessed by histologic analysis. Additionally, cardiac SERCA2 content and redox status were evaluated. KEY FINDINGS: C-OVX rats exhibited reduced cardiac function and cardiac non-enzymatic total antioxidant capacity (TAC). R-Sham animals showed reduced SBP, DP, HR, improved cardiac function, reduced cardiac protein carbonyl derivatives and increased TAC, catalase, and superoxide dismutase activities. R-OVX rats maintained reduced SBP, DP, HR, and increased contractility and relaxation indexes. R-Sham and R-OVX rats exhibited preserved heart mass and reduced cardiomyocyte diameter. Cardiac SERCA2 content did not differ between the groups. SIGNIFICANCE: Taken together, our findings show cardioprotective effects of SCR from birth in adult ovariectomized rats.

Simulated microgravity accelerates aging in Saccharomyces cerevisiae.

The human body experiences physiological changes under microgravity environment that phenocopy aging on Earth. These changes include early onset osteoporosis, skeletal muscle atrophy, cardiac dysfunction, and immunosenescence, and such adaptations to the space environment may pose some risk to crewed missions to Mars. To investigate the effect of microgravity on aging, many model organisms have been used such as the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and mice. Herein we report that the budding yeast Saccharomyces cerevisiae show decreased replicative lifespan (RLS) under simulated microgravity in a clinostat. The reduction of yeast lifespan is not a result of decreased tolerance to heat shock or oxidative stress and could be overcome either by deletion of FOB1 or calorie restriction, two known interventions that extend yeast RLS. Deletion of the sirtuin gene SIR2 worsens the simulated microgravity effect on RLS, and together with the fob1Δ mutant phenotype, it suggests that simulated microgravity augments the formation of extrachromosomal rDNA circles, which accumulate in yeast during aging. We also show that the chronological lifespan in minimal medium was not changed when cells were grown in the clinostat. Our data suggest that the reduction in longevity due to simulated microgravity is conserved in yeast, worms, and flies, and these findings may have potential implications for future crewed missions in space, as well as the use of microgravity as a model for human aging.

The Interconnections Between Somatic and Ovarian Aging in Murine Models.

The mammalian female is born with a limited ovarian reserve of primordial follicles. These primordial follicles are slowly activated throughout the reproductive lifecycle, thereby determining lifecycle length. Once primordial follicles are exhausted, women undergo menopause, which is associated with several metabolic perturbations and a higher mortality risk. Long before exhaustion of the reserve, females experience severe declines in fertility and health. As such, significant efforts have been made to unravel the mechanisms that promote ovarian aging and insufficiency. In this review, we explain how long-living murine models can provide insights in the regulation of ovarian aging. There is now overwhelming evidence that most life-span-extending strategies, and long-living mutant models simultaneously delay ovarian aging. Therefore, it appears that the same mechanisms that regulate somatic aging may also be modulating ovarian aging and germ cell exhaustion. We explore several potential contributing mechanisms including insulin resistance, inflammation, and DNA damage-all of which are hallmarks of cellular aging throughout the body including the ovary. These findings are in alignment with the disposable soma theory of aging, which dictates a trade-off between growth, reproduction, and DNA repair. Therefore, delaying ovarian aging will not only increase the fertility window of middle age females, but may also actively prevent menopausal-related decline in systemic health parameters, compressing the period of morbidity in mid-to-late life in females.

Prolonged fasting induces long-lasting metabolic consequences in mice.

To endure prolonged fasting, animals undergo important acute physiological adjustments. However, whether severe fasting also leads to long-term metabolic adaptations is largely unknown. Forty-eight-hour fasting caused a pronounced weight loss in adult C57BL/6 male mice. Seven days of refeeding increased body adiposity to levels above baseline, whereas fasting-induced reductions in lean body mass and energy expenditure were not fully recovered. Respiratory exchange ratio and locomotor activity also remained altered. A fasting/refeeding cycle led to persistent suppression of Pomc mRNA levels and significant changes in the expression of histone deacetylases and DNA methyltransferases in the hypothalamus. Additionally, histone acetylation in the ventromedial nucleus of the hypothalamus was reduced by prolonged fasting and remained suppressed after refeeding. Mice subjected to 48-h fasting 30 days earlier exhibited higher body weight and fat mass compared to aged-matched animals that were never food-deprived. Furthermore, a previous fasting experience altered the changes in body weight, lean mass, energy expenditure and locomotor activity induced by a second cycle of fasting and refeeding. Notably, when acutely exposed to high-palatable/high-fat diet, mice that went through cumulative fasting episodes presented higher calorie intake and reduced energy expenditure and fat oxidation, compared to mice that had never been subjected to fasting. When chronically exposed to high-fat diet, mice that experienced cumulative fasting episodes showed higher gain of body and fat mass and reduced energy expenditure and calorie intake. In summary, cumulative episodes of prolonged fasting lead to hypothalamic epigenetic changes and long-lasting metabolic adaptations in mice.

Dieta Intermitente Atenua a Remodelação Cardíaca Causada pelo Exercício Físico / Intermittent Fasting Attenuates Exercise Training-Induced Cardiac Remodeling

Resumo Fundamento A influência de intervenções não farmacológicas como restrição calórica e exercício físico sobre a saúde e prevenção de enfermidades cardíacas tem sido documentada em estudos clínicos e experimentais. Objetivo Analisar a influência da combinação entre dieta intermitente e exercício físico sobre a capacidade funcional, metabolismo glicêmico e remodelação cardíaca. Métodos Foram utilizados 60 ratos Wistar machos distribuídos em quatro grupos: Controle (C), Exercício Físico (EF), Dieta Intermitente (DI) e Exercício Físico e Dieta Intermitente (EDI). Durante 12 semanas, enquanto C e EF foram tratados diariamente com dieta comercial padrão ad libitum, DI e EDI receberam dieta similar em dias alternados com dias de jejum. Os grupos EF e EDI foram submetidos a protocolo de corrida em esteira rolante. Posteriormente, foram analisadas capacidade funcional, comportamento nutricional e metabolismo glicêmico. Além da morfologia do coração, a expressão proteica das proteínas extracellular signal-regulated kinase (ERK) e c-Jun N-terminal kinase (JNK) no coração foi avaliada por Western-blot. A análise dos resultados foi feita por meio de Two-Way ANOVA e teste de Student-Newman-Keuls. O nível de significância considerado foi de 5%. Resultados O exercício físico aumentou a capacidade funcional nos grupos EF e EDI, e acarretou fibrose cardíaca. A combinação entre dieta intermitente e exercício físico resultou em menor área sob a curva de glicemia e menores medidas de área e interstício cardíaco no EDI em relação ao EF. A expressão de proteínas ERK e JNK foi similar entre os grupos (p>0,05). Conclusões Dieta intermitente se associa com melhor tolerância glicêmica e atenua o processo de remodelação cardíaca decorrente do exercício físico. (Arq Bras Cardiol. 2020; 115(2):184-193)

Abstract Background The effects of non-pharmacological interventions such as calorie restriction and exercise training on health and prevention of cardiovascular diseases have been investigated in clinical and experimental studies. Objective To analyze the influence of intermittent fasting and exercise training on functional fitness, glycemia and cardiac remodeling. Methods Wistar rats (n=60) were randomly divided into four groups: control, exercise training (ET), intermittent fasting (IF) and exercise training plus intermittent fasting (ETI). Over 12 weeks, control and ET animals were fed daily a standard commercial diet ad libitum , while IF and ETI animals were fed every other day. In addition, the ET and ETI groups were submitted to a running protocol on a treadmill. After this period, functional fitness, nutritional parameters and blood glucose levels were analyzed. In addition to heart morphology, myocardial protein expression of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) was assessed by Western-blot. The results were analyzed using two-way ANOVA and Student-Newman-Keuls test. The level of significance considered was 5%. Results Exercise training increased functional fitness in the ET and ETI groups and promoted cardiac fibrosis. The combination of intermittent fasting and exercise training resulted in a smaller area under the blood glucose curve and reduced cardiomyocyte cross-sectional area and interstitial collagen fraction in the ETI group compared to ET. ERK and JNK expression levels were similar among groups (p>0.05). Conclusions Intermittent fasting is associated with improved glucose tolerance and attenuates cardiac remodeling induced by exercise training (Arq Bras Cardiol. 2020; 115(2):184-193)

Refeeding abolishes beneficial effects of severe calorie restriction from birth on adipose tissue and glucose homeostasis of adult rats.

OBJECTIVES: Calorie restriction (CR) is an important intervention for reducing adiposity and improving glucose homeostasis. Recently we found that in rats, a severe calorie restriction (SCR) beginning at birth up to adult age promotes positive effects on cardiometabolic risk factors and heart. The aim of this study was to investigate the effects of this new model of SCR on adipose tissue and glucose homeostasis of rats and to evaluate the effects of refeeding. METHODS: From birth to 90 d of age, rats were divided into an ad libitum (AL) group, which had free access to food, and a CR50 group, which had food limited to 50% of that consumed by the AL group. From this moment, half of the CR50 animals had free access to food (the refeeding group [CR50-R]), and the other half continued 50% restricted for an additional 90-d period. Food intake was assessed daily and body weight weekly. In the final week of the SCR/refeeding protocol, oral glucose and intraperitoneal insulin tolerance tests were performed. Thereafter, rats were sacrificed and visceral fat was collected and used for histologic and Western blot analysis. RESULTS: Findings from this study revealed that SCR beginning at birth and up to adult life promoted a large decrease in visceral adiposity; improvement in glucose/insulin tolerance; and upregulation of adipose proliferating cell nuclear antigen, sirtuin 1, peroxisome proliferator-activated receptor-γ, and adiponectin. Refeeding abolished all of these effects. SCR from birth to adult age promoted beneficial effects on adipose tissue and glucose homeostasis; whereas refeeding abolished these effects.

Influence of intermittent fasting on myocardial infarction-induced cardiac remodeling.

BACKGROUND: Information on the role of intermittent fasting (IF) on pathologic cardiac remodeling is scarce. We compared the effects of IF before and after myocardial infarction (MI) on rat cardiac remodeling and survival. METHODS: Wistar rats were intermittently fasted (food available every other day) or fed ad libitum for 12 weeks and then divided into three groups: AL - fed ad libitum; AL/IF - fed AL before MI and IF after MI; and IF - fed IF before and after MI. Echocardiogram was performed before MI and 2 and 12 weeks after surgery. Isolated hearts were evaluated in Langendorff preparations. RESULTS: Before surgery, body weight (BW) was lower in IF than AL. Final BW was lower in AL/IF and IF than AL. Perioperative mortality did not change between AL (31.3%) and IF (27.3%). Total mortality was lower in IF than AL. Before surgery, echocardiographic parameters did not differ between groups. Two weeks after surgery, MI size did not differ between groups. Twelve weeks after MI, left ventricular (LV) diastolic posterior wall thickness was lower in AL/IF and IF than AL. The percentage of variation of echocardiographic parameters between twelve and two weeks showed that MI size decreased in all groups and the reduction was higher in IF than AL/IF. In Langendorff preparations, LV volume at zero end-diastolic pressure (V0; AL: 0.41 ± 0.05; AL/IF: 0.34 ± 0.06; IF: 0.28 ± 0.05 mL) and at 25 mmHg end-diastolic pressure (V25; AL: 0.61 ± 0.05; AL/IF: 0.54 ± 0.07; IF: 0.44 ± 0.06 mL) was lower in AL/IF and IF than AL and V25 was lower in IF than AL/IF. V0/BW ratio was lower in IF than AL and LV weight/V0 ratio was higher in IF than AL. Myocyte diameter was lower in AL/IF and IF than AL (AL: 17.3 ± 1.70; AL/IF: 15.1 ± 2.21; IF: 13.4 ± 1.49 µm). Myocardial hydroxyproline concentration and gene expression of ANP, Serca 2a, and α- and ß-myosin heavy chain did not differ between groups. CONCLUSION: Intermittent fasting initiated before or after MI reduces myocyte hypertrophy and LV dilation. Myocardial fibrosis and fetal gene expression are not modulated by feeding regimens. Benefit is more evident when intermittent fasting is initiated before rather than after MI.

Calorie restriction attenuates hypertrophy-induced redox imbalance and mitochondrial ATP-sensitive K+ channel repression.

Oxidative stress has been implicated in the pathogenesis of cardiac hypertrophy and associated heart failure. Cardiac tissue grows in response to pressure or volume overload, leading to wall thickening or chamber enlargement. If sustained, this condition will lead to a dysfunctional cardiac tissue and oxidative stress. Calorie restriction (CR) is a powerful intervention to improve health and delay aging. Here, we investigated whether calorie restriction in mice prevented isoproterenol-induced cardiac hypertrophy in vivo by avoiding reactive oxygen species (ROS) production and maintaining antioxidant enzymatic activity. Additionally, we investigated the involvement of mitochondrial ATP-sensitive K+ channels (mitoKATP) in cardiac hypertrophy. CR was induced by 40% reduction in daily calorie ingestion. After 3 weeks on CR or ad libitum (Control) feeding, Swiss mice were treated intraperitoneally with isoproterenol (30 mg/kg per day) for 8 days to induce hypertrophy. Isoproterenol-treated mice had elevated heart weight/tibia length ratios and cardiac protein levels. These gross hypertrophic markers were significantly reduced in CR mice. Cardiac tissue from isoproterenol-treated CR mice also produced less H2O2 and had lower protein sulfydryl oxidation. Additionally, calorie restriction blocked hypertrophic-induced antioxidant enzyme (catalase, superoxide dismutase and glutathione peroxidase) activity repression during cardiac hypertrophy. MitoKATP opening was repressed in isolated mitochondria from hypertrophic hearts, in a manner sensitive to calorie restriction. Finally, mitoKATP inhibition significantly blocked the protective effects of calorie restriction. Altogether, our results suggest that CR improves intracellular redox balance during cardiac hypertrophy and prevents this process in a mechanism involving mitoKATP activation.