ArticleLiterature Review

Flipping the Metabolic Switch: Understanding and Applying the Health Benefits of Fasting: Flipping the Metabolic Switch

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Abstract

Objective: Objective: Intermittent fasting (IF) is a term used to describe a variety of eating patterns in which no or few calories are consumed for time periods that can range from 12 hours to several days, on a recurring basis. This review is focused on the physiological responses of major organ systems, including the musculoskeletal system, to the onset of the metabolic switch: the point of negative energy balance at which liver glycogen stores are depleted and fatty acids are mobilized (typically beyond 12 hours after cessation of food intake). Results and conclusions: Emerging findings suggest that the metabolic switch from glucose to fatty acid-derived ketones represents an evolutionarily conserved trigger point that shifts metabolism from lipid/cholesterol synthesis and fat storage to mobilization of fat through fatty acid oxidation and fatty acid-derived ketones, which serve to preserve muscle mass and function. Thus, IF regimens that induce the metabolic switch have the potential to improve body composition in overweight individuals. Moreover, IF regimens also induce the coordinated activation of signaling pathways that optimize physiological function, enhance performance, and slow aging and disease processes. Future randomized controlled IF trials should use biomarkers of the metabolic switch (e.g., plasma ketone levels) as a measure of compliance and of the magnitude of negative energy balance during the fasting period.

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... Current dietary recommendations for patients with PCOS include regular eating, avoidance of refined sugars, low-glycaemic-index foods, and carbohydrate-rich diets, with calcium/vitamin D supplementation [37]. While the restriction of calories and an increase in exercise improve insulin sensitivity in overweight patients with PCOS, sustained calorie-restricted diets over a prolonged period of time are difficult to sustain [38]. More recently, the effect of time-restricted eating (also termed intermittent fasting) in PCOS has been examined [39]. ...
... More recently, the effect of time-restricted eating (also termed intermittent fasting) in PCOS has been examined [39]. In contrast to diets based specifically on food restriction, time-restricted eating, where patients are asked to consume all energy within a restricted daily time period, appears to offer more sustainable weight loss and cardiometabolic changes and may be more acceptable as a permanent lifestyle change [38]. ...
... is bioenergetic challenge activates signalling pathways that strengthen mitochondrial function and stress resistance and upregulate autophagy of damaged molecules adopting a stress resistance mode [40]. is reduces insulin signalling and overall protein synthesis. During refeeding following the daily "fast," glucose levels rise and ketones are cleared with increased protein synthesis allowing growth and repair allowing more efficient cellular performance, leading to cellular resilience and disease resistance as a longterm adaptation [38]. A time-restricted eating regimen where evening food intake is restricted reportedly improves postprandial insulin and glucose handling due to alignment of circadian rhythm with diurnal food intake [41]. ...
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Results: 2662 papers were identified with 37 selected for full-text review and one paper meeting criteria for inclusion. Ramadan fasting was the only time-restricted eating regimen trialled in this population with no strong evidence of a significant effect on insulin levels. Conclusion: As the systematic review retrieved only one study investigating time-restricted eating to reduce insulin in patients with PCOS, there is no evidence to suggest that this intervention is effective. From the narrative review, based on studies in other patient groups, time-restricted eating could improve insulin resistance in those with PCOS; however, well-designed studies are required before this intervention can be recommended.
... Fasting has shown tremendous results in enhancing the cancer therapy, as it is a natural process of every cell to defend itself from various situations. Starting from prevention of age-related heart complications to improvement in glucose metabolism, fasting has shown significantly good results [5]. In this study, fasting techniques will be used instead of administration of many drugs at a time with high dose, which will enhance the anticancer activity while reducing the toxicity [6]. ...
... All the animals were fasted for 9h. The animals were deprived from food, from 8:00 am to 5:00 pm every day and remaining hours, food and water were provided ad libitum [5]. At the end of the study, parameters like body weight analysis, mean survival time, percentage increase in life span, hematological parameters and biochemical parameters were estimated [12,13]. ...
... Alternate days of fasting was followed where every alternate day the animal was only provided with water and on the other alternate days food and water both were provided ad libitum. 5 At the end of the study, parameters like body weight analysis, mean survival time, percentage increase in life span, hematological parameters and biochemical parameters were estimated [14,15]. Anticancer Activity For measurement of anticancer activity in DAL bearing mice the following parameters were considered. ...
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Objective: To evaluate the effect of Nanoparticles loaded with cyclophosphamide by implementing various fasting techniques for anticancer activity in DAL mice. Methods: Nanoparticles were formulation using the technique of Ionic Gelation. Sodium alginate cyclophosphamide nanoparticles were synthesized and characterized with SEM, AFM and Tyndall effect. Two fasting models namely, intermittent fasting and alternate day fasting technique was used in the present study. Mice were divided into 10 groups under each model. All the groups were inoculated with DAL cell line, except normal group and this was considered as Day '0'. 24hrs after inoculation all the groups were treated as per the following protocol. At the end of study period all the, hematological parameters, body weight measurements, tumour volume, life span and survival time measurement were analyzed. Results: The drug loaded nanoparticles was developed and particle size are ranging from 59 to 149nm. Intermittent fasting and alternate day fasting techniques showed significant anticancer activity when compare to positive control. The animals treated with nanoparticle loaded cyclophosphamide with fasting techniques showed highly significant anticancer activity then standard cyclophosphamide alone treated animals. Conclusion-Fasting approaches can bring significant changes in the current cancer therapy. Further, more detailed studied could be conducted to calibrate the fasting treatment approach in a graded manner. A combination of anticancer drug and fasting can lead to immense benefits, effectivity and a huge drop in side effects.
... Calculated homeostatic model of insulin resistance (HOMA-IR) scores, which reduced after fasting, had increased significantly after the refeeding period, indicating increased insulin resistance. We hypothesized that these effects may be a transient rebound phenomena observed during the refeeding period as fatty acid metabolism, activated during fasting, switches back to glucose metabolism during refeeding [6,11]. To further elucidate these findings, we conducted a follow-up, single-arm, open-label, observational study on the effects of water-only fasting and refeeding with an additional six-week post-treatment in a non-diabetic, overweight/obese population. ...
... However, we found that reductions in BW, BMI, and AC were all sustained for at least six weeks following the fasting and refeeding period ( Figure 2). Long-term follow-up data is lacking, but there does not appear to be a substantial difference in weight loss between caloric restriction, time restricted eating, and intermittent fasting interventions lasting 8 or more weeks [4,11,24]. A recent umbrella review of 11 meta-analyses reported a mean difference in weight of less than 2 kg for intermittent fasting interventions, with the highest level of evidence for modified alternateday fasting [25]. ...
... Fasting causes a well-defined transition from glucose metabolism to fatty acid oxidation [11,31] with the majority of cells efficiently metabolizing ketones as an alternative energy source. During prolonged fasting, rates of hepatic and renal gluconeogenesis also increase in order to meet any remaining glucose needs. ...
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(1) Background: Chronic inflammation and insulin resistance are associated with cardiometabolic diseases, such as cardiovascular disease, type 2 diabetes mellitus, and non-alcoholic fatty liver disease. Therapeutic water-only fasting and whole-plant-food refeeding was previously shown to improve markers of cardiometabolic risk and may be an effective preventative treatment but sustained outcomes are unknown. We conducted a single-arm, open-label, observational study with a six-week post-treatment follow-up visit to assess the effects of water-only fasting and refeeding on markers of cardiometabolic risk. (2) Methods: Patients who had voluntarily elected and were approved to complete a water-only fast were recruited from a single-center residential medical facility. The primary endpoint was to describe changes to Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) scores between the end-of-refeed visit and the six-week follow-up visit. Additionally, we report on changes in anthropometric measures, blood lipids, high-sensitivity C-reactive protein (hsCRP), and fatty liver index (FLI). Observations were made at baseline, end-of-fast (EOF), end-of-refeed (EOR), and six-week follow-up (FU). (3) Results: The study enrolled 40 overweight/obese non-diabetic participants, of which 33 completed the full study protocol. Median fasting, refeeding, and follow-up lengths were 14, 6, and 45 days, respectively. At the FU visit, body weight (BW), body mass index (BMI), abdominal circumference (AC), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein (LDL), hsCRP, and FLI were significantly decreased from baseline. Triglycerides (TG) and HOMA-IR scores, which had increased at EOR, returned to baseline values at the FU visit. (4) Conclusion: Water-only fasting and whole-plant-food refeeding demonstrate potential for long-term improvements in markers of cardiovascular risk including BW, BMI, AC, SBP, DBP, blood lipids, FLI, and hsCRP.
... Growing evidence consistently shows that intermittent fasting can efficiently prevent a wide range of diseases, including diabetes, obesity, cancers, and neurodegenerative disorders (Di Francesco et al., 2018;Li et al., 2017;Nencioni et al., 2018). It even functions to increase lifespan or retard the aging process in different animal models (Anton et al., 2018;Catterson et al., 2018;Honjoh et al., 2009;Longo et al., 2021;Ulgherait et al., 2021;Xie et al., 2017). However, there are currently many intermittent fasting regimens (Anton et al., 2018;de Cabo and Mattson, 2019;Longo et al., 2021), while the strong evidence of exclusivity for the predominance of each regimen is limited. ...
... It even functions to increase lifespan or retard the aging process in different animal models (Anton et al., 2018;Catterson et al., 2018;Honjoh et al., 2009;Longo et al., 2021;Ulgherait et al., 2021;Xie et al., 2017). However, there are currently many intermittent fasting regimens (Anton et al., 2018;de Cabo and Mattson, 2019;Longo et al., 2021), while the strong evidence of exclusivity for the predominance of each regimen is limited. The temporal functional signatures of fasting remain to be elucidated. ...
... It is assumed that flipping the metabolic switch from glucose to fatty-acid-derived ketones is a key mechanism responsible for the intermittent-fasting-induced health benefits (Anton et al., 2018;de Cabo and Mattson, 2019;Mattson et al., 2018), and plasma ketone levels can serve as a biomarker of the metabolic switch (Anton et al., 2018). While there is a wide consensus that prolonged fasting can trigger the metabolic switch, and multifaceted evidence supports a crucial role of the metabolic switch in optimizing metabolism and improving metabolic diseases, the metabolic switch that occurs between 12 and 36 h after food deprivation varies greatly between individuals (Anton et al., 2018). ...
Article
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While intermittent fasting is a safe strategy to benefit health, it remains unclear whether a “timer” exists in vivo to record fasting duration and trigger a transcriptional switch. Here, we map a circadian transcriptional pathway atlas from 600 samples across four metabolic tissues of mice under five feeding regimens. Results show that 95.6% of detected canonical pathways are rhythmic in a tissue-specific and feeding-regimen-specific manner, while only less than 25% of them induce changes in transcriptional function. Fasting for 16 h initiates a circadian resonance of 43 pathways in the liver, and the resonance punctually switches following refeeding. The hepatic proteasome coordinates the resonance, and most genes encoding proteasome subunits display a 16-h fasting-dependent transcriptional switch. These findings indicate that the hepatic proteasome may serve as a fasting timer and a coordinator of pathway transcriptional resonance, which provide a target for revealing the underlying mechanism of intermittent fasting.
... Numerous studies have revealed that humans face difficulties in maintaining daily CR for prolonged periods [158]. However, IF has a higher compliance rate and is effective in weight loss and the reduction of obesity-related risk factors for metabolic disease [21,159,160]. Because of the positive effects of fasting, the body uses fatty acids and ketones as fuel. ...
... Because of the positive effects of fasting, the body uses fatty acids and ketones as fuel. As shown by research, altering one's metabolic process to one that utilizes fatty acids for energy rather than glucose preserves muscle mass and function while increasing one's ability to perform daily activities [159]. Finally, IF has been shown to reduce adipose tissue mass, notably visceral and abdominal fat, due to its mild energy deficits [161,162]. ...
... This effect has the additional effect of improving the cardiovascular risk profile by lowering BMI and blood pressure, decreasing resting heart rate, decreasing ischemic injury, decreasing lipid peroxidation, and enhancing cardiovascular stress adaptation and resistance to a cardiac muscle injury in myocardial infarction animal models. CVS risk factors are intimately related to MetS components, and intermittent fasting may play a crucial role in the prevention and management of CVD and MetS [25,159,162]. Figure 4 represents the beneficial effects of IF on CVS, metabolic and periodontal health. ...
Article
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Metabolic syndrome (MetS) prevalence continues to climb significantly worldwide in today’s ad libitum society. MetS has tremendous societal and economic ramifications, making it imperative to develop effective strategies for preventing and controlling it to alleviate this growing burden. Periodontal disease and MetS are associated with several risk factors. Studies in the past have demonstrated that obesity, cardiovascular illness, and type 2 diabetes mellitus have a negative effect on the severity of the periodontal disease. Patients with metabolic syndrome have elevated serum levels of proinflammatory mediators such as tumor necrosis factor-alpha interleukin-6 and C-reactive protein. Similar inflammatory mediators, such as interleukin-6, tumor necrosis factor-alpha, and C-reactive protein, are increased in patients with severe periodontal disease. Remarkably, intermittent fasting is underpinned by scientific evidence, claiming to be the most effective non-pharmacological, potential therapeutic alternative for combating a wide range of metabolic, inflammatory, and lifestyle-related diseases. Nonetheless, an insufficient investigation has been performed to determine whether intermittent fasting has therapeutic benefits on periodontal inflammation and diseases. Here, we show the interrelationship between metabolic syndrome and periodontal disease and contextualize the beneficial impact of intermittent fasting in modulating the chronic metabolic and periodontal inflammatory response. We also anticipate that this review paves the way for further exploration of intermittent fasting as a unique research paradigm representing a cost-effective alternative strategy to conventional disease management in patients with periodontal diseases and metabolic syndrome which may serve as the foundation for an integrative vision relevant to primary, diagnostic, and therapeutic purposes.
... Several obesity studies, on the other hand, have found that humans have a hard time sticking to a daily calorie restriction for long periods of time (Anton et al., 2017). Intermittent fasting, on the other hand, has a higher compliance rate and has been shown to help obese people improve metabolic risk factors, body composition, and weight loss (Albosta & Bakke, 2021;Anton et al., 2017;Spezani et al., 2020). ...
... Several obesity studies, on the other hand, have found that humans have a hard time sticking to a daily calorie restriction for long periods of time (Anton et al., 2017). Intermittent fasting, on the other hand, has a higher compliance rate and has been shown to help obese people improve metabolic risk factors, body composition, and weight loss (Albosta & Bakke, 2021;Anton et al., 2017;Spezani et al., 2020). The shift in the body's main fuel source during fasting from glucose to fatty acids and ketones has been related to these favorable outcomes. ...
... The shift in the body's main fuel source during fasting from glucose to fatty acids and ketones has been related to these favorable outcomes. (Anton et al., 2017). ...
Article
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Diabetes is a global, costly, and growing public health issue. Intermittent fasting (IF) and exercise therapy have been shown to improve insulin sensitivity (IS) in large studies, although the underlying processes are still unknown. The goal of this study, which included both nondiabetic and diabetic rats, was to look at the mechanisms of intermittent fasting and exercise in the management of diabetotoxicity. The effects of starvation and honey on the oral glucose tolerance test, insulin tolerance test, adipocytokines, oxidative glucose metabolic enzymes, glycolytic enzymes, food intake, and body weight in rats with streptozotocin‐induced diabetes were also investigated. In the nondiabetic phase, rats were administered an oral regimen of distilled water (0.5 ml/rat), honey (1 g/kg body weight), and interventions with IF, and starvation for 4 weeks while in the diabetic phase, after STZ or citrate buffer injections, interventions with IF, exercise, starvation, and honey treatment began for 4 weeks. At all OGTT and ITT points, there was a substantial rise in glucose in the STZ group. Adipocytokines hormone, oxidative glucose metabolic enzymes, glycolytic enzymes, and body weight were all affected by STZ when compared to starvation and honey, however, IF and exercise significantly reduced these alterations. In diabetic rats, intermittent fasting and exercise enhanced serum adipocytokines levels. These findings imply that adipokines modulate glycolytic/nonmitochondrial enzymes and glucose metabolic/mitochondrial dehydrogenase to mediate the antidiabetic effects of intermittent fasting and exercise. Intermittent fasting and exercise therapy abates STZ‐induced diabetotoxicity in rats through modulation of adipocytokines hormone, oxidative glucose metabolic, and glycolytic pathway.
... The IF regimen is expected to induce certain cellular changes such as depleted levels of glycogen stores and increased blood ketones as a result of higher rate of lipolysis [10,11]. Weight loss and baseline blood glucose levels are often the byproducts of increased energy expenditure through lipid metabolism [10,12]. ...
... The IF regimen is expected to induce certain cellular changes such as depleted levels of glycogen stores and increased blood ketones as a result of higher rate of lipolysis [10,11]. Weight loss and baseline blood glucose levels are often the byproducts of increased energy expenditure through lipid metabolism [10,12]. The beneficial effects of IF are demonstrated in a study by Spezani et al. (2020). ...
... Weight loss and lower glucose levels are often associated with the metabolic switch that occurs during an IF regimen, which results in an increase in BHB levels due to lipid metabolism [10,12]. In this study, obese rats fed SD on IF had higher ketone levels than their AL-SD counterparts. ...
Article
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Intermittent fasting (IF) is an alternating pattern of restricting eating. This study evaluated mental and physical fatigue secondary to IF (daily 18-hour fast, 7-days-a-week) in the high-fat diet (HFD)-induced male obese Sprague Dawley rats. Fifty-four rats were randomly assigned to a HFD (n = 28) or a standard diet (SD; n = 26). After six weeks, the HFD rats were divided into one of four groups: obese HFD ad libitum (OB-HFD-AL), obese HFD-IF (OB-HFD-IF), obese SD-AL (OB-SD-AL), and obese SD-IF (OB-SD-IF). Similarly, non-obese controls were grouped into HFD-AL (C-HFD-AL), non-obese HFD-IF (C-HFD-IF), non-obese SD-AL (C-SD-AL), and non-obese SD-IF (C-SD-IF). After 2 weeks of IF, mental and physical fatigue were measured using open field (OF) and novel object recognition (NOR) tests. Rats on IF gained weight at a slower pace ( p< 0.05) and had lower glucose levels ( p <0.01) compared to the AL group. In non-obese rats, ketone levels were higher in the IF-HFD group than IF-SD (p<0.05) and AL-SD ( p <0.01) animals. Obese rats exhibited elevated blood ketone levels in IF-SD conditions versus AL-SD rats ( p <0.01). AL-HFD rats had higher ketone levels than AL-SD animals in both obese and non-obese groups ( p <0.05). In conclusion, rats with higher blood ketone levels, whether they were on IF or AL, traveled a greater distance during OF suggesting a lack of physical fatigue. There was no significant difference between IF and AL during NOR indicating a lack of mental fatigue. Thus, IF results in reduced body weight and blood glucose levels but does not induce physical or mental fatigue.
... Path 2: Decreased circulating glucose and amino acids with fasting inhibit rapamycin (mTOR), the intracellular energy sensor [14]. Path 3: Due to the need for energy, glycolysis starts in the liver, with a fatty acid release from adipose tissue [15]. Health is positively affected by increasing autophagy and decreasing oxidative stress. ...
... The metabolic effects caused by IF administration in experimental animal models have been investigated. It has been reported that a "metabolic switch" occurs with IF, and the activation of many pathways occurs with it [15]. It is thought that these mechanisms of action are also valid in humans and that beneficial metabolic effects occur in this way. ...
Article
Background: One of the most important components of treatment for diabetic patients is diet and healthy nutrition therapy. Calorie restriction is effective and without cost increases its appeal for both patients and physicians. Unfortunately, continuous calorie restriction is a difficult method. For this reason, alternative calorie restriction methods, such as intermittent fasting (IF), have been investigated by some researchers. Methods: IF refers to a wide range of diet programmes covering periods of eating and fasting, which vary according to the different regimens. In this article, first, some general information will enable us to understand the concept of IF, and then scientific evidence with respect to IF applications in diabetes will be discussed in detail. Thereafter our clinical experience will be summarised, finally, the author will try to answer the question "are the IF applications beneficial or harmful for diabetic patients?" Results: Considering animal studies, epidemiological studies, pilot studies, clinical experiences and a small number of randomized controlled trials conducted so far, it seems possible to say that the beneficial effects of IF for diabetes patients are greater than potential harms. However, there are not yet enough studies with a high level of evidence to recommend IF as a routine part of the treatment in patients with diabetes. Discussion: It is necessary to show which IF regimen is safe and effective, how often and for how long, for diabetic patients. This seems possible with well-designed randomized controlled trials focusing on long-term clinical outcomes and eliminating confounding factors. This will make the answer clearer.
... The low glucose levels during fasting stimulate pancreatic glucagon secretion and favor glucose synthesis through glycogenolysis and gluconeogenesis. After liver glycogen depletion, there is a switch from glucose to lipid metabolism, with a preferential utilization of fatty acid-derived ketones in spite of glucose by cells with high metabolic activity such as skeletal muscles and neurons [79]. Moreover, prolonged fasting determines an increase in serum level of catecholamines and corticosteroids that favors white adipose tissue lipolysis with the subsequent release of increased levels of free fatty acids into the bloodstream as a primary source for β oxidation [79]. ...
... After liver glycogen depletion, there is a switch from glucose to lipid metabolism, with a preferential utilization of fatty acid-derived ketones in spite of glucose by cells with high metabolic activity such as skeletal muscles and neurons [79]. Moreover, prolonged fasting determines an increase in serum level of catecholamines and corticosteroids that favors white adipose tissue lipolysis with the subsequent release of increased levels of free fatty acids into the bloodstream as a primary source for β oxidation [79]. Apart from being an energy source, ketone bodies also have important signaling functions, including the activation of transcription factor cyclic AMP response element-binding protein (CREB) and regulating the expression and activity of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), fibroblast growth factor and sirtuins [80]. ...
Article
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Hepatocellular carcinoma (HCC), one of the leading causes of cancer-related deaths worldwide, is a multistep process that usually develops in the background of cirrhosis, but also in a non-cirrhotic state in patients with non-alcoholic fatty liver disease (NAFLD) or viral hepatis. Emerging evidence suggests that intermittent fasting can reduce the risk of cancer development and could improve response and tolerance to treatment through the metabolic and hormonal adaptations induced by the low energy availability that finally impairs cancer cells’ adaptability, survival and growth. The current review will outline the beneficial effects of fasting in NAFLD/NASH patients and the possible mechanisms that can prevent HCC development, including circadian clock re-synchronization, with a special focus on the possibility of applying this dietary intervention to cirrhotic patients.
... 15 Several animal 18,19 and human 20,21 studies report that some benefits of IF are independent of weight loss and may be due to metabolic switching. 22 Metabolic switching occurs 12 to 36 hours after fasting is initiated, when glycogen stores are depleted, and free fatty acids are released into the blood. 22 Generally, IF is believed to upregulate autophagy through inhibiting the mammalian target of rapamycin protein synthesis pathway, and activation of adaptive cellular stress response signaling pathways that promote mitochondrial health, and DNA repair. ...
... 22 Metabolic switching occurs 12 to 36 hours after fasting is initiated, when glycogen stores are depleted, and free fatty acids are released into the blood. 22 Generally, IF is believed to upregulate autophagy through inhibiting the mammalian target of rapamycin protein synthesis pathway, and activation of adaptive cellular stress response signaling pathways that promote mitochondrial health, and DNA repair. 23 The role of metabolic switching in fasting is unknown, as autophagy cannot yet be measured in human beings. ...
Article
Background Intermittent fasting (IF) has gained favor as an alternative regimen to daily caloric restriction (DCR). Therefore, there is a need for systematic reviews of randomized controlled/comparison trials (RCTs) examining the effects of isocaloric IF vs. DCR on metabolic risk factors for non-communicable chronic diseases (NCDs). Objective To systematically investigate the effects of isocaloric IF vs. DCR on metabolic risk factors for NCDs in adults with overweight and obesity. Methods Five online databases (PubMed, Scopus, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar) were searched for articles published from January 2000 through April 2022. The updated Cochrane Risk of Bias Assessment tool (ROB2) for RCTs was used to assess risk of bias in the included studies. This review includes RCTs with matched energy intakes (isocaloric) between IF and DCR among adults with overweight and obesity with ≥ 8-week durations, that assessed risk factors related to obesity and for diabetes, cardiovascular diseases (CVDs), and cancers. Results Thirteen RCTs with matched energy intakes (isocaloric) between IF and DCR were identified. The effects of IF on weight loss and metabolic risk markers of diabetes, CVDs, and cancers were varied but generally comparable to DCR. IF (4:3 and 5:2 diets) was superior to DCR for improving insulin sensitivity in two studies. Reductions in body fat were significantly greater with IF (5:2 diet and time-restricted eating) than DCR in two isocaloric studies. Conclusions With matched energy intakes, IF interventions produced similar beneficial effects for weight loss and chronic disease risk factors as compared to DCR. Very limited evidence suggests that IF may be more effective vs. DCR for fat loss and insulin sensitivity, but conclusions cannot be drawn based on the current evidence. Future clinical studies with larger populations and longer durations are needed for further elucidation of any potential effects of IF regimens for prevention of NCDs.
... Dietary patterns have changed worldwide to converge on Western-type diets [36]. On the other hand, fasting and consuming foods rich in protein and/or fiber have been associated with increasing gut microbiota diversity and health benefits [37][38][39]. ...
... In a recent study, CM or Probiotic-FCM exhibited various gut microbiota diversity, which increased SCFA and weight loss more than cow and goat milk [13]. These findings were also confirmed in weight gain and organ weight, as previously mentioned [37][38][39]42]. FCM improved the anthropometric measures and blood pressure of adolescents with MetS, as previously found [55]. ...
Article
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Obesity causes metabolic syndrome disorders that are detrimental to health. The current study examined the effects of intermittent fasting (IF), fermented camel milk (FCM), and fermented camel milk incorporating 10% Sukkari date (FCM-D) on weight loss, blood profile, and antioxidant status in obese rats for 6 weeks. Subsequently, leptin and adiponectin levels and histopathological examination of adipose tissue were carried out. Results showed that IF with FCM or FCM-D decreased body weight by 0.92 and −5.45%, respectively. IF alone lowered non-fasting blood glucose (NFBG) and fasting blood glucose FBG after 6 weeks, whereas adding FCM or FCM-D reduced NFBG after 4 weeks. Intermittently fasting obese rats given FCM or FCM-D had the lowest blood glucose levels (BGL). The hypolipidemic effects of IF, FCM, and FCM-D on obese rats reduced triglycerides (TG), cholesterols (CHO), and their derivatives. FCM-D with IF presented a superior effect on lipid profile. A reduction rate of 40, 37, 66, and 40% for TG, CHO, low-density lipoprotein (LDL-c), and very low-density lipoprotein (VLDL-c), respectively, and an increase in HDL-C by 34% were noticed. Reductions of 40, 37, 66, and 40% for TG, CHO, LDL-c, and VLDL-c, respectively, and a 34% rise in high-density lipoprotein (HDL-C) were noted. Combining IF with FCM or FCM-D lowered the atherogenic index (AI) by 42% and 59%, respectively. Remarkably, treating rats with FCM+IF or FCM-D+IF effectively attenuated leptin and adiponectin levels. Malondialdehyde (MDA) was significantly decreased in a type-dependent manner. Implementing FCM-D or FCM with IF significantly attenuated reduced glutathione (GSH), superoxide dismutase (SOD), MDA, and catalase (CAT) levels. The most efficient treatment was giving FCM-D with IF. Histopathologically, adipocyte lipolysis increases free fatty acids (FFAs) and promotes inflammation. Only IF+FCM-D indicated no histopathological alteration except for a few focal areas of a few inflammatory cell infiltrations in the parenchyma. In conclusion, combining IF and Probiotic-FCM or Probiotic-FCM-D effectively accelerated weight loss, attenuated metabolic markers, and reversed histopathological alterations. Thus, IF combined with Probiotic-FCM or Probiotic-FCM-D is highly recommended for weight loss, strengthening antioxidative status, and preventing health disorders.
... In periodic fasting, individuals are advised to restrict food for 1 or 2 days per week but are permitted to consume their usual diet intake for 5 or 6 days per week. 17 Time-restricted feeding (TRF) is defined as abstention of eating for a specific period of time during the day, typically for between 8 hours and 12 hours each day, followed by unlimited food intake. 17 Various religious fasting diets, such as Ramadan, are considered to be other forms of fasting. ...
... 17 Time-restricted feeding (TRF) is defined as abstention of eating for a specific period of time during the day, typically for between 8 hours and 12 hours each day, followed by unlimited food intake. 17 Various religious fasting diets, such as Ramadan, are considered to be other forms of fasting. 18 In humans, 12 hour-24 hour food deprivation usually leads to a reduction in serum glucose and hepatic glycogen, and a switch to ketogenesis (in which nonhepatic glucose, fat-derived ketone bodies, and free fatty acids are utilized as energy fuels). ...
Article
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. There is no confirmed treatment for NAFLD as yet. Recently, fasting regimens and their relationship to NAFLD have drawn a great deal of attention in the literature. We review the current evidence that supports fasting diets as an adjunctive therapeutic strategy for patients with NAFLD and address potential action mechanisms. We reason that the fasting diets might be a promising approach for modulating hepatic steatosis, fibroblast growth factors 19 and 21 signaling, lipophagy, and the metabolic profile.
... IF and CR seem to produce adaptive and integrated cellular responses [16], all orchestrated by the metabolic switch of lipogenesis to lipolysis and ketogenesis [17]. For this reason, their popularity has increased, and more studies are being published on the subject, most of them finding that IF not only favors significant weight loss but also leads to metabolic adaptations, such as stress resistance, improvement of blood glucose regulation, and suppression of inflammation [17]. ...
... IF and CR seem to produce adaptive and integrated cellular responses [16], all orchestrated by the metabolic switch of lipogenesis to lipolysis and ketogenesis [17]. For this reason, their popularity has increased, and more studies are being published on the subject, most of them finding that IF not only favors significant weight loss but also leads to metabolic adaptations, such as stress resistance, improvement of blood glucose regulation, and suppression of inflammation [17]. Ketogenesis has been described as the primary activator of these adaptations because ketone bodies (KBs) (i.e., βhydroxybutyrate and acetoacetate), besides their role as energy substrates, also function as signaling molecules with important effects on gene expression, lipid metabolism regulation, and metabolic rate, among others [16,18]. ...
Article
Western-style diet often leads to food overconsumption, which triggers the development of comorbidities such as obesity, insulin resistance, hypercholesterolemia, hypertriglyceridemia, type 2 diabetes, and heart failure (HF). Several studies suggested that intermittent fasting (IF) protects against the development of those morbidities. This study presents evidence of the beneficial effects of IF on HF. Based on the current evidence, we discuss the potential molecular mechanisms by which IF works and where liver ketone bodies (KBs) play important roles. There is evidence that IF promotes a metabolic switch in highly metabolic organs, such as the heart, which increases the use of KBs during fasting. However, besides their role as energy substrates, KBs participate in the signaling pathways that control the expression of genes involved in oxidative stress protection and metabolism. Several molecular factors, such as adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor, fibroblast growth factor 21 (FGF21), sirtuins, and nuclear factor erythroid 2-related factor 2 (Nrf2) are involved. Furthermore, IF appears to maintain circadian rhythms, essential in highly metabolically active organs. Finally, we highlight the important research topics that need to be pursued to improve current knowledge and strengthen the potential of IF as a preventive and therapeutic approach to HF.
... For example, during Ramadan, Muslims fast from sunrise to sunset every day for 30 days. Intermittent fasting includes a variety of eating patterns where fasting happens over specific time periods on a repeating basis (Anton et al. 2018). Recently, intermittent fasting has been considered as a means to promote weight loss (Cho et al. 2019, Harris et al. 2018, Welton et al. 2020). ...
... Because there is very little evidence regarding the safety and effectiveness for weight loss in individuals with diabetes, intermittent fasting should only be considered under the advisement of a physician (Horne et al. 2020). Proper education and medication management by a health care professional is needed to reduce the risk of hypoglycemic Anton et al. (2018) and Patterson et al. (2015) events while practicing intermittent fasting (Corley et al. 2018). ...
Article
Weight loss can be challenging. Starting a restrictive diet can be emotionally draining and difficult to adhere to. Is there a more effective way to lose weight? Does the timing and frequency of meals help to lose weight? This new 4-page publication of the UF/IFAS Food Science and Human Nutrition Department describes the benefits and risks of intermittent fasting for weight loss. Written by Michelle Yavelow, Daniela Rivero Mendoza, and Wendy Dahl.https://edis.ifas.ufl.edu/fs409
... For example, patients subjected to a very-low calorie ketogenic diet showed increased serum cholesterol (Saslow et al., 2017) and liver function markers such as AST and ALT (Colica et al., 2017;Schwenger et al., 2018). Recently intermittent fasting, a strong inducer of ketogenesis, gained attention in effectively treating the NAFLD patients (Anton et al., 2018). Intermittent fasting in the form of time-restricted fasting, periodic fasting or calorie restriction significantly reduce the liver lipid accumulation and improve biochemical liver function indices such as AST and ALT levels Wilhelmi de Toledo et al., 2019). ...
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Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver diseases, arise from non-alcoholic fatty liver (NAFL) characterized by excessive fat accumulation as triglycerides. Although NAFL is benign, it could progress to non-alcoholic steatohepatitis (NASH) manifested with inflammation, hepatocyte damage and fibrosis. A subset of NASH patients develops end-stage liver diseases such as cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is highly complex and strongly associated with perturbations in lipid and glucose metabolism. Lipid disposal pathways, in particular, impairment in condensation of acetyl-CoA derived from β-oxidation into ketogenic pathway strongly influence the hepatic lipid loads and glucose metabolism. Current evidence suggests that ketogenesis dispose up to two-thirds of the lipids entering the liver, and its dysregulation significantly contribute to the NAFLD pathogenesis. Moreover, ketone body administration in mice and humans shows a significant improvement in NAFLD. This review focuses on hepatic ketogenesis and its role in NAFLD pathogenesis. We review the possible mechanisms through which impaired hepatic ketogenesis may promote NAFLD progression. Finally, the review sheds light on the therapeutic implications of a ketogenic diet in NAFLD.
... Fasting. Fasting is defined as a voluntary abstinence from food and drink for specified, recurring periods of time, ranging from 12 h to 3 weeks in humans (148). Fasting can also be considered a cR diet in periods of free access to food which are interrupted by fasting (149). ...
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Mitochondria are considered the 'powerhouses' of cells, generating the essential energy in the form of adenosine triphosphate that they need for their energy demands. Nevertheless, their function is easily adaptable as regards the energy demands and the availability of chemical substrates. This allows cells to buffer sudden changes and reassure cellular metabolism, growth or survival. currently, humans have different dietary habits, which provide several stimuli to the cell. According to the energy substrate availability due to the diet quality and diet temporality, mitochondrial physiology is greatly affected. The present review article aimed to collect all the available information that has been published to date concerning the impact of five different popular diets (high-fat diet, ketogenic diet, fasting, caloric restriction diet and the Mediterranean diet) on specific mitochondrial physiological aspects, such as function, biogenesis, mitophagy and mitochondrial fission/fusion.
... A more pronounced reduction in FM was reported in subjects with 29 Hp2-2 in comparison with Hp2-1.Conclusion: Hp gene polymorphism modulates IF-induced 30 changes in cardiometabolic markers. 40 A growing body of evidence supports the role of weight-reducing regimens, intermittent fasting (IF), 41 and physical activity in reversing (or protecting against) the adverse metabolic derangements 42 associated with obesity [1]. IF is a widely adopted dietary practice, used for both religious and non- 43 religious (e.g., health improvement) purposes [2]. ...
Article
Haptoglobin (Hp) is a multifaceted marker of inflammation, and mediates the interplay between obesity, inflammation, and cardiometabolic dysfunction. However, the role of the Hp phenotype in modulating intermittent fasting (IF)-induced changes in cardiometabolic markers remains to be elucidated. Methods: Hp phenotype was determined for the study subjects. Cardiometabolic markers were assessed before and at the end of four consecutive weeks, dawn to sunset IF. Results: A total of 114 subjects (75 males and 39 females, 38.7 ± 11.7 years, body mass index (BMI) of 30.41±5.09 kg/m2) were recruited. Hp2-2 (n=55, 48.2 %) and Hp2-1 (n=53, 46.5 %) were the predominant phenotypes. Significant reductions were observed in serum Hp, IL-6, TNF-α, triglycerides (TG), total cholesterol (TC), LDL, BMI, and fat mass (FM), while a significant elevation was observed in serum CD163, HDL, and IL-10 at the end of the IF month for the whole population. Based on the Hp polymorphism, significant decreases in Hp, BMI, FM, TG, LDL, and TNF-α, with significant increases in HDL and CD163 levels were observed among subjects with Hp2-2 and Hp2-1 phenotypes. A more pronounced reduction in FM was reported in subjects with Hp2-2 in comparison with Hp2-1.Conclusion: Hp gene polymorphism modulates IF-induced changes in cardiometabolic markers.
... GO analysis indicated that CR enhances energy reserve metabolic process/pathway through three key genes (Nr1d1, Per2, Ppp1r1a). Energy reserve metabolic process help in deriving energy from the stored fat and/or glycogen (Anton et al. 2018). Circadian rhythmrelated research supports the crosstalk between nutrient-sensing (CR), metabolic pathways, and molecular components of the circadian clock for healthy aging and longevity (Reinke and Asher 2019;Acosta-Rodriguez et al. 2021). ...
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Over the past decade, extensive efforts have focused on understanding age-associated diseases and how to prolong a healthy lifespan. The induction of dietary protocols such as caloric restriction (CR) and protein restriction (PR) has positively affected a healthy lifespan. These intervention ideas (nutritional protocols) have been the subject of human cohort studies and clinical trials to evaluate their effectiveness in alleviating age-related diseases (such as type II diabetes, cardiovascular disease, obesity, and musculoskeletal fragility) and promoting human longevity. This study summarizes the literature on the nutritional protocols, emphasizing their impacts on bone and muscle biology. In addition, we analyzed several CR studies using Gene Expression Omnibus (GEO) database and identified common transcriptome changes to understand the signaling pathway involved in musculoskeletal tissue. We identified nine novel common genes, out of which five were upregulated (Emc3, Fam134b, Fbxo30, Pip5k1a, and Retsat), and four were downregulated (Gstm2, Per2, Fam78a, and Sel1l3) with CR in muscles. Gene Ontology enrichment analysis revealed that CR regulates several signaling pathways (e.g., circadian gene regulation and rhythm, energy reserve metabolic process, thermogenesis) involved in energy metabolism. In conclusion, this study summarizes the beneficiary role of CR and identifies novel genes and signaling pathways involved in musculoskeletal biology.
... A growing body of evidence supports the role of weight-reducing regimens, intermittent fasting (IF), and physical activity in reversing (or protecting against) the adverse metabolic derangements associated with obesity [1]. IF is a widely adopted dietary practice, used for both religious and non-religious (e.g., health improvement) purposes [2]. ...
Article
Aims Haptoglobin (Hp) is a multifaceted marker of inflammation, and mediates the interplay between obesity, inflammation, and cardiometabolic dysfunction. However, the role of the Hp phenotype in modulating intermittent fasting (IF)-induced changes in cardiometabolic markers remains to be elucidated. Methods: Hp phenotype was determined for the study subjects. Cardiometabolic markers were assessed before and at the end of four consecutive weeks, dawn to sunset IF. Results: A total of 114 subjects (75 males and 39 females, 38.7 ± 11.7 years, body mass index (BMI) of 30.41±5.09 kg/m²) were recruited. Hp2-2 (n=55, 48.2 %) and Hp2-1 (n=53, 46.5 %) were the predominant phenotypes. Significant reductions were observed in serum Hp, IL-6, TNF-α, triglycerides (TG), total cholesterol (TC), LDL, BMI, and fat mass (FM), while a significant elevation was observed in serum CD163, HDL, and IL-10 at the end of the IF month for the whole population. Based on the Hp polymorphism, significant decreases in Hp, BMI, FM, TG, LDL, and TNF-α, with significant increases in HDL and CD163 levels were observed among subjects with Hp2-2 and Hp2-1 phenotypes. A more pronounced reduction in FM was reported in subjects with Hp2-2 in comparison with Hp2-1.Conclusion: Hp gene polymorphism modulates IF-induced changes in cardiometabolic markers.
... Examining the lipidomic changes in the various physiological states, including fasting/feeding states, is of paramount significance in understanding the nature of metabolic changes accompanying these nutritional states. Considering the extended fasting duration and the accompanying metabolic switches presented in the shift from glucogenic to ketogenic pathway [27], and changes in circadian rhythm; IF is expected to be entailed with a list of lipidomic changes [28]. ...
Preprint
Background and Aims: Intermittent fasting has been reported to be associated with massive metabolic switching that underpins the different health impacts of fasting. Among these, changes in lipid metabolism and the associated sphingolipids and ceramides are among the most prominent changes. Therefore, the current work was designed to examine the lipidomics changes associated with the observance of 29-30 days of Ramadan diurnal intermittent fasting (RDIF) in metabolically healthy overweight and obese subjects. Methods: A prospective cohort study on 57 overweight and obese adults (17 females and 40 males, 38.42 ± 11.18 years) was conducted. Anthropometric, biochemical (lipid profile and inflammatory markers), and dietary intake measures were assessed one week before and at the end of the lunar month of Ramadan. Lipidomics analysis for ceramides and sphingolipids was performed using a mass spectrometer. Results: RDIF was associated with improved lipid profile and inflammatory markers. Further, the observance of RDIF was associated with reduced reduction in both plasma sphingosine and sphinganine, while associated with reduced reduction in both S1P and Sa1P. In addition, RDIF was associated with reduced C17, C22, and C24 sphingomyelin, but not C14, C16, C18, C20, C24:1 sphingomyelin and was associated with reduced C20, C22, C24, and C24:1 dihydro sphingomyelin, but not C16 and C18 dihydro sphingomyelin (both P≥0.13). Conclusions: Collectively, the current study demonstrates that observance of RDIF was associated with improvements in plasma sphingosine, sphinganine sphingomyelin, and dihydro sphingomyelin lipid species, along with improved lipid profile and inflammatory markers. 2
... A critical factor in many of these benefits is the "metabolic switch," a phenomenon in which fasting causes the body to preferentially use fatty acids and ketone bodies derived from fatty acids as a fuel instead of glucose. 27 Consequently, ketone bodies can serve as signaling molecules that trigger response against oxidative and metabolic stress, as well as removal of damaged molecules. 18,28 Refeeding, on the other hand, results in increased levels of the incretin hormone glucagonlike peptide 1 (GLP-1) and insulin, which then enhance glucose uptake and promote tissue-specific growth and plasticity. ...
Article
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In recent years, intermittent fasting (IF), including periodic fasting and time‐restricted feeding (TRF), has been increasingly suggested to constitute a promising treatment for cardiometabolic diseases (CMD). A deliberate daily pause in food consumption influences the gut microbiome and the host circadian clock, resulting in improved cardiometabolic health. Understanding the molecular mechanisms by which circadian host‐microbiome interactions affect host metabolism and immunity may add a potentially important dimension to effective implementation of IF diets. In this review, we discuss emerging evidence potentially linking compositional and functional alterations of the gut microbiome with IF impacts on mammalian metabolism and risk of development of hypertension, type 2 diabetes (T2D), obesity, and their long‐term micro‐ and macrovascular complications. We highlight the challenges and unknowns in causally linking diurnal bacterial signals with dietary cues and downstream metabolic consequences and means of harnessing these signals toward future microbiome integration into precision medicine. Highlights Time‐specific diet is a novel nutritional approach to prevent and treat cardiometabolic disease. Feeding‐fasting cycles shape gut microbial composition and metabolite production. These alterations may play a causative role in driving the cardiometabolic benefits of intermittent fasting. Despite the impressive results in animals, human studies show contradicting results, possibly due to intraindividual variation involved in the host‐microbiome response to diet. Better mechanistic understanding is required to develop personalized dietary interventions to treat cardiometabolic diseases.
... The fasting state leads to a metabolic switch, which increases the usage of free fatty acid (FFA) as energy source in comparison to glucose. In addition, IF favors the synthesis of ketone bodies (KBs) by the liver, molecules that act as an energy source during nutrient deprivation and induce a plethora of beneficial effects on the organism by acting upon the muscle, liver, heart, brain, intestine and AT [235][236][237]. Moreover, during prolonged fasting periods, the levels of the bioenergetic sensors NADH, ATP, and acetyl-CoA decrease and the amounts of NAD+, AMP, CoA rise, molecules that act as epigenetic cofactors and lead to the activation of stress resistance mediators, as sirtuins (SIRTs), NRF2 (nuclear factor erythroid 2-related factor 2), and AMPK (AMPactivated protein kinase). ...
Article
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Adipose tissues are dynamic tissues that play crucial physiological roles in maintaining health and homeostasis. Although white adipose tissue and brown adipose tissue are currently considered key endocrine organs, they differ functionally and morphologically. The existence of the beige or brite adipocytes, cells displaying intermediary characteristics between white and brown adipocytes, illustrates the plastic nature of the adipose tissue. These cells are generated through white adipose tissue browning, a process associated with augmented non-shivering thermogenesis and metabolic capacity. This process involves the upregulation of the uncoupling protein 1, a molecule that uncouples the respiratory chain from Adenosine triphosphate synthesis, producing heat. β-3 adrenergic receptor system is one important mediator of white adipose tissue browning, during cold exposure. Surprisingly, hyperthermia may also induce beige activation and white adipose tissue beiging. Physical exercising copes with increased levels of specific molecules, including Beta-Aminoisobutyric acid, irisin, and Fibroblast growth factor 21 (FGF21), which induce adipose tissue browning. FGF21 is a stress-responsive hormone that interacts with beta-klotho. The central roles played by hormones in the browning process highlight the relevance of the individual lifestyle, including circadian rhythm and diet. Circadian rhythm involves the sleep–wake cycle and is regulated by melatonin, a hormone associated with UCP1 level upregulation. In contrast to the pro-inflammatory and adipose tissue disrupting effects of the western diet, specific food items, including capsaicin and n-3 polyunsaturated fatty acids, and dietary interventions such as calorie restriction and intermittent fasting, favor white adipose tissue browning and metabolic efficiency. The intestinal microbiome has also been pictured as a key factor in regulating white tissue browning, as it modulates bile acid levels, important molecules for the thermogenic program activation. During embryogenesis, in which adipose tissue formation is affected by Bone morphogenetic proteins that regulate gene expression, the stimuli herein discussed influence an orchestra of gene expression regulators, including a plethora of transcription factors, and chromatin remodeling enzymes, and non-coding RNAs. Considering the detrimental effects of adipose tissue browning and the disparities between adipose tissue characteristics in mice and humans, further efforts will benefit a better understanding of adipose tissue plasticity biology and its applicability to managing the overwhelming burden of several chronic diseases.
... Calorie restriction can be achieved through overall dietary reduction or by intermittent fasting (IF) [5]. IF is a nutritional strategy that requires fasting for varied periods, typically for 12 h or longer [6]. Fasting as a medicinal aid has been reported to be a reproducible and effective intervention strategy for protecting mammals from tumors and prolonging overall survival [2]. ...
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Background Preclinical studies prove that short-term fasting secures healthy cells against chemotherapy side effects and makes malignant cells more vulnerable to them. This study aimed to examine the effects of intermittent fasting (IF) during adjuvant chemotherapy AC (doxorubicin, cyclophosphamide) protocol in breast cancer (BC) patients. Methods Forty-eight newly diagnosed human epidermal growth factor receptor 2-negative (HER2 negative) BC patients were divided equally into two groups (24 each). The first group was recruited to fast intermittently for three consecutive days around chemotherapy for 18 h a day from 12 am to 6 pm and eats through 6 h a day from 6 pm to 12 am with permission of drinking water during fasting hours (IF group). This IF was repeated every 3 weeks for four cycles. The second group is a non-fasting (NF) group that was allowed to eat regularly. Toxicity in the two groups was compared. Hematologic, metabolic, and inflammatory parameters were measured and compared. Results Toxicity related to the gastrointestinal tract (GIT) was reduced in the IF group. Hematologic parameters showed no significant variations between the two studied groups after cycle 4. There was a significant increase in median glucose and median insulin levels ( P < 0.001 and P = 0.001, respectively) in the NF group between baseline and after cycle 4. In addition, there was a significant decrease in the median insulin level ( P = 0.002) in the IF group between the two time points. Conclusion IF throughout chemotherapy was well tolerated and decreased the toxicity of chemotherapy. Additionally, IF-improved metabolic profiles of patients may have a positive impact on the clinical efficacy of chemotherapy.
... Основной проблемой в этой области является отсутствие общепринятой стандартизованной терминологии для описания раз-личных парадигм прерывистого ограничения энергии. Так, ряд авторов используют термин прерывистое, или интервальное, голодание (intermittent fasting, ИГ) в качестве обобщающего термина для определения режимов питания, при которых люди проводят длительные периоды времени (например, 16-48 ч) с минимальным потреблением энергии или без нее, чередующиеся с периодами нормального приема пищи на регулярной основе [20,51,52]. М. Mattson и соавт. ...
Article
The article provides a review of the current literature about time-restricted eating (TRE) as a new tool for the treatment of obesity and comorbid conditions. The search for new nutritional strategies in obesity, one of which is TRE, is due to the weak adherence of patients to hypocaloric diets in the long term, as well as the available data on the importance of ­desynchronization of food intake with natural circadian rhythms in the development and progression of obesity and cardio-­metabolic complications. The article describes the main mechanisms that regulate the circadian rhythms of food intake and nutrient absorption, substantiates the importance of adhering to a physiological diet for maintaining metabolic health. The main part of the review is devoted to reviewing the currently available researches on the effectiveness of various strategies of intermittent energy restriction for weight loss and the correction of metabolic parameters. Potential mechanisms of the ­effect of TRE on health are discussed, including those mediated by an unintentional decrease in caloric intake and changes in eating behavior, and differences in the effectiveness of early and late TRE. The article contains a detailed discussion of the potential problems and contradictions associated with the use of time-restricted eating in clinical practice, namely: the limitations and inconsistencies of the available clinical trials, the lack of data on long-term efficacy and safety, social and psychological limitations that impede the widespread use of TRE.
... Reductions in muscle mass (which is the major component of lean body mass (LBM)) is undesirable as it is known to impair physical functionality, cardiometabolic health and may place an individual at higher risk for weight regain [14][15][16]. Some studies suggest that IF regimes maybe more protective of LBM compared with continuous energy restriction [17,18], while others have reported greater LBM loss with IF regimens [14,15,19]. Regardless, employing interventions that can promote muscle mass growth such as resistance training which can fully or partially attenuate this unwanted side effect is important when undertaking any energy-restricted diet. ...
The popularity of intermittent fasting (IF) and high intensity (sprint) interval training (SIT) has increased in recent years amongst the general public due to their purported health benefits and feasibility of incorporation into daily life. The number of scientific studies investigating these strategies has also increased, however, very few have examined the combined effects, especially on body composition and cardiometabolic biomarkers, which is the primary aim of this investigation. A total of thirty-four male and female participants (age: 35.4 ± 8.4 y, body mass index (BMI): 31.3 ± 3.5 kg/m2, aerobic capacity (VO2peak) 27.7 ± 7.0 mL·kg-1·min-1) were randomized into one of three 16-week interventions: (1) 5:2 IF (2 non-consecutive days of fasting per week, 5 days on ad libitum eating), (2) supervised SIT (3 bouts per week of 20s cycling at 150% VO2peak followed by 40 s of active rest, total 10 min duration), and (3) a combination of both interventions. Body composition, haemodynamic and VO2peak were measured at 0, 8 and 16 weeks. Blood samples were also taken and analysed for lipid profiles and markers of glucose regulation. Both IF and IF/SIT significantly decreased body weight, fat mass and visceral fat compared to SIT only (p < 0.05), with no significant differences between diet and diet + exercise combined. The effects of diet and/or exercise on cardiometabolic biomarkers were mixed. Only exercise alone or with IF significantly increased cardiorespiratory fitness. The results suggest that energy restriction was the main driver of body composition enhancement, with little effect from the low volume SIT. Conversely, to achieve benefits in cardiorespiratory fitness, exercise is required.
... 13 Therefore, the authors decided to further investigate related lifestyle behaviors. In animal models, case reports, and in a few mostly nonrandomized clinical trials, they found indications for benefits related to AD for hypnotherapy, [14][15][16][17][18] intermittent fasting, plant-based or arachidonic acidrestricted food, [19][20][21][22][23][24][25][26][27][28][29][30][31] and exercise. [32][33][34][35] Treatments in a group setting might reduce costs, have beneficial group effects, and may improve quality of life (QoL) and dermatological symptoms. ...
Article
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Background: Patients with atopic dermatitis (AD) frequently use healthy lifestyle behaviors, although their benefits are unclear. This study's aim was to investigate the effectiveness of hypnotherapy, fasting with diet adjustments, and exercise in AD patients. Methods: In a four-armed randomized controlled monocenter open explorative clinical trial, adult patients with mild-to-moderate severe AD underwent, over 16 weeks, a five-session hypnotherapy group program (HTP), a five-session intermittent fasting with diet adjustment group program (IFDP), a five-session exercise group program (EP), or no study intervention (control) as add-on to topical corticosteroid use if required. Endpoints included subjectively perceived itching on a visual analogue scale (VAS, 0-100 mm); disease severity by SCORing Atopic Dermatitis (SCORAD); and adverse events (AEs). Endpoints were analyzed descriptively in the Full Analysis Set (FAS). Due to the coronavirus disease 2019 (COVID-19) pandemic, relevant changes to the study protocol included online in addition to ''in-presence'' group interventions, closing the study arm EP and premature trial termination before randomization of 120 intended patients. Results: During the COVID-19 pandemic, study recruitment was poor. The FAS included 20 patients (17 female) with 35.0-12.1 (mean-standard deviation [SD]) years of age. At baseline, mean-SD for HTP (n = 6), IFDP (n = 4), EP (n = 1), and control (n = 9) were VAS itching 63.2-18.0, 65.0-13.9, 43.0 mm, 62.1-17.3; SCORAD 43.0-13.6, 47.0-21.0, 60.3, 39.1-15.6. After 16 weeks, endpoints were VAS itching
... This approach is adopted in a variety of protocols; alternate day fasting (no calories on fasting day and ad libitum on feast days), alternate-day modified fasting (consuming <25% of usual caloric intake on fasting days and ad libitum on feast days), 5:2 diet (with 2 days of fasting with 60-100% energy restrictions and 5 days of isocaloric intake), 4:3 (with 3 days of fasting with 60-100% energy restrictions and 4 days of isocaloric intake) (Figure 3) [214,[216][217][218]. Certain religious fasting practices observed including the Islamic month of Ramadan have been studied as part of IF approaches [219]. This approach, as compared to continuous CR, introduces periods of fasting when the metabolism shifts towards the catabolic state and mimics the feast/fast physiology of our hunter-gatherer past [220]. Even though the IF regimen suggests ad libitum feeding on non-fasting days, there is no full compensation for the fasting days/time, and overall there is an energy deficit or lack of calories. ...
Article
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Obesity is a chronic and relapsing public health problem with an extensive list of associated comorbidities. The worldwide prevalence of obesity has nearly tripled over the last five decades and continues to pose a serious threat to wider society and the wellbeing of future generations. The pathogenesis of obesity is complex but diet plays a key role in the onset and progression of the disease. The human diet has changed drastically across the globe, with an estimate that approximately 72% of the calories consumed today come from foods that were not part of our ancestral diets and are not compatible with our metabolism. Additionally, multiple nutrient-independent factors, e.g., cost, accessibility, behaviours, culture, education, work commitments, knowledge and societal set-up, influence our food choices and eating patterns. Much research has been focused on ‘what to eat’ or ‘how much to eat’ to reduce the obesity burden, but increasingly evidence indicates that ‘when to eat’ is fundamental to human metabolism. Aligning feeding patterns to the 24-h circadian clock that regulates a wide range of physiological and behavioural processes has multiple health-promoting effects with anti-obesity being a major part. This article explores the current understanding of the interactions between the body clocks, bioactive dietary components and the less appreciated role of meal timings in energy homeostasis and obesity.
... The need for regulation of ketone bodies occurs when the glycogen stores in the liver are depleted and since exercise increases glycogen consumption, it is expected that ketone bodies would be affected due to an increase in fatty acid oxidation in response to exercise [53][54][55]. Vieira et al. [56] showed increases in 3-hydroxybutyrate with exercise training and this increase was associated with increased glucose metabolism, lower serum triglycerides and reduced hepatic lipid content [56], as well as improved energy production in brain and skeletal muscle [57,58]. However, there are also contradictory findings, with one in newly enlisted soldiers, showing that fatty acids and ketone body substrates were dramatically decreased in plasma in response to increased aerobic fitness after 80 days of combined training [59]. ...
Article
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Increases in longevity and obesity have led to a higher prevalence of Metabolic Syndrome (MetS) and several chronic conditions, such as hypertension. The prevalence of MetS and hypertension increases with advancing age and their detrimental effects on health can be attenuated by physical activity. Combined aerobic and resistance exercise training (CT) is recommended to maintain good health in older adults and is known to generate important metabolic adaptations. In this study we performed a metabolomics analysis, based on Hydrogen Nuclear Magnetic Resonance (1H NMR), to investigate the kinetics of changes in metabolism in non-physically active older women with MetS in response to 16 weeks of CT. A subset of women with MetS were selected from a larger randomized trial (that included men and women without MetS), with 12 participants on CT and 13 from the Control Group (CG). CT comprised walking/running at 63% of VO2max, three times/week, and resistance training (RT), consisting of 15 repetitions of seven exercises at moderate intensity, twice/week. Serum metabolomic profile was analysed at baseline (0W), 4 (4W), 8 (8W), 12 (12W) and 16 weeks (16W) for CT or CG. Cardiorespiratory fitness, RT load, blood pressure, body composition, lipid and glycaemic profile were also assessed. After 16 weeks CT increased cardiorespiratory fitness (13.1%, p < 0.05) and RT load (from 48% in the lat pulldown to 160% in the leg press, p < 0.05), but there were no changes in MetS parameters, such as body composition (Body Mass, Body Mass Index (BMI), body fat percentage and waist circumference), blood pressure, lipid and glycaemic profile. However, we identified potential higher substrate to the tricarboxylic acid cycle (increase in 2-Oxobutyrate from 0W (0.0029 ± 0.0009) to 4W (0.0038 ± 0.0011) and 8W (0.0041 ± 0.0015), p < 0.05), followed by alterations (different from 0W, p < 0.05) in the production of ketone bodies (3-Hydroxybutyrate, 0W (0.0717 ± 0.0377) to 16W (0.0397 ± 0.0331), and Acetoacetate, 0W (0.0441 ± 0.0240) to 16W (0.0239 ± 0.0141)), which together might explain the known improvement in fatty acid oxidation with exercise. There was also a late increase in ornithine at 16W of CT. Further studies are needed to investigate the association between these metabolic pathways and clinical outcomes in this population.
... The mechanisms through which TRF conveys the observed benefits have not been fully elucidated and are likely pleiotropic. The alterations brought about by TRF may result from changes in metabolite interactions, bioenergetic pathway responses, modulation of circadian rhythm timing and strength, epigenetic modifications, and effects on food-anticipatory activity and reward circuits [22][23][24][25][26][27][28] . ...
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Alzheimer′s disease (AD) is a tragic neurodegenerative disease affecting more than 5 million Americans. Circadian disruptions impact nearly all AD patients, with reversal of sleep/wake cycles and agitation in the evening being common disturbances that manifest early in disease. These alterations support a role for circadian dysfunction as a driver of AD, emphasizing a critical need to investigate the therapeutic potential of circadian-modulating interventions. One of the most powerful regulators of the circadian system is the daily feed/fast cycle. Here we show that time-restricted feeding (TRF) without caloric restriction, improved key disease components including behavior, disease pathology and transcription in the APP23 mouse model of Alzheimer′s disease. We found that TRF had the remarkable capability of simultaneously reducing amyloid deposition, increasing Aβ42 clearance, improving sleep and hyperactivity, and normalizing transcription of circadian, AD and neuroinflammation-associated genes in APP23 mice. Thus, our study unveils for the first time that circadian modulation through timed feeding has far-reaching effects beyond metabolism and affects the brain as the substrate for neurodegeneration. Since the pleiotropic effects of TRF can substantially modify disease trajectory, this intervention has immediate translational value, addressing the crucial need for accessible approaches to reduce or halt AD progression.
... Cells are able to adapt to this bioenergetic challenge (glucose depletion, oversupply of FFAs/ketones) by activating protective signaling pathways that up-regulate mitochondrial function and antioxidant defenses, while up-regulating autophagy to remove damaged molecules and recycle their components [32]. Periodic flipping of the metabolic switch not only provides the ketones that are important fuels for cells during fasting, but also elicits highly orchestrated systemic and cellular adaptive responses that remain active also in the fed state and confer chronic disease resistance [33,34]. Ketones are not only energy fuels but also potent signaling molecules with important effects on multiple cell functions [35]. ...
Article
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Conventional hypocaloric diets, providing continuous energy restriction, are considered to be the cornerstone of dietary management of obesity. Although energy-restricted diets are overall safe, healthy, and modestly effective, their long-term adherence is difficult to accomplish. Intermittent fasting and ketogenic diets have emerged as attractive alternative dietary options for weight loss and improvement in cardiometabolic risk. Intermittent fasting is a unique dietary pattern characterized by periods of eating alternated with periods of fasting. Ketogenic diets are very low in carbohydrate, modest in protein, and high in fat. Several systematic reviews and meta-analyses of randomized controlled trials (RCTs) have reported beneficial but short-lived effects of intermittent fasting and ketogenic diets on various obesity-related health outcomes. Although for both diets, the current evidence is promising and steadily evolving, whether they are better than traditional calorie-restricted diets, whether they can safely lead to sustained weight loss and overall health benefits, and their effects on body composition, weight loss maintenance, energy intake and expenditure, diet quality, and cardiometabolic risk factors are still not unequivocally proven. The aim of the present review is to summarize the current state of evidence regarding the effects of these two popular modern diets, namely intermittent fasting and ketogenic diets. We describe the rationale and characteristics of different dietary protocols, we analyze the major mechanisms explaining their weight loss and cardiometabolic effects, and we provide a concise update on their effects on body weight and cardiometabolic risk factors, focusing on meta-analyses of RCTs. We also discuss knowledge gaps in the field of these diets, and we indicate directions for future research.
... In a symposium review (58), Cienfuegos and colleagues attributed the cardiometabolic benefits of TRE to circadian rhythm and biological clocks, which affected glucose regulation, beta cell responsiveness, body composition, and body composition body weight, reduction of oxidative stress and metabolic switch (24,(59)(60)(61)(62). As such, since fasting deprives the body of glucose, and after glycogen stores are depleted (within 12 h of fasting), the energy production is shifted to alternative energy sources such as fatty acids and ketone bodies, leading to the metabolic switch flipping (63). In addition, studies have shown that IF improves glucose regulation and decrease inflammatory biomarkers in the blood (64). ...
Article
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Intermittent fasting (IF), time-restricted eating (TRE) and fasting-mimicking diets (FMD) are gaining popularity as weight loss programs. As such, the timing and frequency of meals have been recognized as essential contributors to improving cardiometabolic health and a role as adjuvant therapy in cancer. Randomized controlled trials suggested that the weight loss associated with IF is due to a reduced energy intake due to time restriction. Although the supervised TRE clinical trials documented the dietary caloric intake, many free-living studies focused on the timing of meals without a complete characterization of the dietary intake, caloric density, or macronutrient composition. It is possible that both caloric-restriction diets and time-restriction protocols could work synergistically or additively to improve metabolic health outcomes. Like personalized medicine, achieving precision nutrition mandates the provision of the right nutrients to the right patient at the right time. To accomplish this goal, future studies need to evaluate the benefits of IF and TRE. Randomized controlled trials were conducted in different populations, ethnic groups, ages, geographic distribution, physical activity levels, body composition and in patients with obesity, diabetes, and cardiovascular diseases. Also, it is crucial to analyze the dietary composition and caloric density as related to circadian rhythm and timing of meals. It is conceivable that IF and TRE may contribute to precision nutrition strategies to achieve optimal health. However, more research is needed to evaluate IF and TRE effects on health outcomes and any side effects.
Article
Intervallfasten (IF), also die zeitlich beschränkte Nahrungsaufnahme mit markanten Zeitphasen ohne Mahlzeiten, ist gesundheitsförderlich und hat sich bewährt zur Gewichtsreduktion und in der Therapie und Prävention von Diabetes mellitus vom Typ 2. Dieser Beitrag beschreibt die positiven Effekte, die das Intervallfasten auf die sportliche Leistungsfähigkeit haben kann – ohne das Risiko einer verringerten Mikronährstoffzufuhr.
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The main aim of the study was to determine the effectiveness of time-restricted eating (TRE) in reducing body fat and lowering body mass index in early elderly men with overweight (65–74 years). An additional goal was to determine the feasibility of applying TRE for extensive use in elderly men. This study included a group of 46 healthy men (EXP = 23 persons, CON = 23 persons). The six-week intervention in the experimental group involved complete abstinence from food intake for 16 h per day, from 08:00 to 12:00 p.m. After the intervention, the body weight decreased in the EXP group (− 1.92 kg) with a 95% CI (1.14–2.70) compared to the CON group. There was also a decrease in the Visceral fat mass (− 0.64 l) with 95% CI (0.46–0.82) and in the waist circumference (− 3.11 cm) with 95% CI (1.89–4.33) in the EXP group compared to the CON group. The skeletal muscle mass did not change significantly. There was no significant change in the control group, either. The application of TRE in early elderly overweight men resulted in positive changes in body composition and visceral fat. All participants succeed in the prescribed diet plan, which shows that TRE is easy to maintain for early elderly overweight men and may become an essential obesity treatment tool in these age groups.
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Fasting provokes fundamental changes in the activation of metabolic and signaling pathways leading to longer and healthier lifespans in animal models. Although the involvement of different metabolites in fueling human fasting metabolism is well known, the contribution of tissues and organs to their supply remains partly unclear. Also, changes in organ volume and composition remain relatively unexplored. Thus, processes involved in remodeling tissues during fasting and food reintroduction need to be better understood. Therefore, this study will apply state-of-the-art techniques to investigate the effects of long-term fasting (LF) and food reintroduction in humans by a multi-systemic approach focusing on changes in body composition, organ and tissue volume, lipid transport and storage, sources of protein utilization, blood metabolites, and gut microbiome profiles in a single cohort. This is a prospective, single-arm, monocentric trial. One hundred subjects will be recruited and undergo 9 ± 3 day-long fasting periods (250 kcal/day). We will assess changes in the composition of organs, bones and blood lipid profiles before and after fasting, as well as high-density lipoprotein (HDL) transport and storage, untargeted metabolomics of peripheral blood mononuclear cells (PBMCs), protein persulfidation and shotgun metagenomics of the gut microbiome. The first 32 subjects, fasting for 12 days, will be examined in more detail by magnetic resonance imaging (MRI) and spectroscopy to provide quantitative information on changes in organ volume and function, followed by an additional follow-up examination after 1 and 4 months. The study protocol was approved by the ethics board of the State Medical Chamber of Baden-Württemberg on 26.07.2021 and registered at ClinicalTrials.gov (NCT05031598). The results will be disseminated through peer-reviewed publications, international conferences and social media. Clinical trial registration [ ClinicalTrials.gov ], identifier [NCT05031598].
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Objectives Drug treatment of metabolic associated fatty liver disease (MAFLD) remains lacking. This study analyzes the efficacy and mechanism underlying intermittent fasting combined with lipidomics.Methods Thirty-two male rats were randomly divided into three groups: Normal group, administered a standard diet; MAFLD group, administered a 60% high-fat diet; time-restricted feeding (TRF) group, administered a 60% high-fat diet. Eating was allowed for 6 h per day (16:00–22:00). After 15 weeks, liver lipidomics and other indicators were compared.ResultsA total of 1,062 metabolites were detected. Compared with the Normal group, the weight, body fat ratio, aspartate aminotransferase, total cholesterol, low-density cholesterol, fasting blood glucose, uric acid, and levels of 317 lipids including triglycerides (TG) (17:0−18:1−20:4) were upregulated, whereas the levels of 265 lipids including phosphatidyl ethanolamine (PE) (17:0−20:5) were downregulated in the MAFLD group (P < 0.05). Compared with the MAFLD group, the weight, body fat ratio, daily food intake, and levels of 253 lipids including TG (17:0−18:1−22:5) were lower in the TRF group. Furthermore, the levels of 82 lipids including phosphatidylcholine (PC) (20:4−22:6) were upregulated in the TRF group (P < 0.05), while serum TG level was increased; however, the increase was not significant (P > 0.05). Enrichment analysis of differential metabolites showed that the pathways associated with the observed changes mainly included metabolic pathways, regulation of lipolysis in adipocytes, and fat digestion and absorption, while reverse-transcription polymerase chain reaction showed that TRF improved the abnormal expression of FAS and PPARα genes in the MAFLD group (P < 0.05).Conclusion Our results suggest that 6 h of TRF can improve MAFLD via reducing food intake by 13% and improving the expression of genes in the PPARα/FAS pathway, thereby providing insights into the prevention and treatment of MAFLD.
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Background & aims: Although intermittent energy restriction (IER) seems to be as effective as continuous energy restriction (CER) for weight loss, there is still a need to determine the putative effect of this strategy upon the metabolic-inflammatory status. This study aimed to compare the effects of IER versus CER on cardiometabolic and inflammatory markers, over a 12-week period, in adults with obesity. Methods: Twenty-eight Norwegian adults (20-55 years) with obesity [body mass index: 35.4 (3.7) kg/m2] from a clinical trial (NCT02169778) who completed a 12-weeks diet-induced weight loss as IER (n = 14) or CER (n = 14) were included in this study. Cardiometabolic, adipokines and inflammatory markers were evaluated at baseline and after the intervention. Plasma levels of 13 inflammatory cytokines and chemokines (IL-1β, IFN-α2, IFN-γ, TNF-α, MCP-1, IL-6, IL-8, IL-10, IL-12, IL-17A, IL-18, IL-23, and IL-33) and 4 adipokines (adiponectin, adipsin, leptin and resistin) were measured through multiplex bead-based flow cytometric immunoassays. Results: Both interventions resulted in comparable reductions in fasting glucose and insulin concentrations, lipid profile biomarkers, and adipokines. There were significant differences in HOMA-IR between interventions, with a more pronounced reduction in the IER group (-3.7 vs -1.6, P = 0.040). Inflammatory cytokines and chemokines decreased significantly in the IER group only. Differences in the relative changes of IL-1β (-48.5 vs 58.2%, P = 0.011), IFN-γ (-53.2 vs 45.1%, P = 0.023), MCP-1 (-22.0 vs 17.4%, P = 0.023), IL-18 (-40.8 vs 10.1%, P = 0.019), IL-23 (-64.8 vs 44.0%, P = 0.011) and IL-33 (-53.4 vs 35.7%, P = 0.028) were statistically significant between groups, with improvements in the inflammatory profile in the IER group. Conclusions: Our results suggest that a 12-weeks intermittent energy restriction, in comparison to a continuous energy strategy, could be advantageous to reduce inflammation associated with obesity, and consequently improve insulin resistance, regardless of the amount of weight loss. Registered under ClinicalTrials.gov Identifier no. NCT02169778.
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Background: Intermittent energy restriction (IER) and continuous energy restriction (CER) are increasingly popular dietary approaches used for weight loss and overall health. These energy restriction protocols combined with exercise on weight loss and other health outcomes could achieve additional effects in a short-term intervention. Objectives: To evaluate the effects of a 4-week IER or CER program on weight, blood lipids, and CRF in overweight/obese adults when combined with high-intensity interval training (HIIT). Methods: Forty-eight overweight/obese adults [age: 21.3 ± 2.24 years, body mass index (BMI): 25.86 ± 2.64 kg⋅m-2] were randomly assigned to iER, cER, and normal diet (ND) groups (n = 16 per group), each consisting of a 4-week intervention. All of the groups completed HIIT intervention (3 min at 80% of V̇O2max followed by 3 min at 50% of V̇O2max ), 30 min/training sessions, five sessions per week. iER subjects consumed 30% of energy needs on 2 non-consecutive days/week, and 100% of energy needs on another 5 days; cER subjects consumed 70% of energy needs; and ND subjects consumed 100% of energy needs. Body composition, waist circumference (WC) and hip circumference (HC), triglyceride (TG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c), high-density lipoprotein-cholesterol (HDL-c), and cardiorespiratory fitness (CRF) were measured before and after the intervention. Results: Of the total 57 participants who underwent randomization, 48 (84.2%) completed the 4-week intervention. After intervention body composition and body circumference decreased in three groups, but no significant differences between groups. The iER tends to be superior to cER in the reduction of body composition and body circumference. The mean body weight loss was 4.57 kg (95% confidence interval [CI], 4.1-5.0, p < 0.001) in iER and 2.46 kg (95% CI, 4.1-5.0, p < 0.001) in iER. The analyses of BMI, BF%, WC, and HC were consistent with the primary outcome results. In addition, TG, TC, HDL-c, and CRF improved after intervention but without significant changes (p > 0.05). Conclusion: Both IER and CER could be effective in weight loss and increased CRF when combined with HIIT. However, iER showed greater benefits for body weight, BF%, WC, and HC compared with cER.
Article
Background. Obesity is a problem present in almost all societies, which has led to the search for different methods to combat it. One of them is intermittent fasting (IF), characterized by periods without eating (16 to 24 hours), limited or no caloric intake, combined with normal eating windows. Target. To determine the effectiveness of intermittent fasting on biochemical and anthropometric markers in obese adults. Materials and methods. A systematic review was proposed that postulated to study blinded or open clinical trials of IA interventions, compared with a control group. The response variables were: systolic and diastolic blood pressure, total cholesterol, LDL, HDL and triglycerides, blood glucose, fat mass, weight, waist circumference, BMI and heart rate. The search and identification of studies was masked. The risks of bias for the Cochrane collaboration were assessed. They underwent meta-analysis (random effect), with R 4.0.0. Results. Six studies were included, involving 10-48 weeks of intervention with alternate-day fasting and time-restricted feeding, reporting some statistically significant changes for different variables. Conclusion. Intermittent fasting could intervene in the reduction of cardiovascular risk due to improvement in BMI and biochemical parameters.
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Disturbances in sleep/wake cycles are common among patients with neurodegenerative diseases including Huntington’s disease (HD) and represent an appealing target for chrono-nutrition-based interventions. In the present work, we sought to determine whether a low-carbohydrate, high-fat diet would ameliorate the symptoms and delay disease progression in the BACHD mouse model of HD. Adult WT and BACHD male mice were fed a normal or a ketogenic diet (KD) for 3 months. The KD evoked a robust rhythm in serum levels of β-hydroxybutyrate and dramatic changes in the microbiome of male WT and BACHD mice. NanoString analysis revealed transcriptional changes driven by the KD in the striatum of both WT and BACHD mice. Disturbances in sleep/wake cycles have been reported in mouse models of HD and are common among HD patients. Having established that the KD had effects on both the WT and mutant mice, we examined its impact on sleep/wake cycles. KD increased daytime sleep and improved the timing of sleep onset, while other sleep parameters were not altered. In addition, KD improved activity rhythms, including rhythmic power, and reduced inappropriate daytime activity and onset variability. Importantly, KD improved motor performance on the rotarod and challenging beam tests. It is worth emphasizing that HD is a genetically caused disease with no known cure. Life-style changes that not only improve the quality of life but also delay disease progression for HD patients are greatly needed. Our study demonstrates the therapeutic potential of diet-based treatment strategies in a pre-clinical model of HD.
Chapter
In the long run of human history, a key responsibility has been the fight for food. Food is not always abundant, and the human body has to adjust by regulating nutrient-sensing signals to varying food availability. During the fed state, extra nutrients are stored in the body for further use. During the fasting state, the human body needs to adjust its metabolism to fight against low nutrient supply. Upon aging, the body has a decreased need for food intake and digestion and absorption are reduced, resulting in a state of unbalanced supply of various nutrients. This activates or inactivates corresponding nutrient sensing signals to adjust to the aging process. In this chapter, we discuss major nutrient sensing signals during aging, including the AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), sirtuin (SIRT), and insulin-like growth factor 1 (IGF-1) pathways. We also discuss the effects of calorie restriction on aging and the relative nutrient sensing signaling pathways.
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Aim: The objective of the article is to demonstrate the research on the effectiveness of physical therapy in renewal of health of women with alimentary-constitutional type of I degree obesity. The task was also to study the initial level of obesity of women, to develop the structure of the therapeutic rehabilitation complex, to implement the developed programme of physical therapy and evaluate its effectiveness. Materials and Methods: The study was conducted for six months on the basis of a sports and recreation complex, which includes a gym, aerobics and a swimming pool with professional equipment. It was attended by 40 people aged from 33 to 56, with overweight and obesity of I degree. They were divided into two groups: the main (20 people) and control (20 people). The main group used a set of strength physical exercises of aerobic and anaerobic types, diet therapy andconstant online psychological support. The women in the control group performed the standard set of physical exercises that are usually offered in sports facilities and ate at their own discretion. We also used elements of therapeutic exercise to increase energy expenditure, reduce excess weight and strengthen muscles, restore and maintain physical and professional performance. There wereno people with serious disorders of the cardiovascular, endocrine and other body systems among the participants of the study. Results: During the therapeutic programme, we performed monthly control measurements of body parameters and body weight in order to monitor their dynamics and compare it with that in the control group, which was engaged in the standard complex. At the beginning of the study, the results in both groups were quite positive, after some time the rate of weight loss began to slow down, and in the control group, among some participants it even worsened – the weight returned. 6 months after the initial control, a final control of both groups of women of second adulthood was performed. When comparing the data obtained before and after rehabilitation measures, we observed a significant decrease in body weight in individuals of the study group in contrast to the control, where there was a decrease in body weight, but it was statistically insignificant. Analysis of the dynamics of monthly weight loss for the entire rehabilitation period showed that in the control group there was a decrease in body weight in the first and second months of the rehabilitation complex, relative to the main group, then the dynamics was marked by significant weight loss in the 1st, 2nd, 3rd month. Conclusions: Based on the obtained results, we proved the high efficiency of the proposed therapeutic and rehabilitation complex (combination of diet therapy, exercises of aerobic and anaerobic directions) for the treatment of persons with I degree of obesity (significantly reduced body weight and reduced the size of body parts). Rehabilitation measures used in our study activate metabolic processes, increase energy expenditure, reduce excess body weight, strengthen the body. By following a healthy lifestyle, eating rationally, you can prevent a number of diseases, improve efficiency and general well-being, avoid premature aging. Physical therapy of obese patients requires a combination of dietary and physiotherapeutic methods (massage, physiotherapy, psychological training), which allows to achieve sustainable weight loss for a long period.
Article
Urotensin receptor (UT) is a G-protein-coupled receptor, whose endogenous ligand is urotensin-II (U-II). Skeletal muscle mass is regulated by various conditions, such as nutritional status, exercise, and diseases. Previous studies have pointed out that the urotensinergic system is involved in skeletal muscle metabolism and function, but its mechanism remains unclear, especially given the lack of research on the effect and mechanism of fasting. In this study, UT receptor knockout mice were generated to evaluate whether UT has effects on fasting induced skeletal muscle atrophy. Furthermore, the UT antagonist palosuran (3, 10, 30 mg/kg) was intraperitoneally administered daily for 5 days to clarify the therapeutic effect of UT antagonism. Our results found the mice that fasted for 48 hours exhibited skeletal muscle atrophy, accompanied by enhanced U-II levels in both skeletal muscles and blood. UT receptor knockout effectively prevented fasting-induced skeletal muscle atrophy. The UT antagonist ameliorated fasting-induced muscle atrophy in mice as determined by increased muscle strengths, weights, and muscle fiber areas (including fast, slow, and mixed types). In addition, the UT antagonist reduced skeletal muscle atrophic markers, including F-box only protein 32 (FBXO32) and tripartite motif containing 63 (TRIM63). Moreover, the UT antagonist was also observed to enhance PI3K/AKT/mTOR while inhibiting autophagy signaling. In summary, our study provides the first evidence that UT antagonism may represent a novel therapeutic approach for the treatment of fasting-induced skeletal muscle atrophy.
Article
Background: Intermittent fasting (IF) is an increasingly popular approach to dietary control that focuses on the timing of eating rather than the quantity and content of caloric intake. IF practitioners typically seek to improve their weight and other health factors. Millions of practitioners have turned to purpose-built mobile apps to help them track and adhere to their fasts and monitor changes in their weight and other biometrics. Objective: This study aimed to quantify user retention, fasting patterns, and weight loss by users of 2 IF mobile apps. We also sought to describe and model starting BMI, amount of fasting, frequency of weight tracking, and other demographics as correlates of retention and weight change. Methods: We assembled height, weight, fasting, and demographic data of adult users (ages 18-100 years) of the LIFE Fasting Tracker and LIFE Extend apps from 2018 to 2020. Retention for up to 52 weeks was quantified based on recorded fasts and correlated with user demographics. Users who provided height and at least 2 readings of weight and whose first fast and weight records were contemporaneous were included in the weight loss analysis. Fasting was quantified as extended fasting hours (EFH; hours beyond 12 in a fast) averaged per day (EFH per day). Retention was modeled using a Cox proportional hazards regression. Weight loss was analyzed using linear regression. Results: A total of 792,692 users were followed for retention based on 26 million recorded fasts. Of these, 132,775 (16.7%) users were retained at 13 weeks, 54,881 (6.9%) at 26 weeks, and 16,478 (2.1%) at 52 weeks, allowing 4 consecutive weeks of inactivity. The survival analysis using Cox regression indicated that retention was positively associated with age and exercise and negatively associated with stress and smoking. Weight loss in the qualifying cohort (n=161,346) was strongly correlated with starting BMI and EFH per day, which displayed a positive interaction. Users with a BMI ≥40 kg/m2 lost 13.9% of their starting weight by 52 weeks versus a slight weight gain on average for users with starting BMI <23 kg/m2. EFH per day was an approximately linear predictor of weight loss. By week 26, users lost over 1% of their starting weight per EFH per day on average. The regression analysis using all variables was highly predictive of weight change at 26 weeks (R2=0.334) with starting BMI and EFH per day as the most significant predictors. Conclusions: IF with LIFE mobile apps appears to be a sustainable approach to weight reduction in the overweight and obese population. Healthy weight and underweight individuals do not lose much weight on average, even with extensive fasting. Users who are obese lose substantial weight over time, with more weight loss in those who fast more.
Chapter
Undoubtedly, the increase in the incidence of many chronic diseases, especially metabolic syndrome, is related to an unhealthy diet. “Natural-organic nutrition,” which is one of the important elements of a healthy life, will also minimize the entry of “exogenous free radicals” into the body, which are accepted as oxidative stress factors in human metabolism. Recently, the thiol-disulfide balance has been accepted as an indicator for oxidative stress, which is the root cause of most diseases. Among these systemic diseases, metabolic syndrome, cancer, rheumatoid arthritis, type II diabetes, Parkinson’s, Alzheimer’s, cardiovascular diseases, migraine, liver, and kidney failure are the first ones that come to mind. Many factors, including obesity, oxidative stress and unhealthy diet are involved in the etiopathogenesis of many diseases. In this section, the relationship between nutrition and thiol-disulfide homeostasis, which is one of the oxidative stress markers, is presented.
Article
Background: The prevalence of nonalcoholic fatty liver disease (NAFLD) is rapidly growing in China, especially in patients with type 2 diabetes mellitus (T2DM). Weight loss strategies have been shown to treat NAFLD effectively. We conducted a 24-week, prospective, randomized study in T2DM patients with NAFLD to evaluate the effects of a 5:2 fasting diet on liver fat content. Methods: Sixty-one T2DM patients with NAFLD were enrolled and randomly divided into a 5:2 fasting diet intervention group (5:2 diet group, n = 31) and 1.8 mg/day liraglutide intervention group (Lira group, n = 30). The study was performed for 24 weeks. Data of the body weight, waist circumference, plasma lipids and glucose profile, fasting plasma insulin, and liver function parameters were collected. Controlled attenuation parameter (CAP) was measured to assess the liver fat content. Superoxide dismutase (SOD) and malondialdehyde (MDA) were measured to evaluate oxidative stress status. Results: At 24 weeks after intervention, compared with those at baseline, CAP was significantly decreased in both the 5:2 diet group and Lira group, which was 7.4% and 5.5%, respectively. Body weight, plasma lipids and glucose profile, and liver function parameters improved significantly, while homeostasis model assessment-β (HOMA-β) was significantly increased in both groups (all P < 0.05). Stepwise linear regression showed that increased HOMA-β and SOD, as well as reduced body mass index (BMI), were the independent predictors of CAP decrease in the Lira group (P = 0.000, 0.000, 0.015). In contrast, reduced BMI and MDA were the independent influencing factors of CAP decrease in the 5:2 diet group (P = 0.011, 0.043). The common side effects in the 5:2 diet group were hunger (60%), weakness (10%), and constipation (0.3%). Conclusions: A 5:2 fasting diet achieved comparable effects with liraglutide on liver fat content in patients with T2DM with NAFLD by reducing BMI and oxidative stress. Both treatment strategies were safe and effective for glucose control.
Article
Background Intermittent fasting (IF) has grown in popularity as a weight loss tool, where caloric intake is fully/partially restricted on a recurring basis. This study aimed to assess compliance with IF fast-day calorie restriction and whether 5-2 IF leads to reduced overall energy intake, weight loss and compensatory increased energy intake on non-fast days. Method Participants completed diet diaries at baseline and 28 days post 5-2 IF in a repeated measures within-subjects design. 5-2 IF required restricted energy intake to 500kcal/day (women), 650kcal/day (men) on two ‘fast’ days/week whilst eating ad-libitum on other days. Results 52 participants were included (n=42 female; age 44±11.2yrs). Median weight loss after 28 days 5-2 IF was not statistically significant (1.8 [-2 - 7.3 IQR=2.2]kg; 2.8 [-2.7–11.2 IQR=2.5]%). There was a significant reduction in total energy intake during 5-2 IF compared with pre-diet (median 1288.0 [IQR 423.8]kcal and median 1751.5 [IQR 505.3]kcal respectively, p<0.001). Carbohydrate, protein and fat consumption proportionately reduced during 5-2 IF. Participants had significantly higher energy intake (p<0.001) on non-fast days that followed a fast day (1928.4±711.9kcal) compared to non-fast days not following a fast day (1316.2±310.0kcal). 55.8% complied with fast day calorie restrictions. Conclusion 5-2 IF was associated with reduced energy intake, but insignificant weight loss over a 28-day period. Compliance rate was lower than most previous studies. Participants had significantly higher energy intake on non-fast days following fast days suggesting fasting may lead to over-compensation. Further research should investigate strategies to improve compliance and long-term sustainability of IF diets.
Article
Psoriasis is an immune‐mediated inflammatory skin disease affecting approximately 2% of the UK population. Its pathogenesis is suggested to be an outcome of genetic and environmental interplay. People with psoriasis have an increased likelihood of developing other conditions such as type 2 diabetes and cardiovascular disease. Systemic inflammation is hypothesised to be the common link between psoriasis and cardio‐metabolic diseases. Emerging evidence shows diet as a potential therapeutic adjunct in the management of psoriasis. The Diet and Psoriasis Project (DIEPP) aims to investigate whether dietary factors are related to psoriasis severity by conducting an observational study followed by a dietary intervention trial, to assess the effect of the Mediterranean diet (MedD) and time‐restricted eating (TRE) on psoriasis. This review article will explore the potential mechanisms by which the MedD and TRE may exert protective effects on psoriasis, evaluate the current evidence, and outline the design of the DIEPP. Given the early‐stage evidence, we hope to be able to build knowledge to derive medically approved dietary recommendations and contribute to the research gaps exploring the role of diet and psoriasis.
Article
Background: Worldwide, obesity has nearly tripled since 1975 and has become a major healthcare challenge today. Intermittent fasting (IF) is gaining popularity as a weight loss strategy in recent times. This study aimed to study the role of IF as a modern-day weight-loss strategy in obese adults through a real-world pilot experiment conducted at a nutrition clinic in Mumbai. Methodology: To understand the effects of IF on weight loss, 32 overweight/obese [body mass index (BMI) ≥23 kg/m2] adults from a nutrition clinic in Mumbai, were assigned consecutively to an IF plan and followed up for 3 months. Their demographic, anthropometric, and dietary assessments were done pre- and post-intervention. Qualitative interviews were done at the end of the study to record the participants' overall well-being, experience, and sustainability of IF. Results: 56% of study participants were males and their mean age was 35.6 ± 8.9 years. 65.6% of participants were able to maintain 14-16 hours of fasting and 53% managed all 7 days of IF. Analysis of post-intervention data showed a significant reduction in mean body weight (88.5 ± 19 to 83.8 ± 17.6 kg), waist circumference (M: 108.2 ± 11.3 to 103.6 ± 4.4 cm, F: 98.9 ± 8.8 to 93.3 ± 3.3 cm), BMI (31.4 ± 5.3 to 29.6 ± 5.1 kg/m2), daily calories (1782 ± 237 to 1388 ± 243 kcal/day), carbohydrate intake (267 ± 18.4 to 164 ± 4.0 g/day), and an increase in protein intake (39 ± 11 to 55 ± 11 g/day). Participants reported positive experiences of practicing IF such as improved fitness, sleep cycle, and adoption of healthy eating habits. Conclusion: The study demonstrates that IF could aid in weight loss and adoption of a healthier lifestyle.
Article
Objective Time-restricted eating (TRE), which restricts food intake to a limited duration of the day, is one of a key regimen of intermittent fasting (IF). The aim of our study was to provide an up-to-date meta-analysis and systematic review to evaluate the efficacy of TRE on weight loss and other metabolic-related parameters in adults. Methods We searched PubMed, EMBASE and the Cochrane Library for relevant studies published before February 26, 2022. Study duration of TRE was at least 4 weeks. Body weight and other metabolic-related continuous parameters were described as weighted mean difference (WMD) with 95% confidence intervals (CIs). Results Seventeen randomized controlled trials (RCTs) involving 899 participants were analyzed. The pooled meta-analysis showed that TRE contributed to a significant decrease in body weight with a WMD of -1.60 kg (95% CI -2.27 to -0.93) and fat mass with WMD -1.48 kg (95% CI -1.59 to -1.38). Subgroup analysis showed that TRE could reduce body weight and fat mass especially in overweight participants with WMD -1.43 kg (95% CI -2.05 to -0.81) and -1.56 Kg (95% CI -1.67 to -1.44), respectively. TRE also showed beneficial effects on the lipid spectrum in overweight participants, including decreased levels of triglyceride (TG) (WMD -12.71 mg/dl, 95% CI -24.9 to -0.52), total cholesterol (TC) (WMD -6.45 mg/dl, 95% CI -7.40 to -5.49) and LDL-C (WMD -7.0 mg/dl, 95% CI -9.74 to -4.25). However, compared to control, TRE had no significant effects on waist circumference (WC), body mass index (BMI), glycosylated haemoglobin (HbA1c) or blood pressure. Conclusion This updated meta-analysis found that TRE may be an effective approach to improve the metabolic state of non-obese subjects, especially in overweight participants.
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Ketone body metabolism is a central node in physiological homeostasis. In this review, we discuss how ketones serve discrete fine-tuning metabolic roles that optimize organ and organism performance in varying nutrient states and protect from inflammation and injury in multiple organ systems. Traditionally viewed as metabolic substrates enlisted only in carbohydrate restriction, observations underscore the importance of ketone bodies as vital metabolic and signaling mediators when carbohydrates are abundant. Complementing a repertoire of known therapeutic options for diseases of the nervous system, prospective roles for ketone bodies in cancer have arisen, as have intriguing protective roles in heart and liver, opening therapeutic options in obesity-related and cardiovascular disease. Controversies in ketone metabolism and signaling are discussed to reconcile classical dogma with contemporary observations.
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Eating patterns are increasingly varied. Typical breakfast, lunch, and dinner meals are difficult to distinguish because skipping meals and snacking have become more prevalent. Such eating styles can have various effects on cardiometabolic health markers, namely obesity, lipid profile, insulin resistance, and blood pressure. In this statement, we review the cardiometabolic health effects of specific eating patterns: skipping breakfast, intermittent fasting, meal frequency (number of daily eating occasions), and timing of eating occasions. Furthermore, we propose definitions for meals, snacks, and eating occasions for use in research. Finally, data suggest that irregular eating patterns appear less favorable for achieving a healthy cardiometabolic profile. Intentional eating with mindful attention to the timing and frequency of eating occasions could lead to healthier lifestyle and cardiometabolic risk factor management.
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Objectives. The acute fasting-induced cardiovascular autonomic response and its effect on cognition and mood remain debatable. Thus, the main purpose of this study was to estimate the effect of a 48 h, zero-calorie diet on autonomic function, brain activity, cognition, and mood in amateur weight lifters. Methods. Nine participants completed a 48 h, zero-calorie diet program. Cardiovascular autonomic function, resting frontal brain activity, cognitive performance, and mood were evaluated before and after fasting. Results. Fasting decreased ( p<0.05 ) weight, heart rate, and systolic blood pressure, whereas no changes were evident regarding any of the measured heart rate variability indices. Fasting decreased ( p<0.05 ) the concentration of oxygenated hemoglobin and improved ( p<0.05 ) mental flexibility and shifting set, whereas no changes were observed in working memory, visuospatial discrimination, and spatial orientation ability. Fasting also increased ( p<0.05 ) anger, whereas other mood states were not affected by it. Conclusions. 48 h fasting resulted in higher parasympathetic activity and decreased resting frontal brain activity, increased anger, and improved prefrontal-cortex-related cognitive functions, such as mental flexibility and set shifting, in amateur weight lifters. In contrast, hippocampus-related cognitive functions were not affected by it.
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During fasting and vigorous exercise, a shift of brain cell energy substrate utilization from glucose to the ketone 3-hydroxybutyrate (3OHB) occurs. Studies have shown that 3OHB can protect neurons against excitotoxicity and oxidative stress, but the underlying mechanisms are unclear. Neurons maintained in the presence of 3OHB exhibited increased oxygen consumption and ATP production, and an elevated NAD+/NADH ratio. We found that 3OHB metabolism increases mitochondrial respiration which drives changes in expression of brain derived neurotrophic factor (BDNF) in cultured cerebral cortical neurons. The mechanism by which 3OHB induces Bdnf gene expression involves generation of reactive oxygen species, activation of the transcription factor NF-kB and activity of the histone acetyltransferase p300/EP300. Because BDNF plays important roles in synaptic plasticity and neuronal stress resistance, our findings suggest cellular signaling mechanisms by which 3OHB may mediate adaptive responses of neurons to fasting, exercise and ketogenic diets. This article is protected by copyright. All rights reserved.
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Background Intermittent fasting (IF) is an increasingly popular dietary approach used for weight loss and overall health. While there is an increasing body of evidence demonstrating beneficial effects of IF on blood lipids and other health outcomes in the overweight and obese, limited data are available about the effect of IF in athletes. Thus, the present study sought to investigate the effects of a modified IF protocol (i.e. time-restricted feeding) during resistance training in healthy resistance-trained males. Methods Thirty-four resistance-trained males were randomly assigned to time-restricted feeding (TRF) or normal diet group (ND). TRF subjects consumed 100 % of their energy needs in an 8-h period of time each day, with their caloric intake divided into three meals consumed at 1 p.m., 4 p.m., and 8 p.m. The remaining 16 h per 24-h period made up the fasting period. Subjects in the ND group consumed 100 % of their energy needs divided into three meals consumed at 8 a.m., 1 p.m., and 8 p.m. Groups were matched for kilocalories consumed and macronutrient distribution (TRF 2826 ± 412.3 kcal/day, carbohydrates 53.2 ± 1.4 %, fat 24.7 ± 3.1 %, protein 22.1 ± 2.6 %, ND 3007 ± 444.7 kcal/day, carbohydrates 54.7 ± 2.2 %, fat 23.9 ± 3.5 %, protein 21.4 ± 1.8). Subjects were tested before and after 8 weeks of the assigned diet and standardized resistance training program. Fat mass and fat-free mass were assessed by dual-energy x-ray absorptiometry and muscle area of the thigh and arm were measured using an anthropometric system. Total and free testosterone, insulin-like growth factor 1, blood glucose, insulin, adiponectin, leptin, triiodothyronine, thyroid stimulating hormone, interleukin-6, interleukin-1β, tumor necrosis factor α, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured. Bench press and leg press maximal strength, resting energy expenditure, and respiratory ratio were also tested. ResultsAfter 8 weeks, the 2 Way ANOVA (Time * Diet interaction) showed a decrease in fat mass in TRF compared to ND (p = 0.0448), while fat-free mass, muscle area of the arm and thigh, and maximal strength were maintained in both groups. Testosterone and insulin-like growth factor 1 decreased significantly in TRF, with no changes in ND (p = 0.0476; p = 0.0397). Adiponectin increased (p = 0.0000) in TRF while total leptin decreased (p = 0.0001), although not when adjusted for fat mass. Triiodothyronine decreased in TRF, but no significant changes were detected in thyroid-stimulating hormone, total cholesterol, high-density lipoprotein, low-density lipoprotein, or triglycerides. Resting energy expenditure was unchanged, but a significant decrease in respiratory ratio was observed in the TRF group. Conclusions Our results suggest that an intermittent fasting program in which all calories are consumed in an 8-h window each day, in conjunction with resistance training, could improve some health-related biomarkers, decrease fat mass, and maintain muscle mass in resistance-trained males.
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Clinical studies indicate alternate day, intermittent fasting (IMF) protocols result in meaningful weight loss in obese individuals. To further understand the mechanisms sustaining weight loss by IMF, we investigated the metabolic and neural alterations of IMF in obese mice. Male C57/BL6 mice were fed a high-fat diet (HFD; 45 fat) ad libitum for 8 weeks to promote an obese phenotype. Mice were divided into 4 groups and either maintained on ad libitum HFD (HFD), received alternate day access to HFD (IMF- HFD), switched to ad libitum low fat diet (LFD; 10% fat), or received IMF of LFD (IMF- LFD). After 4 weeks, IMF-HFD (∾13%) and IMF-LFD (∾18%) had significantly lower body weights than HFD. Body fat was also lower (∾40-52%) in all diet interventions. Lean mass was increased in the IMF-LFD (∾12-13%) compared with HFD and IMF-HFD groups. Oral glucose tolerance AUC was lower in the IMF-HFD (∾50%), whereas insulin tolerance AUC was reduced in all diet interventions (∾22-42%). HPLC measurements of hypothalamic tissue homogenates indicated higher (∾55-60%) norepinephrine (NE) content in the anterior regions of the medial hypothalamus of IMF compared with ad libitum fed groups, whereas NE content was higher (∾19-32%) in posterior regions in the IMF-LFD group only. Relative gene expression of Npy in the arcuate nucleus was increased (∾65-75%) in IMF groups. Our novel findings indicate that intermittent fasting produces alterations in hypothalamic NE and NPY, suggesting an involvement in the counter regulatory processes of short-term weight loss are associated with an IMF dietary strategy.
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Prolonged fasting (PF) promotes stress resistance, but its effects on longevity are poorly understood. We show that alternating PF and nutrient-rich medium extended yeast lifespan independently of established pro-longevity genes. In mice, 4 days of a diet that mimics fasting (FMD), developed to minimize the burden of PF, decreased the size of multiple organs/systems, an effect followed upon re-feeding by an elevated number of progenitor and stem cells and regeneration. Bi-monthly FMD cycles started at middle age extended longevity, lowered visceral fat, reduced cancer incidence and skin lesions, rejuvenated the immune system, and retarded bone mineral density loss. In old mice, FMD cycles promoted hippocampal neurogenesis, lowered IGF-1 levels and PKA activity, elevated NeuroD1, and improved cognitive performance. In a pilot clinical trial, three FMD cycles decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease, and cancer without major adverse effects, providing support for the use of FMDs to promote healthspan.
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Background: In rodent models, caloric restriction (CR) with maintenance of adequate micronutrient supply has been reported to increase lifespan and to reduce age-induced muscle loss (sarcopenia) during ageing. In the present study, we further investigated effects of CR on the onset and severity of sarcopenia in ageing male C57BL/6 J mice. The aim of this study was to investigate whether CR induces changes in behaviour of the animals that could contribute to the pronounced health-promoting effects of CR in rodents. In addition, we aimed to investigate in more detail the effects of CR on the onset and severity of sarcopenia. Methods: The mice received either an ad libitum diet (control) or a diet matching 70 E% of the control diet (C). Daily activity, body composition (dual energy X-ray absorptiometry), grip strength, insulin sensitivity, and general agility and balance were determined at different ages. Mice were killed at 4, 12, 24, and 28 months. Skeletal muscles of the hind limb were dissected, and the muscle extensor digitorum longus muscle was used for force-frequency measurements. The musculus tibialis was used for real-time quantitative PCR analysis. Results: From the age of 12 months, CR animals were nearly half the weight of the control animals, which was mainly related to a lower fat mass. In the control group, the hind limb muscles showed a decline in mass at 24 or 28 months of age, which was not present in the CR group. Moreover, insulin sensitivity (oral glucose tolerance test) was higher in this group and the in vivo and ex vivo grip strength did not differ between the two groups. In the hours before food was provided, CR animals were far more active than control animals, while total daily activity was not increased. Moreover, agility test indicated that CR animals were better climbers and showed more climbing behaviours. Conclusions: Our study confirms earlier findings that in CR animals less sarcopenia is present. The mice on the CR diet, however, showed specific behavioural changes characterized by higher bursts of activity within a short time frame before consumption of a 70 E% daily meal. We hypothesize that the positive effects of CR on muscle maintenance in rodents are not merely a direct consequence of a lower energy intake but also related to a more active behaviour in a specific time frame. The burst of activity just before immediate start of eating, might lead to a highly effective use of the restricted protein sources available.
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Humans and their predecessors evolved in environments where they were challenged intermittently with: 1) food scarcity; 2) the need for aerobic fitness to catch/kill prey and avoid or repel attackers; and 3) exposure to biological toxins present in foodstuffs. Accordingly, cells and organ systems acquired and retained molecular signaling and metabolic pathways through which the environmental challenges enhanced the functionality and resilience of the cells and organisms. Within the past 60 years there has been a precipitous diminution of such challenges in modern societies because of the development of technologies that provide a continuous supply of energy-dense processed foods and that largely eliminate the need for physical exertion. As a consequence of the modern 'couch potato' lifestyle, signaling pathways that mediate beneficial effects of environmental challenges on health and disease resistance are disengaged, thereby rendering people vulnerable to obesity, diabetes, cardiovascular disease, cancers and neurodegenerative disorders. Reversal of the epidemic of diseases caused by unchallenging lifestyles will require a society-wide effort to re-introduce intermittent fasting, exercise and consumption of plants containing hormetic phytochemicals into daily and weekly routines.
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Because current therapeutics for obesity are limited and only offer modest improvements, novel interventions are needed. Preventing obesity with time-restricted feeding (TRF; 8-9 hr food access in the active phase) is promising, yet its therapeutic applicability against preexisting obesity, diverse dietary conditions, and less stringent eating patterns is unknown. Here we tested TRF in mice under diverse nutritional challenges. We show that TRF attenuated metabolic diseases arising from a variety of obesogenic diets, and that benefits were proportional to the fasting duration. Furthermore, protective effects were maintained even when TRF was temporarily interrupted by ad libitum access to food during weekends, a regimen particularly relevant to human lifestyle. Finally, TRF stabilized and reversed the progression of metabolic diseases in mice with preexisting obesity and type II diabetes. We establish clinically relevant parameters of TRF for preventing and treating obesity and metabolic disorders, including type II diabetes, hepatic steatosis, and hypercholesterolemia. Copyright © 2014 Elsevier Inc. All rights reserved.
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An intriguing aspect of social foraging behaviour is that large groups are often no better at capturing prey than are small groups, a pattern that has been attributed to diminished cooperation (i.e., free riding) in large groups. Although this suggests the formation of large groups is unrelated to prey capture, little is known about cooperation in large groups that hunt hard-to-catch prey. Here, we used direct observations of Yellowstone wolves (Canis lupus) hunting their most formidable prey, bison (Bison bison), to test the hypothesis that large groups are more cooperative when hunting difficult prey. We quantified the relationship between capture success and wolf group size, and compared it to previously reported results for Yellowstone wolves hunting elk (Cervus elaphus), a prey that was, on average, 3 times easier to capture than bison. Whereas improvement in elk capture success levelled off at 2-6 wolves, bison capture success levelled off at 9-13 wolves with evidence that it continued to increase beyond 13 wolves. These results are consistent with the hypothesis that hunters in large groups are more cooperative when hunting more formidable prey. Improved ability to capture formidable prey could therefore promote the formation and maintenance of large predator groups, particularly among predators that specialize on such prey.
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Abstract A key element contributing to deteriorating exercise capacity during physically demanding sport appears to be reduced carbohydrate availability coupled with an inability to effectively utilize alternative lipid fuel sources. Paradoxically, cognitive and physical decline associated with glycogen depletion occurs in the presence of an over-abundance of fuel stored as body fat that the athlete is apparently unable to access effectively. Current fuelling tactics that emphasize high-carbohydrate intakes before and during exercise inhibit fat utilization. The most efficient approach to accelerate the body's ability to oxidize fat is to lower dietary carbohydrate intake to a level that results in nutritional ketosis (i.e., circulating ketone levels >0.5 mmol/L) while increasing fat intake for a period of several weeks. The coordinated set of metabolic adaptations that ensures proper interorgan fuel supply in the face of low-carbohydrate availability is referred to as keto-adaptation. Beyond simply providing a stable source of fuel for the brain, the major circulating ketone body, beta-hydroxybutyrate, has recently been shown to act as a signalling molecule capable of altering gene expression, eliciting complementary effects of keto-adaptation that could extend human physical and mental performance beyond current expectation. In this paper, we review these new findings and propose that the shift to fatty acids and ketones as primary fuels when dietary carbohydrate is restricted could be of benefit for some athletes.
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Abstract The ketogenic diet (KD) is a broad-spectrum therapy for medically intractable epilepsy and is receiving growing attention as a potential treatment for neurological disorders arising in part from bioenergetic dysregulation. The high-fat, low-carbohydrate classic KD - as well as dietary variations such as the medium-chain triglyceride diet, the modified Atkins diet, the low-glycemic index treatment, and caloric restriction - enhance cellular metabolic and mitochondrial function. Hence, the broad neuroprotective properties of such therapies may stem from improved cellular metabolism. Data from clinical and preclinical studies indicate that these diets restrict glycolysis and increase fatty acid oxidation, resulting in ketosis, replenishment of the TCA cycle (i.e., anaplerosis), restoration of neurotransmitter and ion channel function, and enhanced mitochondrial respiration. Further, there is mounting evidence that the KD and its variants can impact key signaling pathways that evolved to sense the energetic state of the cell, and that help maintain cellular homeostasis. These pathways, which include peroxisome proliferator-activated receptors, AMP-activated kinase, mammalian target of rapamycin, and the sirtuins, have all been recently implicated in the neuroprotective effects of the KD. Further research in this area may lead to future therapeutic strategies aimed at mimicking the pleiotropic neuroprotective effects of the KD.
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Intermittent fasting (IF) is neuroprotective across a range of insults, but the question of whether extending the interval between meals alters neurogenesis after ischemia remains unexplored. We therefore measured cell proliferation, cell death, and neurogenesis after transient middle cerebral artery occlusion (MCAO) or sham surgery (SHAM) in mice fed ad libitum (AL) or maintained on IF for 3 months. IF was associated with twofold reductions in circulating levels of the adipocyte cytokine leptin in intact mice, but also prevented further reductions in leptin after MCAO. IF/MCAO mice also exhibit infarct volumes that were less than half those of AL/MCAO mice. We observed a 30% increase in basal cell proliferation in the hippocampus and subventricular zone (SVZ) in IF/SHAM, relative to AL/SHAM mice. However, cell proliferation after MCAO was limited in IF mice, which showed twofold increases in cell proliferation relative to IF/SHAM, whereas AL/MCAO mice exhibit fivefold increases relative to AL/SHAM. Attenuation of stroke-induced neurogenesis was correlated with reductions in cell death, with AL/MCAO mice exhibiting twice the number of dying cells relative to IF/MCAO mice. These observations indicate that IF protects against neurological damage in ischemic stroke, with circulating leptin as one possible mediator.Journal of Cerebral Blood Flow & Metabolism advance online publication, 19 February 2014; doi:10.1038/jcbfm.2014.36.
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Alternate day fasting (ADF; ad libitum "feed day", alternated with 25% energy intake "fast day"), is effective for weight loss and cardio-protection in obese individuals. Whether these effects occur in normal weight and overweight individuals remains unknown. This study examined the effect of ADF on body weight and coronary heart disease risk in non-obese subjects. Thirty-two subjects (BMI 20--29.9 kg/m2) were randomized to either an ADF group or a control group for 12 weeks. Body weight decreased (P < 0.001) by 5.2 +/- 0.9 kg (6.5 +/- 1.0%) in the ADF group, relative to the control group, by week 12. Fat mass was reduced (P < 0.001) by 3.6 +/- 0.7 kg, and fat free mass did not change, versus controls. Triacylglycerol concentrations decreased (20 +/- 8%, P < 0.05) and LDL particle size increased (4 +/- 1 A, P < 0.01) in the ADF group relative to controls. CRP decreased (13 +/- 17%, P < 0.05) in the ADF group relative to controls at week 12. Plasma adiponectin increased (6 +/- 10%, P < 0.01) while leptin decreased (40 +/- 7%, P < 0.05) in the ADF group versus controls by the end of the study. LDL cholesterol, HDL cholesterol, homocysteine and resistin concentrations remained unchanged after 12 weeks of treatment. These findings suggest that ADF is effective for weight loss and cardio-protection in normal weight and overweight adults, though further research implementing larger sample sizes is required before solid conclusion can be reached.
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The hepatocyte-derived hormone fibroblast growth factor 21 (FGF21) is a hormone-like regulator of metabolism. The NAD(+)-dependent deacetylase SIRT1 regulates fatty acid metabolism through multiple nutrient sensors. Hepatic overexpression of SIRT1 reduces steatosis and glucose intolerance in obese mice. We investigated mechanisms by which SIRT controls hepatic steatosis in mice. Mice with liver-specific disruption of Sirt1 (SIRT1 LKO mice) and their wild-type littermates (controls) were divided into groups that were placed on normal chow diets, fasted for 24 hrs, or fasted for 24 hrs and then fed for 6 hrs. Liver tissues were collected and analyzed by histologic, gene expression profile, and real-time PCR assays. Human HepG2 cells were incubated with pharmacologic activators of SIRT1 (resveratrol or SRT1720) and assessed by mitochondrial oxidation and immunoblot analyses. FGF21 was overexpressed in SIRT1 LKO mice using an adenoviral vector. Energy expenditure was assessed by indirect calorimetry. Fasting induced lipid deposition in livers of control mice, but severe hepatic steatosis in SIRT1 LKO mice. Gene expression analysis showed that fasting upregulated FGF21 in livers of control, but not SIRT1 LKO mice. Decreased hepatic and circulating levels of FGF21 in fasted SIRT1 LKO mice were associated with reduced hepatic expression of genes involved in fatty acid oxidation and ketogenesis, and increased expression of genes that control lipogenesis, compared with fasted control mice. Resveratrol or SRT1720 each increased transcriptional activity of the FGF21 promoter (-2070/+117) and levels of FGF21 mRNA and protein in HepG2 cells. Surprisingly, SIRT1 LKO mice developed late-onset obesity with impaired whole-body energy expenditure. Hepatic overexpression of FGF21 in SIRT1 LKO mice increased expression of genes that regulate fatty acid oxidation, decreased fasting-induced steatosis, reduced obesity, increased energy expenditure, and promoted browning of white adipose tissue. SIRT1-mediated activation of FGF21 prevents liver steatosis caused by fasting. This hepatocyte-derived endocrine signaling appears to regulate expression of genes that control a brown fat-like program in white adipose tissue, energy expenditure, and adiposity. Strategies to activate SIRT1 or FGF21 might be used to treat fatty liver disease and obesity.