The Effect of a Ketogenic Low-Carbohydrate,High-Fat Diet on Aerobic Capacity and Exercise Performance in Endurance Athletes: A Systematic Review and Meta-Analysis

A low-carbohydrate, high-fat (LCHF) diet has been proposed to enhance the fat utilization of muscle and the aerobic capacity of endurance athletes, thereby improving their exercise performance. However, it remains uncertain how the macronutrient intake shift from carbohydrate to fat affects endurance exercise training and performance. This study performed a systematic review and meta-analysis to explore the effects of a ketogenic low-carbohydrate, high-fat (K-LCHF) diet on aerobic capacity and exercise performance among endurance athletes. Searches were carried out in five electronic databases, and we followed the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. The search included studies using an LCHF diet as an intervention protocol and compared data on factors such as maximum oxygen uptake (VO₂max) and rating of perceived exertion (RPE) from the graded exercise test. In this case, 10 studies met the criteria and were included in the meta-analysis. We did not find a significant effect of K-LCHF diet interventions on VO₂max, time to exhaustion, HRmax or RPE. However, a significant overall effect in the substrate oxidation response to respiratory exchange rate was observed. The meta-analysis showed that K-LCHF diets did not affect aerobic capacity and exercise performance. Therefore, high-quality interventions of a K-LCHF diet are needed to illustrate its effect on various endurance training programs.     

Ketogenic Diet,Physical Activity,and Hypertension—A Narrative Review

Several studies link cardiovascular diseases (CVD) with unhealthy lifestyles (unhealthy dietary habits, alcohol consumption, smoking, and low levels of physical activity). Therefore, the strong need for CVD prevention may be pursued through an improved control of CVD risk factors (impaired lipid and glycemic profiles, high blood pressure, and obesity), which is achievable through an overall intervention aimed to favor a healthy lifestyle. Focusing on diet, different recommendations emphasize the need to increase or avoid consumption of entire classes of food, with only partly known and only partly foreseeable consequences on the overall level of health. In recent years, the ketogenic diet (KD) has been proposed to be an effective lifestyle intervention for metabolic syndrome, and although the beneficial effects on weight loss and glucose metabolism seems to be well established, the effects of a prolonged KD on the ability to perform different types of exercise and the influence of KD on blood pressure (BP) levels, both in normotensives and in hypertensives, are not so well understood. The objective of this review is to analyze, on the basis of current evidence, the relationship between KD, regular physical activity, and BP.     

A Low-Carbohydrate Ketogenic Diet and Treadmill Training Enhanced Fatty Acid Oxidation Capacity but Did Not Enhance Maximal Exercise Capacity in Mice

The low-carbohydrate ketogenic diet (LCKD) is a dietary approach characterized by the intake of high amounts of fat, a balanced amount of protein, and low carbohydrates, which is insufficient for metabolic demands. Previous studies have shown that an LCKD alone may contribute to fatty acid oxidation capacity, along with endurance. In the present study, we combined a 10-week LCKD with an 8-week forced treadmill running program to determine whether training in conjunction with LCKD enhanced fatty acid oxidation capacity, as well as whether the maximal exercise capacity would be affected by an LCKD or training in a mice model. We found that the lipid pool and fatty acid oxidation capacity were both enhanced following the 10-week LCKD. Further, key fatty acid oxidation related genes were upregulated. In contrast, the 8-week training regimen had no effect on fatty acid and ketone body oxidation. Key genes involved in carbohydrate utilization were downregulated in the LCKD groups. However, the improved fatty acid oxidation capacity did not translate into an enhanced maximal exercise capacity. In summary, while favoring the fatty acid oxidation system, an LCKD, alone or combined with training, had no beneficial effects in our intensive exercise-evaluation model. Therefore, an LCKD may be promising to improve endurance in low- to moderate-intensity exercise, and may not be an optimal choice for those partaking in high-intensity exercise.     

Effects of Ketogenic Diet on Muscle Metabolism in Health and Disease

Dietary intervention is widely used as a therapeutic approach ranging from the treatment of neurological disorders to attempts to extend lifespan. The most important effect of various diets is a change in energy metabolism. Since muscles constitute 40% of total body mass and are one of the major sites of glucose and energy uptake, various diets primarily affect their metabolism, causing both positive and negative changes in physiology and signaling pathways. In this review, we discuss changes in the energy metabolism of muscles under conditions of the low-carbohydrate, high-fat diet/ketogenic diet (KD), fasting, or administration of exogenous ketone bodies, which are all promising approaches to the treatment of various diseases. KD’s main influence on the muscle is expressed through energy metabolism changes, particularly decreased carbohydrate and increased fat oxidation. This affects mitochondrial quantity, oxidative metabolism, antioxidant capacity, and activity of enzymes. The benefits of KD for muscles stay controversial, which could be explained by its different effects on various fiber types, including on muscle fiber-type ratio. The impacts of KD or of its mimetics are largely beneficial but could sometimes induce adverse effects such as cardiac fibrosis.     

An Examination of Serum Acylcarnitine and Amino Acid Profiles at Different Time Point of Ketogenic Diet Therapy and Their Association of Ketogenic Diet Effectiveness

Background: This study aimed to identify metabolic parameters at different time points of ketogenic diet therapy (KDT) and investigate their association with response to KDT in pediatric drug-resistant epilepsy (DRE). Methods: Prospectively, twenty-nine patients (0.67~20 years old) with DRE received classic ketogenic diet with non-fasting, gradual KD initiation protocol (GRAD-KD) for 1 year were enrolled. A total of 22 patients remaining in study received blood examinations at baseline, 3rd, 6th, 9th, and 12th months of KDT. β-hydroxybutyrate, free carnitine, acylcarnitines, and amino acids were compared between responders (seizure reduction rate ≥ 50%) and non-responders (seizure reduction rate < 50%) to identify the effectiveness of KDT. Results: The 12-month retention rate was 76%. The responders after 12 months of KDT were 59% (13/22). The free carnitine level decreased significantly at 9th months (p < 0.001) but increased toward baseline without symptoms. Propionyl carnitine (C3), Isovaleryl carnitine (C5), 3-Hydroxyisovalerylcarnitine (C5:OH) and methylmalonyl carnitine (C4-DC) decreased but 3-hydroxybutyrylcarnitine (C4:OH) increased significantly at 12th months of KDT. The glycine level was persistently higher than baseline after KDT. KDT responders had lower baseline C3 and long-chain acylcarnitines, C14 and C18, as well as lower C5, C18, and leucine/isoleucine. Conclusions: KDT should be avoided in patients with non-ketotic hyperglycemia. Routine carnitine supplementation is not recommended because hypocarnitinemia was transient and asymptomatic during KDT. Better mitochondrial βoxidation function associates with greater KDT response.     

The Effects of a Ketogenic Diet on Patients with Dihydrolipoamide Dehydrogenase Deficiency

Background: Dihydrolipoamide dehydrogenase (DLD lipoamide dehydrogenase, the E3 subunit of the pyruvate dehydrogenase complex (PDHC)) is the third catalytic enzyme of the PDHC, which converts pyruvate to acetyl-CoA catalyzed with the introduction of acetyl-CoA to the tricyclic acid (TCA) cycle. In humans, PDHC plays an important role in maintaining glycose homeostasis in an aerobic, energy-generating process. Inherited DLD-E3 deficiency, caused by the pathogenic variants in DLD, leads to variable presentations and courses of illness, ranging from myopathy, recurrent episodes of liver disease and vomiting, to Leigh disease and early death. Currently, there is no consensus on treatment guidelines, although one suggested solution is a ketogenic diet (KD). Objective: To describe the use and effects of KD in patients with DLD-E3 deficiency, compared to the standard treatment. Results: Sixteen patients were included. Of these, eight were from a historical cohort, and of the other eight, four were on a partial KD. All patients were homozygous for the D479V (or D444V, which corresponds to the mutated mature protein without the mitochondrial targeting sequence) pathogenic variant in DLD. The treatment with partial KD was found to improve patient survival. However, compared to a historical cohort, the patients’ quality of life (QOL) was not significantly improved. Conclusions: The use of KD offers an advantage regarding survival; however, there is no significant improvement in QOL.     

Effects of a Mediterranean Diet,Dairy, and Meat Products on Different Phenotypes of Dyslipidemia: A Preliminary Retrospective Analysis

Background: Dyslipidemia is one of the major causes of atherosclerotic cardiovascular disease (ASCVD) and a Mediterranean Diet (MD) is recommended for its prevention. The objectives of this study were to evaluate adherence to an MD at baseline and follow-up, in a cohort of dyslipidemic patients, and to evaluate how different food intakes can influence lipid profile, especially how different sources of saturated fatty acids impact lipid phenotype. Methods: A retrospective analysis was conducted on 106 dyslipidemic patients. Clinical characteristics, lipid profile, and food habits data were collected at baseline and after three months of follow-up with counseling. Adherence to an MD was evaluated with a validated food-frequency questionnaire (MEDI-LITE score). Results: The cross-sectional analysis showed that higher consumption of dairy products correlated independently with higher levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) and with lower triglycerides (TG) levels. Instead, lower HDL-C and TG levels and higher TC levels were independently associated with higher consumption of meat products. Adherence to an MD significantly improved after the follow-up period, from a mean value of 10 ± 3 (median 10, IQR 8–12) to 13 ± 2 (median 14, IQR 12–15), p < 0.0001. Conclusions: Dyslipidemic patients benefit from counseling for improving their adherence to an MD. The high intake of dairy products was associated with less atherogenic hyperlipidemia, which was characterized by higher levels of TC and HDL-C as compared withs the intake of an excessive amount of meat products, which was associated with higher levels of TC and TG and lower levels of HDL-C.     

Distinct Effects of High-Fat and High-Phosphate Diet on Glucose Metabolism and the Response to Voluntary Exercise in Male Mice

The prevalence of metabolic diseases is rapidly increasing and a principal contributor to this is diet, including increased consumption of energy-rich foods and foods with added phosphates. Exercise is an effective therapeutic approach to combat metabolic disease. While exercise is effective to combat the detrimental effects of a high-fat diet on metabolic health, the effects of exercise on a high-phosphate diet have not been thoroughly investigated. Here, we investigated the effects of a high-fat or high-phosphate diet in the presence or absence of voluntary exercise on metabolic function in male mice. To do this, mice were fed a low-fat, normal-phosphate diet (LFPD), a high-phosphate diet (HPD) or a high-fat diet (HFD) for 6 weeks and then subdivided into either sedentary or exercised (housed with running wheels) for an additional 8 weeks. An HFD severely impaired metabolic function in mice, increasing total fat mass and worsening whole-body glucose tolerance, while HPD did not induce any notable effects on glucose metabolism. Exercise reverted most of the detrimental metabolic adaptations induced by HFD, decreasing total fat mass and restoring whole-body glucose tolerance and insulin sensitivity. Interestingly, voluntary exercise had a similar effect on LFPD and HPD mice. These data suggest that a high-phosphate diet does not significantly impair glucose metabolism in sedentary or voluntary exercised conditions.     

Effects of Mediterranean Diet or Low-Fat Diet on Blood Fatty Acids in Patients with Coronary Heart Disease. A Randomized Intervention Study

The Mediterranean diet (MD) prevents cardiovascular disease by different putative mechanisms, including modifications in the blood fatty acid (FA) profile. Polytherapy for secondary cardiovascular prevention might mask the effect of MD on the FA profile. This study was aimed to assess whether MD, in comparison with a low-fat diet (LFD), favorably modifies the blood FA profile in patients with coronary heart disease (CHD) on polytherapy. One hundred and twenty patients with a recent history of coronary stenting, randomized to MD or to LFD, completed 3 months of this open-label dietary intervention study. Diet Mediterranean-ness was evaluated using the Mediterranean Diet Adherence Screener (MeDAS) score. Both diets significantly reduced saturated FA (p < 0.01). Putative favorable changes in total n-3 FA (p = 0.03) and eicosapentaenoic acid plus docosahexaenoic acid (EPA + DHA; p = 0.04) were significantly larger with MD than with LFD. At 3 months, in the whole cohort, the MeDAS score correlated inversely with palmitic acid (R = −0.21, p = 0.02), and with palmitoleic acid (R = −0.32, p = 0.007), and positively with total n-3 FA (R = 0.19, p = 0.03), EPA (R = 0.28, p = 0.002), and EPA + DHA (R = 0.21, p = 0.02). In CHD patients on polytherapy, both MD and LFD shift FA blood composition towards a healthier profile, with a more favorable effect of MD on omega−3 levels.     

Physical Activity and Low Glycemic Index Mediterranean Diet: Main and Modification Effects on NAFLD Score. Results from a Randomized Clinical Trial

Background: Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common chronic liver disease worldwide, and lifestyle modification is the current standard treatment. The aim of the study was to estimate the effect of two different physical activity (PA) programs, a Low Glycemic Index Mediterranean Diet (LGIMD), and their combined effect on the NAFLD score as measured by FibroScan^®. Methods: Moderate or severe NAFLD subjects (n = 144) were randomly assigned to six intervention arms during three months. Interventions arms were a control diet, LGIMD, aerobic activity program (PA1), combined activity program (PA2), and LGIMD plus PA1 or LGIMD plus PA2. The data were compared at baseline, at 45 days, and at 90 days. Analysis of variance was performed under the intention-to-treat principle. Results: There was a statistically significant reduction in the NAFLD score after 45 days of treatment in every working arm except for Arm 1 (control diet). After 90 days, the best results were shown by the intervention arms in which LGIMD was associated with PA: LGIMD plus PA1 (−61.56 95% CI −89.61, −33.50) and LGIMD plus PA2 (−38.15 95% CI −64.53, −11.77). Conclusion: All treatments were effective to reduce NAFLD scores, but LGIMD plus PA1 was the most efficient.     

Development of insulin resistance and its relation to diet in the obese child

The incidence rate of obesity in youth has continued to increase worldwide and about 30% of obese children display insulin resistance (IR) and other metabolic abnormalities. The present study reviews the mechanisms for development of IR in the obese child and possible links between IR and dietary factors in childhood and adolescence. Although increased concentrations of plasma free fatty acids (FFA) and their counter part at intracellular level, long-chain acyl-coenzyme A (LC acyl-CoA), have been related to the early onset of IR in childhood obesity, a new endocrine paradigm states that adipose tissue secretes a wide variety of hormones and cytokines that regulate lipid energy metabolism. These hormonal changes precede any changes in metabolites such as FFA and glucose and appear to be associated with early IR in childhood. Excessive caloric intake increases IR in children; opposite, substantial reduction of overweight achieved by a hypocaloric diet decreases it. Elevated consumption of animal protein, particularly in early life, as well as diets rich in saturated, trans, and n-6 polyunsaturated fatty acids, and diets with a high carbohydrate to fat ratio, besides a high glycaemic and low-fiber diet also appear to exacerbate adiposity and IR.     

Effects of a Diet Rich in N-3 Polyunsaturated Fatty Acids on Systemic Inflammation in Renal Transplant Recipients

Objective: n-3 Polyunsaturated fatty acids (PUFAs) supplementation reduces systemic inflammation and improves renal and cardiovascular prognosis in kidney transplant recipients. However, patient compliance is poor because bad-tasting fish oils are used as an n-3 PUFA source. Therefore, we explored whether the beneficial effects of n-3 can be obtained by administering a diet based on n-3-rich foods.

Methods: Sixty kidney transplant recipients were assigned to 2 different groups: the CON group (n = 28), which continued with their usual diet, and the DIET group (n = 32), which followed an n-3-rich diet for 6 months. Twenty-six patients in the DIET group and 24 in the CON group completed the study. End points of the study were changes in n-3 PUFAs intake, n-6:n-3 PUFAs ratio, systemic inflammation markers, and renal function during the 6 months of the dietary treatment.

Results: Three and 6 months after the beginning of the study, n-3 PUFA intake was significantly higher and the n-6:n-3 PUFA ratio was markedly lower than baseline in the DIET group. Plasma total cholesterol, triglycerides, C-reactive protein, and interleukin (IL)-6 decreased as well. IL-6 mRNA levels in peripheral blood mononuclear cells were also lower than at the beginning of the study. Proteinuria and microalbuminuria were reduced by 50% with respect to the baseline, whereas glomerular filtration rate (GFR) was unchanged. No change in the aforementioned parameters was observed in the CON group throughout the study.

Conclusion: In long-term kidney transplant recipients a naturally n-3 PUFA-rich dietary plan causes an increase in n-3 PUFA intake, decreases systemic inflammation and proteinuria, and improves plasma lipid pattern.     

A Ketogenic Low-Carbohydrate High-Fat Diet Increases LDL Cholesterol in Healthy,Young, Normal-Weight Women: A Randomized Controlled Feeding Trial

Ketogenic low-carbohydrate high-fat (LCHF) diets are popular among young, healthy, normal-weight individuals for various reasons. We aimed to investigate the effect of a ketogenic LCHF diet on low-density lipoprotein (LDL) cholesterol (primary outcome), LDL cholesterol subfractions and conventional cardiovascular risk factors in the blood of healthy, young, and normal-weight women. The study was a randomized, controlled, feeding trial with crossover design. Twenty-four women were assigned to a 4 week ketogenic LCHF diet (4% carbohydrates; 77% fat; 19% protein) followed by a 4 week National Food Agency recommended control diet (44% carbohydrates; 33% fat; 19% protein), or the reverse sequence due to the crossover design. Treatment periods were separated by a 15 week washout period. Seventeen women completed the study and treatment effects were evaluated using mixed models. The LCHF diet increased LDL cholesterol in every woman with a treatment effect of 1.82 mM (p < 0.001). In addition, Apolipoprotein B-100 (ApoB), small, dense LDL cholesterol as well as large, buoyant LDL cholesterol increased (p < 0.001, p < 0.01, and p < 0.001, respectively). The data suggest that feeding healthy, young, normal-weight women a ketogenic LCHF diet induces a deleterious blood lipid profile. The elevated LDL cholesterol should be a cause for concern in young, healthy, normal-weight women following this kind of LCHF diet.     

Effects of a Non-Energy-Restricted Ketogenic Diet on Clinical Oral Parameters. An Exploratory Pilot Trial

Ketogenic diets (KDs) may be a helpful complement in the prevention of and therapy for several diseases. Apart from their non-cariogenic properties, it is still unclear how KDs affect oral parameters. The aim of this study was to investigate the influence of a KD on clinical periodontal parameters. Twenty generally healthy volunteers with an average age of 36.6 years underwent a KD for 6 weeks. Their compliance was monitored by measuring their urinary ketones daily and by keeping 7-day food records. Clinical oral parameters included plaque (PI), gingival inflammation (GI), a complete periodontal status (probing depths, bleeding on probing), and general physical and serologic parameters at baseline and after 6 weeks. The results showed a trend towards lower plaque values, but with no significant changes from baseline to the end of the study with regard to the clinical periodontal parameters. However, their body weight and BMI measurements showed a significant decrease. The regression analyses showed that the fat mass and the BMI were significantly positively correlated to periodontal inflammation, while HDL, fiber, and protein intake were negatively correlated to periodontal inflammation. The KD change did not lead to clinical changes in periodontal parameters in healthy participants under continued oral hygiene, but it did lead to a significant weight loss.     

Effect of Ethyl Pyruvate on Skeletal Muscle Metabolism in Rats Fed on a High Fat Diet

Impaired mitochondrial capacity may be implicated in the pathology of chronic metabolic diseases. To elucidate the effect of ethyl pyruvate supplementation on skeletal muscles metabolism we examined changes in activities of mitochondrial and antioxidant enzymes, as well as sulfhydryl groups oxidation (an indirect marker of oxidative stress) during the development of obesity. After 6 weeks feeding of control or high fat diet, Wistar rats were divided into four groups: control diet, control diet and ethyl pyruvate, high fat diet, and high fat diet and ethyl pyruvate. Ethyl pyruvate was administered as 0.3% solution in drinking water, for the following 6 weeks. High fat diet feeding induced the increase of activities 3-hydroxyacylCoA dehydrogenase, citrate synthase, and fumarase. Moreover, higher catalase and superoxide dismutase activities, as well as sulfhydryl groups oxidation, were noted. Ethyl pyruvate supplementation did not affect the mitochondrial enzymes’ activities, but induced superoxide dismutase activity and sulfhydryl groups oxidation. All of the changes were observed in soleus muscle, but not in extensor digitorum longus muscle. Additionally, positive correlations between fasting blood insulin concentration and activities of catalase (p = 0.04), and superoxide dismutase (p = 0.01) in soleus muscle were noticed. Prolonged ethyl pyruvate consumption elevated insulin concentration, which may cause modifications in oxidative type skeletal muscles.     

Effects of the Ketogenic Diet in the Treatment of Gliomas: A Systematic Review

The ketogenic diet (KD) is a restrictive therapeutic diet, distinguished by being hyperlipidic, normoproteic, and hypoglucidic. This diet simulates biochemical changes related to fasting periods to achieve systemic ketosis. The metabolic particularities of glioma tumors motivated the rise in investigations and nutritional strategies, such as KD, to modulate the glycemic response as a treatment. This systematic review followed the PRISMA recommendations and was published in PROSPERO, with the identification CRD42021264173. The databases used were EMBASE, PubMed/Medline, Scopus, and Web of Science, and the studies were analyzed using the web-based application Rayyan. To analyze the risk of bias, Cochrane RevMan 5 software was used. For the analysis and treatment of statistical data, Microsoft® Excel® was used. A total of nine original articles were included. Data on survival, symptomology, and quality of life were collected. Mean overall survival was 15.9 months. Constipation and fatigue were the most reported symptoms. In 44.4% of the studies, an improvement in the quality of life was found. The KD is supported by most published studies as an effective therapy in the treatment of malignant gliomas due to its positive effects on patient survival. It was not possible to conclude the effectiveness of KD on quality of life.     

Aerobic Exercise Training Prevents Insulin Resistance and Hepatic Lipid Accumulation in LDL Receptor Knockout Mice Chronically Fed a Low-Sodium Diet

Background: A low-sodium (LS) diet reduces blood pressure, contributing to the prevention of cardiovascular diseases. However, intense dietary sodium restriction impairs insulin sensitivity and worsens lipid profile. Considering the benefits of aerobic exercise training (AET), the effect of LS diet and AET in hepatic lipid content and gene expression was investigated in LDL receptor knockout (LDLr-KO) mice. Methods: Twelve-week-old male LDLr-KO mice fed a normal sodium (NS) or LS diet were kept sedentary (S) or trained (T) for 90 days. Body mass, plasma lipids, insulin tolerance testing, hepatic triglyceride (TG) content, gene expression, and citrate synthase (CS) activity were determined. Results were compared by 2-way ANOVA and Tukey’s post-test. Results: Compared to NS, LS increased body mass and plasma TG, and impaired insulin sensitivity, which was prevented by AET. The LS-S group, but not the LS-T group, presented greater hepatic TG than the NS-S group. The LS diet increased the expression of genes related to insulin resistance (ApocIII, G6pc, Pck1) and reduced those involved in oxidative capacity (Prkaa1, Prkaa2, Ppara, Lipe) and lipoprotein assembly (Mttp). Conclusion: AET prevented the LS-diet-induced TG accumulation in the liver by improving insulin sensitivity and the expression of insulin-regulated genes and oxidative capacity.