ArticleLiterature Review

Impact of ketosis on appetite regulation – A review

February 2020
Nutrition Research 77

DOI:10.1016/j.nutres.2020.02.010

Authors:

Sarah E. Deemer

University of Alabama at Birmingham

Catia Martins

Norwegian University of Science and Technology

To reduce the health burden of obesity, it is important to identify safe and practical treatments that are effective for weight loss while concurrently preventing weight regain. Diet-induced weight loss is usually followed by a concomitant increase in ghrelin secretion and feelings of hunger, which may compromise weight loss goals and increase the risk of weight regain. The aim of this review is to describe the status of knowledge regarding the impact of ketosis, induced by diet or exogenous ketones (ketone esters), on appetite and the potential mechanisms involved. Ketogenic diets (KDs) have been shown to prevent an increase in ghrelin secretion, otherwise seen with weight loss, as well as to reduce hunger and/or prevent hunger. However, the exact threshold of ketosis needed to induce appetite suppression, as well as the exact mechanisms that mediate such an effect, has yet to be elucidated. Use of exogenous ketones may provide an alternative to KDs, which have poor long-term adherence due to their restrictive nature. Ketone esters have been shown to have concentration-dependent effects on food intake and body weight in rodent models, with effects becoming apparent when 30% of total dietary energy comes from ketone esters (threshold effect). In humans, acute consumption of a ketone ester drink reduced feelings of hunger and increased satiety compared to a dextrose drink. With the emerging widespread acceptance of KDs and exogenous ketones in mainstream media and the diet culture, it is important to fully understand their role on appetite control and weight management and the potential mechanisms mediating this role.

Artículo de Revisión DIETA CETOGÉNICA COMO ALTERNATIVA EN EL TRATAMIENTO DE LA OBESIDAD: UN ESTUDIO DE REVISIÓN BIBLIOGRÁFICA. KETOGENIC DIET AS AN ALTERNATIVE IN THE TREATMENT OF OBESITY: A BIBLIOGRAPHIC REVIEW STUDY

Article

Full-text available

May 2022

RESUMEN Introducción. El reciente interés del uso de la dieta cetogénica como alternativa al tratamiento de obesidad, ha despertado la necesidad en los profesionales de la salud de volver a examinar los posibles beneficios de este estilo de alimentación. Objetivo: Resumir los antecedentes y sintetizar las diferentes aplicaciones de dietas cetogénicas en el tratamiento de la obesidad a través de las publicaciones científicas. Material y Método: Se usaron tres bases de datos (PubMed, Google Scholar y Clinical Trials). Los términos usados en la búsqueda fueron dieta cetogénica, obesidad, cuerpos cetónicos, entre otros. Se combinaron con operadores lógicos como cetólisis, oxidación de ácidos grasos, regulación hormonal, saciedad, ejercicio, entre otros. Resultados: Se consideraron para la revisión un total de 23 artículos de reciente publicación con ensayos clínicos y aplicados en modelos animales. Los artículos excluidos no cumplieron con criterios de los niveles de evidencia y de la guía PRISMA. Conclusión: Aunque se han demostrado los numerosos beneficios de las dietas cetogénicas, la utilización debe ir acompañada de un asesoramiento dietético y no abusar de su uso. El modelo de evolución de la nutrición es integrar e individualizar los diversos factores dietéticos que puedan contribuir a mejorar el estilo de vida a largo plazo. ABSTRACT Introduction: There is great interest in the use of the ketogenic diet as an alternative to the treatment of obesity, which has raised the need for health professionals to reexamine the possible benefits of this eating style. Objective: To evaluate the information of the different applications of ketogenic diets in the treatment of obesity through scientific publications. Material and method: Three databases were used (PubMed, Google Scholar, and Clinical Trials). They were combined with logical operators and terms such as ketogenic diet, obesity, ketone bodies, among others. They were combined with logical operators such as ketolysis, fatty acid oxidation, hormonal regulation, satiety and exercise. Results: Twenty-three articles containing randomized clinical trials and animal experiments were considered for the review. The excluded articles did not meet the criteria for levels of evidence and the PRISMA guideline. Conclusions: Although the many benefits of ketogenic diets have been demonstrated, the use should be accompanied by dietary advice and not overuse. The evolutionary model of nutrition is to integrate and individualize the various dietary factors that can contribute to improving the long-term lifestyle.

Metabolic Derangement in Pediatric Patient with Obesity: The Role of Ketogenic Diet as Therapeutic Tool

Article

Full-text available

Aug 2021

Obesity is defined as a condition characterized by an excessive fat accumulation that has negative health consequences. Pediatric obesity is associated with an increased risk for many diseases, including impaired glycemic and lipidic control that may lead to the development of chronic, and potentially disabling, pathologies, such as type 2 diabetes mellitus (T2DM) and cardiovascular events, in adult life. The therapeutic strategy initially starts with interventions that are aimed at changing lifestyle and eating behavior, to prevent, manage, and potentially reverse metabolic disorders. Recently, the ketogenic diet (KD) has been proposed as a promising dietary intervention for the treatment of metabolic and cardiovascular risk factors related to obesity in adults, and a possible beneficial role has also been proposed in children. KD is very low in carbohydrate, high in fat, and moderate to high in protein that may have the potential to promote weight loss and improve lipidic derangement, glycemic control, and insulin sensitivity. In this review, we present metabolic disorders on glycemic and lipidic control in children and adolescents with obesity and indication of KD in pediatrics, discussing the role of KD as a therapeutic tool for metabolic derangement. The results of this review may suggest the validity of KD and the need to further research its potential to address metabolic risk factors in pediatric obesity.

Dieta cetogénica como alternativa en el tratamiento de la obesidad

Article

Full-text available

Jul 2021

Introducción. El reciente interés del uso de la dieta cetógenica como alternativa al tratamiento de obesidad, ha despertado la necesidad en los profesionales de la salud de volver a examinar los posibles beneficios de este estilo de alimentación. Objetivo. Resumir los antecedentes y sintetizar las diferentes aplicaciones de dietas cetogénicas en el tratamiento de la obesidad. Métodos. Se usaron tres bases de datos (PubMed, Google Scholar y Clinical Trials). Los términos usados en la búsqueda fueron dieta cetogénica, obesidad, cuerpos cetónicos, entre otros. Se combinaron con operadores lógicos como cetólisis, oxidación de ácidos grasos, regulación hormonal, saciedad, ejercicio, entre otros. Resultados. Se consideraron para la revisión un total de 23 artículos de reciente publicación con ensayos clínicos y aplicados en modelos animales. Los artículos excluidos no cumplieron con criterios de los niveles de evidencia y de la guía PRISMA. Conclusiones. Aunque se han demostrado los numerosos beneficios de las dietas cetogénicas, la utilización debe ir acompañada de un asesoramiento dietético y no abusar de su uso. El modelo de evolución de la nutrición es integrar e individualizar los diversos factores dietéticos que puedan contribuir a mejorar el estilo de vida a largo plazo.

Supplementation with medium-chain fatty acids increases body weight loss during very low-calorie ketogenic diet: a retrospective analysis in a real-life setting

Article

Full-text available

Jan 2023
J TRANSL MED

Background Very low-calorie ketogenic diet (VLCKD) has shown to significantly reduce body weight and fat mass, as well as inflammation. These effects are supported by nutritional ketosis, which triggers the utilization of the ketone body as an energy source. Medium-chain fatty acids (MCTs) might serve as potential enhancers of ketone bodies production with a greater effect on weight loss. Nevertheless, no clinical studies have evaluated the effect of MCTs supplementation in addition to VLCKD. Therefore, the present study aimed to evaluate whether the supplementation with MCTs can induce a greater weight reduction during the ketogenic phase of VLCKD. Methods In this retrospective study, 263 women with overweight/obesity (body mass index, BMI: 35.7 ± 5.3 kg/m ² ) aged 37.5 ± 14.2 years followed one of these dietary protocols for 45 days: (a) Control group, 83 participants (31.6%) (VLCKD without MCTs), (b) VLCKD + MCTs group, 86 participants (32.7%) (MCTs supplementation − 20 g/day- during VLCKD starting from the first day of the active phase), (c) VLCKD + earlyMCTs, 94 participants (35.7%) (MCTs supplementation − 20 g/day-starting from 5 days before the beginning of the VLCKD active phase. Anthropometric measures, body composition, and c-reactive protein (CRP) concentrations were collected at the beginning and at the end (45 days) of the VLCKD intervention. Results MCTs supplementation significantly decreased body weight, BMI, and waist circumference as compared to the control group, with a greater effect in the VLCKD + earlyMCTs group. A two-fold decrease in fat mass and an increase in muscle mass were observed in the VLCKD + earlyMCTs group as compared to the control group. As for inflammation, hs-CRP concentrations (assessed as absolute percent change) were significantly lower in the VLCKD + MCTs group ( p = 0.009) and the VLCKD + earlyMCTs group ( p = 0.011) than in the control group. A logistic regression model showed that VLCKD + earlyMCTs increase the likelihood of improvement of BMI classes (OR: 1.85, 95% CI 1.02–3.36) also after adjusting for the potential confounding factors. Conclusion MCTs supplementation (20 g/day) may be a useful tool to enhance the beneficial effect of VLCKD on the reduction of body weight and fat mass. In particular, MCTs supplementation before the beginning of the VLCKD active phase might facilitate ketosis thus contributing to the effectiveness of the nutritional intervention.

Gastrointestinal hormones and appetite ratings after weight loss induced by diet or bariatric surgery

Article

Full-text available

Dec 2022
OBESITY

Objective The aim of this study was to compare changes in gastrointestinal hormones and appetite ratings after a similar weight loss induced by a very low-energy diet alone or in combination with sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB). Methods Patients with severe obesity scheduled for SG (n = 15) and RYGB (n = 14) and 15 controls (very low-energy diet alone) were recruited. Body weight/composition, plasma concentrations of ß-hydroxybutyric acid, acylated ghrelin, total glucagon-like peptide-1, total peptide YY, cholecystokinin, and ratings of hunger, fullness, desire to eat, and prospective food consumption were measured pre- and postprandially, before and after 10 weeks of intervention. Results Changes in body weight/composition and level of ketosis were similar across groups. In SG and RYGB, basal and postprandial acylated ghrelin declined, and postprandial glucagon-like peptide-1 increased, both significantly more compared with controls. Postprandial peptide YY increased in all groups. Overall, postprandial hunger decreased, and postprandial fullness increased. But ratings of desire to eat and prospective food consumption were more favorable after both surgeries compared with controls. Conclusions Weight loss with SG and RYGB leads to more favorable changes in gastrointestinal hormones compared with diet alone, although ratings of appetite were reduced across all groups.

Activation of G protein-coupled receptors by ketone bodies: Clinical implication of the ketogenic diet in metabolic disorders

Article

Full-text available

Oct 2022

Ketogenesis takes place in hepatocyte mitochondria where acetyl-CoA derived from fatty acid catabolism is converted to ketone bodies (KB), namely β-hydroxybutyrate (β-OHB), acetoacetate and acetone. KB represent important alternative energy sources under metabolic stress conditions. Ketogenic diets (KDs) are low-carbohydrate, fat-rich eating strategies which have been widely proposed as valid nutritional interventions in several metabolic disorders due to its substantial efficacy in weight loss achievement. Carbohydrate restriction during KD forces the use of FFA, which are subsequently transformed into KB in hepatocytes to provide energy, leading to a significant increase in ketone levels known as “nutritional ketosis”. The recent discovery of KB as ligands of G protein-coupled receptors (GPCR) - cellular transducers implicated in a wide range of body functions - has aroused a great interest in understanding whether some of the clinical effects associated to KD consumption might be mediated by the ketone/GPCR axis. Specifically, anti-inflammatory effects associated to KD regimen are presumably due to GPR109A-mediated inhibition of NLRP3 inflammasome by β-OHB, whilst lipid profile amelioration by KDs could be ascribed to the actions of acetoacetate via GPR43 and of β-OHB via GPR109A on lipolysis. Thus, this review will focus on the effects of KD-induced nutritional ketosis potentially mediated by specific GPCRs in metabolic and endocrinological disorders. To discriminate the effects of ketone bodies per se , independently of weight loss, only studies comparing ketogenic vs isocaloric non-ketogenic diets will be considered as well as short-term tolerability and safety of KDs.

Régimes cétogènes : potentiels effets thérapeutiques

Article

Sep 2022

Résumé Depuis les années 1920, les diètes cétogènes ont été utilisées avec succès pour traiter des épilepsies résistantes au traitement pharmacologique. Des études complémentaires ont proposé que les corps cétoniques puissent avoir également des effets bénéfiques sur la santé et sur d’autres pathologies que les épilepsies. Nous proposons ici de résumer les effets bénéfiques démontrés des corps cétoniques sur la masse musculaire et la sarcopénie, sur l’insuffisance cardiaque, sur la fonction rénale, sur les troubles neuropsychiques, et sur le poids corporel. D’autre part, les variations des concentrations de corps cétoniques dans le sang circulant pourraient expliquer une partie des effets bénéfiques des gliflozines sur la dysfonction myocardique et l’insuffisance rénale. L’ensemble de ces données ouvre une nouvelle stratégie thérapeutique basée sur l’amélioration de l’énergétique métabolique et de la génération de l’ATP dans les organes pathologiques.

A Review of the Uses of the Ketogenic Diet

Article

Full-text available

Jun 2022

The use of the ketogenic diet is a safe and effective process to reduce the health complications of obesity, thus losing weight while preventing weight regain at the same time. Humans have metabolic flexibility and the potential to utilize ketones as an energy source by reducing carbohydrate intake in the diet, this reduces insulin levels, and ketogenesis occurs. These conditions promote the release of excess stored fat, avoid muscle weakness, and improve insulin sensitivity. Losing weight by diet causes appetite feeling and a rise in ghrelin release, that raises the likelihood of regaining weight and is thus counterproductive to goals for weight reduction. The study's aim is to review evidence on a ketogenic diet for weight loss and metabolic illnesses like insulin resistance, lipid disorders, cardiovascular disease, fatty liver disease development, and Polycystic Ovarian Syndrome and exercise and delay aging, in addition to addressing the side effects of the ketogenic diet, and thus we provide basic information about nutritional ketones and the mechanism of their generation.

Benefits of Low Carbohydrate Diets: a Settled Question or Still Controversial?

Article

Full-text available

Sep 2021

Purpose of Review The purpose of this review was to provide an update on the available data on the benefits of low-carbohydrate (low-carb) diets for weight management and type 2 diabetes (T2DM) and determine if low-carb diets were a settled question or still controversial. Recent Findings Most of the recent published literature in this area consists of reviews of past trials, with a relatively smaller number of recent trials. Low-carb is most commonly compared to low-fat, with problematically inconsistent definitions of both. There are numerous challenges in trying to draw clear conclusions about efficacy and effectiveness. Short-term vs. long-term effects can differ, which is likely impacted by adherence. Adherence is very different between metabolic chamber or feeding studies vs. free-living. Body weight alone is a crude measure that fails to capture potentially important differences in lean-mass, fat-mass, and body water. Benefits for glycemic control need to be balanced with impacts on non-glycemic outcomes such as LDL-cholesterol, the microbiome, and inflammation. It is important to differentiate between low-carb and very-low carbohydrate diets (VLCD). To date no large-scale long-term clinical trials have been conducted testing whether low-carb diets can prevent T2DM. Summary Many issues regarding benefits and risks of low-carb diets remain controversial or unresolved, particularly for VLCD. Some of the recent, better studies highlighted in this review suggest strategies for resolving these controversies.

Obesity-associated deterioration of the hippocampus is partially restored after weight loss

Article

Full-text available

Jun 2021
BRAIN BEHAV IMMUN

Objective Obesity is a multidimensional condition that is treatable by the restoration of a lean phenotype; however, some obesity-related outcomes may persist after weight normalization. Among the organs of the human body, the brain possesses a relatively low regenerative capacity and could retain perturbations established as a result of developmental obesity. Calorie restriction (CR) or a restricted ketogenic diet (KD) are successfully used as weight loss approaches, but their impact on obesity-related effects in the brain have not been previously evaluated. Methods We performed a series of experiments in a rat model of developmental obesity induced by a 12-week cafeteria diet, followed by CR to implement weight loss. First, we assessed the impact of obesity on neurogenesis (BrdU incorporation into the hippocampus), cognitive function (water maze), and concomitant changes in hippocampal protein expression (GC/MS-MS, western blot). Next, we repeated these experiments in a rat model of weight loss induced by CR. We also measured mitochondrial enzyme activity in rats after weight loss during the fed or fasting state. This study was extended by additional experiments with restricted KD used as a weight loss approach in order to compare the efficacy of two different nutritional interventions used in the treatment of obesity on hippocampal functions. By using a modified version of the water maze we evaluated cognitive abilities in rats subjected to weight loss by CR or a restricted KD. Results In this study, obesity affected metabolic processes, upregulated hippocampal NF-κB, and induced proteomic differences which were associated with impaired cognition and neurogenesis. Weight loss improved neurogenesis and enhanced cognition. While the expression pattern of some proteins persisted after weight loss, most of the changes appeared de novo revealing metabolic adjustment by overactivation of citrate synthase and downregulation of ATP synthase. As a consequence of fasting, the activity of these enzymes indicated hippocampal adaptation to negative energy balance during the weight loss phase of CR. Moreover, the effects on cognitive abilities measured after weight loss were negatively correlated with the animal weight measured at the final stage of weight gain. This was alleviated by KD, which improved cognition when used as a weight loss approach. Conclusions The study shows that cognition and mitochondrial metabolism in the hippocampus are affected by CR- or KD-induced weight loss.

Exogenous Ketones Lower Post-exercise Acyl-Ghrelin and GLP-1 but Do Not Impact Ad libitum Energy Intake

Article

Full-text available

Jan 2021

Ketosis and exercise are both associated with alterations in perceived appetite and modification of appetite-regulating hormones. This study utilized a ketone ester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE) to examine the impact of elevated ketone body D-β-hydroxybutyrate (βHB) during and after a bout of exercise on appetite-related hormones, appetite perception, and ad libitum energy intake over a 2 h post-exercise period. In a randomized crossover trial, 13 healthy males and females (age: 23.6 ± 2.4 years; body mass index: 25.7 ± 3.2 kg·m−2) completed an exercise session @ 70% VO2peak for 60 min on a cycling ergometer and consumed either: (1) Ketone monoester (KET) (0.5 g·kg−1 pre-exercise + 0.25 g·kg−1 post-exercise); or (2) isocaloric dextrose control (DEX). Transient ketonaemia was achieved with βHB concentrations reaching 5.0 mM (range 4.1–6.1 mM) during the post-exercise period. Relative to the dextrose condition, acyl-ghrelin (P = 0.002) and glucagon-like peptide-1 (P = 0.038) were both reduced by acute ketosis immediately following exercise. AUC for acyl-ghrelin was lower in KET compared to DEX (P = 0.001), however there were no differences in AUC for GLP-1 (P = 0.221) or PYY (P = 0.654). Perceived appetite (hunger, P = 0.388; satisfaction, P = 0.082; prospective food consumption, P = 0.254; fullness, P = 0.282) and 2 h post-exercise ad libitum energy intake (P = 0.488) were not altered by exogenous ketosis. Although KE modifies homeostatic regulators of appetite, it does not appear that KE acutely alters energy intake during the post-exercise period in healthy adults.

Comparing weight loss between the Keyto app + device and the WW app: Protocol for a mHealth randomized trial (Preprint)

Article

Full-text available

Apr 2020

Background Obesity and being overweight are major contributing factors for many diseases. Calorie restricted diets often fail to result in sustained long-term weight loss. Very low–carbohydrate, high-fat ketogenic diets have been suggested to have superior metabolic and weight loss effects. Keyto is a low-cost, highly scalable mobile health (mHealth) app paired with a noninvasive biofeedback tool aimed at facilitating weight loss through a personalized healthy and predominantly plant- and fish-based ketogenic diet. Objective This protocol describes a randomized trial comparing the efficacy of the Keyto mHealth app and device intervention to that of Weight Watchers’ WW app in individuals who are overweight or obese. The primary outcome is weight loss after 12 weeks. Secondary and exploratory outcomes, including metabolic and cardiovascular risk factors, will be assessed at 12, 24, and 48 weeks. Methods A total of 144 participants will be recruited and randomized to either the Keyto program or Weight Watchers program. Study participants will be guided through the study via video conference or phone calls and will undergo a fasting blood analysis performed by a third-party diagnostic lab at weeks 0 and 12 to assess metabolic and cardiovascular risk markers. All participants will be asked to weigh themselves daily on a study-provided Bluetooth-enabled scale. Participants randomized to the Keyto arm will also be asked to measure their breath acetone levels, a measure of ketosis, with the Keyto device 3 times per day. Results Recruitment started in December 2019. Rolling recruitment is expected to be completed by July 2020. Data collection and analysis of the primary intervention phase is expected to be completed in October 2020. The 24- and 48-week follow-ups are expected to be completed in January 2021 and July 2021, respectively. Conclusions This trial will provide high-quality evidence regarding the efficacy of the Keyto weight loss program in individuals who are overweight and obese in a free-living condition. This study also fills a gap by examining the impact of a ketogenic diet emphasizing plant- and fish-based fats on blood lipid profile and cardiovascular disease risk. Trial Registration ClinicalTrials.gov NCT04165707; https://clinicaltrials.gov/ct2/show/NCT04165707. International Registered Report Identifier (IRRID) DERR1-10.2196/19053

Ketogenic Diet and Ketone Bodies against Ischemic Injury: Targets, Mechanisms, and Therapeutic Potential

Article

Full-text available

Jan 2023
INT J MOL SCI

The ketogenic diet (KD) has been used as a treatment for epilepsy since the 1920s, and its role in the prevention of many other diseases is now being considered. In recent years, there has been an intensive investigation on using the KD as a therapeutic approach to treat acute pathologies, including ischemic ones. However, contradictory data are observed for the effects of the KD on various organs after ischemic injury. In this review, we provide the first systematic analysis of studies conducted from 1980 to 2022 investigating the effects and main mechanisms of the KD and its mimetics on ischemia–reperfusion injury of the brain, heart, kidneys, liver, gut, and eyes. Our analysis demonstrated a high diversity of both the composition of the used KD and the protocols for the treatment of animals, which could be the reason for contradictory effects in different studies. It can be concluded that a true KD or its mimetics, such as β-hydroxybutyrate, can be considered as positive exposure, protecting the organ from ischemia and its negative consequences, whereas the shift to a rather similar high-calorie or high-fat diet leads to the opposite effect.

Positive effects of ketogenic diet on weight control in children with obesity due to Prader–Willi syndrome

Article

Dec 2022

Objective Prader-Willi Syndrome (PWS) is the most common genetic cause of obesity. Prevention and management of obesity, which represents the main cause of morbidity and mortality in these patients, is essential. Ketogenic diet (KD) is used in the treatment of various disorders, however knowledge on its effect in PWS is lacking. The present study assesses the characteristics of patients with PWS who were on ketogenic diet. Patients This is a retrospective, cross-sectional descriptive study investigating the subjects with PWS, who had received KD for at least 6 months. Results Ten patients with PWS [median age 52.5 (47-77) months] complied with KD. The median treatment period was 16.5 [11-52] months. Of the daily calorie, 75-85% were from fat, and 15-25% from protein+carbohydrate. The baseline body weight SD score prior to diet therapy was 2.10 [-1.11-4.11], whereas it was 0.05 [-0.92-1.2] at final evaluation (p=0.007). The baseline median BMI SD score prior to diet therapy was 3.05 [-0.21-3.72], whereas it was 0.41 [-0.87-1.57] at final evaluation (p=0.002). The height SD score remained unchanged. Mild hypercholesterolemia was the most common biochemical abnormality during treatment with KD. Conclusion Our results indicate that KD might have a favorable effect on weight management in PWS. This article is protected by copyright. All rights reserved.

Possible Weight Regain Managements after Bariatric Surgery

Article

Aug 2022

Obesity is an uprising trend across the world resulting in huge costs for healthcare systems and declines in the quality of life in patients. Bariatric surgery is one of the most effective approaches to weight loss. Although bariatric surgery can be considered as a minimally invasive approach it has a series of complications such as weight regain 1 to 4 years after surgery. Nonetheless, most patients achieve sufficient weight loss, but the other subjects with supervised strategies would be able to manage food intake and change problematic lifestyles to continue the weight loss process. In this review article, we aim to gather valuable interventions performed and reported by researchers to manage weight regain in bariatric patients. Weight regain is a multi-factorial condition owing to hormonal imbalances, nutritional deficiencies, physical inactivity, mental health disorders, problematic dietary behaviors, medical issues such as thyroid, adrenal, kidney, or heart problems, taking new medications, diabetes relapse, and pregnancy, as well as anatomic and surgical factors. Therefore, its remission needs interdisciplinary approaches.

Pola Konsumsi Sehat dan Ekonomis Selama Ramadhan

Article

Full-text available

Jun 2022

Asupan makanan dan cairan yang seimbang penting saat berpuasa. Ginjal sangat efisien dalam menjaga air dan garam tubuh, seperti natrium dan kalium. Untuk mencegah kerusakan otot, makanan harus mengandung tingkat 'makanan energi' yang cukup, seperti karbohidrat dan sedikit lemak. Oleh karena itu, diet seimbang dengan jumlah nutrisi, garam, dan air yang cukup sangat penting. Untuk mendapatkan manfaat penuh dari puasa, seseorang harus banyak memikirkan jenis dan jumlah makanan yang akan mereka nikmati. Makan berlebihan tidak hanya dapat membahayakan tubuh tetapi juga dianggap mengganggu pertumbuhan spiritual seseorang. Oleh karena itu, sosialisasi mengenai pola makan sehat dan ekonomis selama Ramadhan ini dilakukan dengan harapan masyarakat menjadi tahu apa yang terjadi pada tubuh selama berpuasa sehingga dapat memilih makanan sehat untuk sahur dan berbuka supaya tetap sehat, aktif dan produktif. Pengabdian ini dilakukan di Universitas Esa Unggul via Zoom Meeting menggunakan metode ceramah diskusi dan tanya jawab. Hasil pengabdian ini yaitu antusias peserta sangat tinggi yang tercermin dari keaktifan dalam bertanya. Selain itu mereka mengatahui pentingnya berpuasa bagi tubuh serta dapat memilih makanan sehat dan ekonomis selama puasa.

The janus face of ketone bodies in hypertension

Article

Aug 2022
J Hypertens

Hypertension is the most important risk factor for the development of terminal cardiovascular diseases, such as heart failure, chronic kidney disease, and atherosclerosis. Lifestyle interventions to lower blood pressure are generally desirable prior to initiating pharmaceutical drug treatments, which may have undesirable side effects. Ketogenic interventions are popular but the scientific literature supporting their efficacy is specific to certain interventions and outcomes in animal models and patient populations. For example, although caloric restriction has its own inherent difficulties (e.g. it requires high levels of motivation and adherence is difficult), it has unequivocally been associated with lowering blood pressure in hypertensive patients. On the other hand, the antihypertensive efficacy of ketogenic diets is inconclusive, and this is surprising, given that these diets have been largely helpful in mitigating metabolic syndrome and promoting longevity. It is possible that side effects associated with ketogenic diets (e.g. dyslipidemia) aggravate the hypertensive phenotype. However, given the recent data from our group, and others, reporting that the most abundant ketone body, β-hydroxybutyrate, can have positive effects on endothelial and vascular health, there is hope that ketone bodies can be harnessed as a therapeutic strategy to combat hypertension. Therefore, we conclude this review with a summary of the type and efficacy of ketone supplements. We propose that ketone supplements warrant investigation as low-dose antihypertensive therapy that decreases total peripheral resistance with minimal adverse side effects. Graphical abstract:http://links.lww.com/HJH/C54.

Beta-Hydroxybutyrate Suppresses Hepatic Production of the Ghrelin Receptor Antagonist LEAP2

Article

Full-text available

Mar 2022

Introduction Liver-expressed antimicrobial peptide-2 (LEAP2) is an endogenous ghrelin receptor antagonist, which is upregulated in the fed state and downregulated during fasting. We hypothesized that the ketone body, beta-hydroxybutyrate (BHB), is involved in the downregulation of LEAP2 during conditions with high circulating levels of BHB. Methods Hepatic and intestinal Leap2 expression were determined in three groups of mice with increasing circulating levels of BHB: prolonged fasting, prolonged ketogenic diet and oral BHB treatment. LEAP2 levels were measured in lean and obese individuals, in human subjects following endurance exercise and in mice after BHB treatment. Lastly, we investigated Leap2 expression in isolated murine hepatocytes challenged with BHB. Results We confirmed increased circulating LEAP2 levels in individuals with obesity compared to lean individuals. The recovery period after endurance exercise was associated increased plasma levels of BHB levels and decreased LEAP2 in humans. Leap2 expression was selectively decreased in the liver after fasting and after exposure to a ketogenic diet for three weeks. Importantly, we found that oral administration of BHB increased circulating levels of BHB in mice and decreased expression of Leap2 and systemic LEAP2 plasma levels, as did Leap2 expression after direct exposure to BHB in isolated murine hepatocytes. Conclusion From our data, we suggest that LEAP2 is downregulated during different states of energy deprivation in both humans and rodents. Furthermore, we here provide evidence that the highly upregulated ketone body during fasting metabolism, BHB, directly downregulates LEAP2 levels. This may be relevant in ghrelin receptor-induced hunger signaling during energy deprivation.

The Effect of Carbohydrate Intake on Strength and Resistance Training Performance: A Systematic Review

Article

Full-text available

Feb 2022

High carbohydrate intakes are commonly recommended for athletes of various sports, including strength trainees, to optimize performance. However, the effect of carbohydrate intake on strength training performance has not been systematically analyzed. A systematic literature search was conducted for trials that manipulated carbohydrate intake, including supplements, and measured strength, resistance training or power either acutely or after a diet and strength training program. Studies were categorized as either (1) acute supplementation, (2) exercise-induced glycogen depletion with subsequent carbohydrate manipulation, (3) short-term (2–7 days) carbohydrate manipulation or (4) changes in performance after longer-term diet manipulation and strength training. Forty-nine studies were included: 19 acute, six glycogen depletion, seven short-term and 17 long-term studies. Participants were strength trainees or athletes (39 studies), recreationally active (six studies) or untrained (four studies). Acutely, higher carbohydrate intake did not improve performance in 13 studies and enhanced performance in six studies, primarily in those with fasted control groups and workouts with over 10 sets per muscle group. One study found that a carbohydrate meal improved performance compared to water but not in comparison to a sensory-matched placebo breakfast. There was no evidence of a dose-response effect. After glycogen depletion, carbohydrate supplementation improved performance in three studies compared to placebo, in particular during bi-daily workouts, but not in research with isocaloric controls. None of the seven short-term studies found beneficial effects of carbohydrate manipulation. Longer-term changes in performance were not influenced by carbohydrate intake in 15 studies; one study favored the higher- and one the lower-carbohydrate condition. Carbohydrate intake per se is unlikely to strength training performance in a fed state in workouts consisting of up to 10 sets per muscle group. Performance during higher volumes may benefit from carbohydrates, but more studies with isocaloric control groups, sensory-matched placebos and locally measured glycogen depletion are needed.

Does a Higher Protein Diet Promote Satiety and Weight Loss Independent of Carbohydrate Content? An 8-Week Low-Energy Diet (LED) Intervention

Article

Full-text available

Jan 2022

Both higher protein (HP) and lower carbohydrate (LC) diets may promote satiety and enhance body weight (BW) loss. This study investigated whether HP can promote these outcomes independent of carbohydrate (CHO) content. 121 women with obesity (BW: 95.1 ± 13.0 kg, BMI: 35.4 ± 3.9 kg/m2) were randomised to either HP (1.2 g/kg BW) or normal protein (NP, 0.8 g/kg BW) diets, in combination with either LC (28 en%) or normal CHO (NC, 40 en%) diets. A low-energy diet partial diet replacement (LEDpdr) regime was used for 8 weeks, where participants consumed fixed-energy meal replacements plus one ad libitum meal daily. Four-day dietary records showed that daily energy intake (EI) was similar between groups (p = 0.744), but the difference in protein and CHO between groups was lower than expected. Following multiple imputation (completion rate 77%), decrease in mean BW, fat mass (FM) and fat-free mass (FFM) at Week 8 in all was 7.5 ± 0.7 kg (p < 0.001), 5.7 ± 0.5 kg (p < 0.001), and 1.4 ± 0.7 kg (p = 0.054) respectively, but with no significant difference between diet groups. LC (CHO×Week, p < 0.05), but not HP, significantly promoted postprandial satiety during a preload challenge. Improvements in blood biomarkers were unrelated to LEDpdr macronutrient composition. In conclusion, HP did not promote satiety and BW loss compared to NP LEDpdr, irrespective of CHO content.

Very-Low-Calorie Ketogenic Diet: A Potential Treatment for Binge Eating and Food Addiction Symptoms in Women. A Pilot Study

Article

Full-text available

Dec 2021
Int J Environ Res Publ Health

Background: many patients who struggle to lose weight are unable to cut down certain ultra-processed, refined types of food with a high glycemic index. This condition is linked to responses similar to addiction that lead to overeating. A very-low-calorie ketogenic diet (VLCKD) with adequate protein intake could be considered a valid dietary approach. The aim of the present study was to evaluate the feasibility of a VLCKD in women with binge eating and/or food addiction symptoms. Methods: subjects diagnosed with binge eating and/or food addiction symptoms (measured with the Binge Eating Scale and the Yale Food Addiction Scale 2.0) were asked to follow a VLCKD with protein replacement for 5-7 weeks (T1) and a low-calorie diet for 11-21 weeks (T2). Self-reported food addiction and binge eating symptoms and body composition were tested at T0 (baseline) and at the end of each diet (T1 and T2 respectively); Results: five women were included in the study. Mean age was 36.4 years (SEM = 4.95) and mean BMI was 31.16 (SEM = 0.91). At T0, two cases of severe food addiction, one case of mild food addiction, one case of binge eating with severe food addiction, and one case of binge eating were recorded. Weight loss was recorded at both T1 and T2 (ranging from 4.8% to 11.6% of the initial body weight at T1 and from 7.3% to 12.8% at T2). No case of food addiction and/or binge eating symptoms was recorded at T2. Muscle mass was preserved. Conclusions: recent findings have highlighted the potential therapeutic role of ketogenic diets for the treatment of addiction to high-calorie, ultra-processed and high-glycemic food. Our pilot study demonstrates the feasibility of a ketogenic diet in women with addictive-like eating disorders seeking to lose weight.

Dietary Interventions in Autosomal Dominant Polycystic Kidney Disease

Article

Nov 2021

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive growth of renal cysts, leading to the loss of functional nephrons. Recommendations for individuals with ADPKD to maintain a healthy diet and lifestyle are largely similar to those for the general population. However, recent evidence from preclinical models suggests that more tightly specified dietary regimens including caloric restriction, intermittent fasting, and ketogenic diets hold promise to slow disease progression, and the results of ongoing human clinical trials are eagerly awaited. These dietary interventions directly influence nutrient signalling and substrate availability in the cystic kidney, while also conferring systemic metabolic benefits. The present review focuses on the importance of local and systemic metabolism in ADPKD and summarizes current evidence for dietary interventions to slow disease progression and improve quality of life.

Ketogenic diet with medium‐chain triglycerides restores skeletal muscle function and pathology in a rat model of Duchenne muscular dystrophy

Article

Full-text available

Sep 2021

Duchenne muscular dystrophy (DMD) is an intractable genetic disease associated with progressive skeletal muscle weakness and degeneration. Recently, it was reported that intraperitoneal injections of ketone bodies partially ameliorated muscular dystrophy by increasing satellite cell (SC) proliferation. Here, we evaluated whether a ketogenic diet (KD) with medium‐chain triglycerides (MCT‐KD) could alter genetically mutated DMD in model rats. We found that the MCT‐KD significantly increased muscle strength and fiber diameter in these rats. The MCT‐KD significantly suppressed the key features of DMD, namely, muscle necrosis, inflammation, and subsequent fibrosis. Immunocytochemical analysis revealed that the MCT‐KD promoted the proliferation of muscle SCs, suggesting enhanced muscle regeneration. The muscle strength of DMD model rats fed with MCT‐KD was significantly improved even at the age of 9 months. Our findings suggested that the MCT‐KD ameliorates muscular dystrophy by inhibiting myonecrosis and promoting the proliferation of muscle SCs. As far as we can ascertain, this is the first study to apply a functional diet as therapy for DMD in experimental animals. Further studies are needed to elucidate the underlying mechanisms of the MCT‐KD‐induced improvement of DMD.

Macronutrient Determinants of Obesity, Insulin Resistance and Metabolic Health

Article

Full-text available

Apr 2021

Obesity caused by the overconsumption of calories has increased to epidemic proportions. Insulin resistance is often associated with an increased adiposity and is a precipitating factor in the development of cardiovascular disease, type 2 diabetes, and altered metabolic health. Of the various factors contributing to metabolic impairments, nutrition is the major modifiable factor that can be targeted to counter the rising prevalence of obesity and metabolic diseases. However, the macronutrient composition of a nutritionally balanced “healthy diet” are unclear, and so far, no tested dietary intervention has been successful in achieving long-term compliance and reductions in body weight and associated beneficial health outcomes. In the current review, we briefly describe the role of the three major macronutrients, carbohydrates, fats, and proteins, and their role in metabolic health, and provide mechanistic insights. We also discuss how an integrated multi-dimensional approach to nutritional science could help in reconciling apparently conflicting findings.

Acute ketosis inhibits appetite and decreases plasma concentrations of acyl ghrelin in healthy humans

Article

Apr 2021

Aim: To investigate the acute effect of ketone ester (KE) ingestion on appetite and plasma concentrations of acyl ghrelin (AG), unacylated ghrelin (UAG) and glucagon-like peptide-1 (GLP-1) secretion, and to compare responses with those elicited by isocaloric glucose (GLU) administration. Methods: We examined 10 healthy young men on three separate occasions using a placebo (PBO)-controlled crossover design. A KE versus taste-matched isovolumetric and isocaloric 50% GLU and taste-matched isovolumetric PBO vehicle was orally administered. Our main outcome measures were plasma concentrations of AG, UAG, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 along with appetite sensation scores assessed by visual analogue scale. Results: KE ingestion resulted in an average peak beta-hydroxybutyrate concentration of 5.5 mM. AG and UAG were lowered by approximately 25% following both KE and GLU intake compared with PBO. In the case of AG, the differences were -52.1 (-79.4, -24.8) for KE and -48.4 (-75.4, -21.5) pg/mL for GLU intake (P < .01). Concentrations of AG remained lower with KE but returned to baseline and were comparable with PBO levels after GLU intake. GLP-1, GIP, gastrin and cholecystokinin were not affected by KE ingestion. Conclusion: Our results suggest that the suppressive effects on appetite sensation scores associated with hyperketonaemia are more probable to be mediated through reduced ghrelin concentrations than by increased activity of cholecystokinin, gastrin, GIP or GLP-1.

Effect of a Free-Living Ketogenic Diet on Feasibility, Satiety, Body Composition, and Metabolic Health in Women: The Grading Level of Optimal Carbohydrate for Women (GLOW) Study

Article

Full-text available

Mar 2021

Objective The study's purpose was to examine a free-living, ketogenic diet (WFKD) on feasibility, satiety, body composition, and metabolic health in women. Methods Twenty-two women (age (yr.) 42.2 ± 8.1, Ht. (cm) 164.2 ± 5.9, BMI 27.3 ± 6.0) participated in a 21-day, free-living dietary intervention. Daily ketone measurements and satiety/craving surveys, weekly diet records, and PRE and POST assessments of anthropometrics, body composition, blood pressure, and fasted capillary-blood glucose (BG) and cholesterol panels were collected. Results Women maintained calories (PRE: 1938 kcal vs POST: 1836 kcal) and protein (PRE: 17% vs POST: 20%) but decreased carbohydrate (PRE: 36% vs POST: 13%) and increased fat (PRE: 45% vs POST: 65%) PRE to POST (p ≤ 0.05). Daily self-reports suggested no changes in satiety or food cravings between PRE, WK 1, WK 2, and WK 3. Ketones increased (PRE 0.3 ± 0.2 mmol vs POST 0.8 ± 0.6 mmol) PRE to POST with significant differences between PRE and all other time points (p ≤ 0.05). Bodyweight (PRE: 73.9 kg vs POST: 72.3 kg) and body fat (PRE: 28.9 ± 13.4 kg vs POST 27. 4 ± 13.5 kg) decreased but there were no differences in fat-free mass PRE to POST (p ≤ 0.05). Systolic blood pressure decreased (PRE: 119.2 ± 8.9 mmHg vs POST: 109.5 ± 10.9 mmHg), diastolic blood pressure increased (PRE: 74.1 ± 7.5 mmHg vs POST: 78.8 ± 7.4 mmHg), and BG improved (94.0 ± 8.3 mg/dL vs POST 89.9 ± 9.0 mg/dL) PRE to POST (p ≤ 0.05). No differences were observed in total cholesterol (TC), high-density lipoprotein (HDL), and triglycerides (TG) but TC/HDL decreased and low-density lipoprotein increased PRE to POST (p ≤ 0.05). Conclusion Women were able to maintain calories, improve body composition, blood pressure, and BG, increase ketones, and improve some but not all cholesterol markers after 21 days on a free-living WFKD.

Intermittent fasting for obesity and related disorders: Unveiling myths, facts, and presumptions

Article

Full-text available

Jan 2021

Intermittent fasting (IF) is an increasingly popular method of weight loss, as an alternative to daily caloric restriction (DCR). Several forms of IF exist, such as alternate-day fasting or time-restricted feeding regimens. Some of its proponents claim several health benefits unrelated to caloric restriction or weight loss, which rely mainly on animal models. Although several studies published in the last few years confirm that IF can be a useful and safe therapeutical option for obesity and related disorders, no superiority to conventional caloric restriction diets have emerged. There are still several questions left answered. In this Review, we discuss some of the claims, unveiling myths, facts, and presumptions about several models of IF. The focus of this article is obesity, but there is a brief discussion of the potential benefits of IF on overall human health.

Dietary Management of Obesity: A Review of the Evidence

Article

Full-text available

Dec 2020

Obesity is a multi-factorial disease and its prevention and management require knowledge of the complex interactions underlying it and adopting a whole system approach that addresses obesogenic environments within country specific contexts. The pathophysiology behind obesity involves a myriad of genetic, epigenetic, physiological, and macroenvironmental factors that drive food intake and appetite and increase the obesity risk for susceptible individuals. Metabolically, food intake and appetite are regulated via intricate processes and feedback systems between the brain, gastrointestinal system, adipose and endocrine tissues that aim to maintain body weight and energy homeostasis but are also responsive to environmental cues that may trigger overconsumption of food beyond homeostatic needs. Under restricted caloric intake conditions such as dieting, these processes elicit compensatory metabolic mechanisms that promote energy intake and weight regain, posing great challenges to diet adherence and weight loss attempts. To mitigate these responses and enhance diet adherence and weight loss, different dietary strategies have been suggested in the literature based on their differential effects on satiety and metabolism. In this review article, we offer an overview of the literature on obesity and its underlying pathological mechanisms, and we present an evidence based comparative analysis of the effects of different popular dietary strategies on weight loss, metabolic responses and diet adherence in obesity.

Very-low-calorie ketogenic diet for the management of obesity, overweight and related disorders

Article

Nov 2020
Minerva Endocrinol

Introduction: Very-low-calorie ketogenic diet (VLCKD) is a promising lifestyle intervention for the management of overweight and obesity. It is characterized by a restriction of both calories and carbohydrates, while assuring the adequate proteins, fats and micronutrients intake. Significant results in terms of excess body weight loss have been reported and this strategy considered also in the preoperative settings. Improvements in hypertension, type 2 diabetes and dyslipidemia follows. Evidence acquisition: PubMed and Google Scholar were searched for papers reporting data on VLCKD as a strategy for the management of overweight, obesity and related disorders in adults. Evidence synthesis: Four main documents are available in the literature and were included in the present narrative review. Conclusions: The present review discusses available evidence and provides practical recommendations for the management of VLCKD.

Ketogenic diets as treatment of obesity and type 2 diabetes mellitus

Article

Full-text available

Sep 2020
REV ENDOCR METAB DIS

During the last decades, several interventions for the management of overweight and obesity have been proposed. Among diets, the first studies focused on the effect of water only and total fasting diets with or without proteins. Unfortunately, they were found to be associated with adverse events which lead to the abandon of these strategies. Interestingly, despite the radical approach, total fasting was effective and generally well tolerated. A strict connection between protein-calorie malnutrition and increased in morbidity and mortality in hospitalized patients was found at that time. Then, the seminal works of Blackburn and his collaborators lead to the introduction of the protein-sparing modified fast. Encouraged by the early results using this intervention, diets evolved to the current very-low-calorie ketogenic diets (VLCKD). In the present review, results of studies on the VLCKDs are presented and discussed, with a particular reference to the protocolled VLCKD. Also, a recent proposal on the nomenclature on the ketogenic diets is reported. Available evidence suggests VLCKDs to be effective in achieving a rapid and significant weight loss by means of an easily reversible intervention which could be repeated, if needed. Muscle mass and strength are preserved, resting metabolic rate is not impaired, hunger, appetite and mood are not worsened. Symptoms and abnormal laboratory findings can be there, but they have generally been reported as of mild intensity and transient. Preliminary studies suggest VLCKDs to be a potential game-changer in the management of type 2 diabetes too. Therefore, VLCKDs should be considered as an excellent initial step in properly selected and motivated patients with obesity or type 2 diabetes, to be delivered as a part of a multicomponent strategy and under strict medical supervision.

Nutritional Ketosis with Ketogenic Diets or Exogenous Ketones: Features, Convergence, and Divergence

Article

Jul 2020
Curr Sports Med Rep

Athletes, clinicians, and practitioners are increasingly interested in the proposed performance and therapeutic benefits of nutritional ketosis (NK). NK is best operationally defined as a nutritionally induced metabolic state resulting in blood β-hydroxybutyrate concentrations of ≥0.5 mM. Most tissues readily metabolize ketone bodies (KBs), and KBs in turn regulate metabolism and signaling in both a systemic and tissue-specific manner. During fasting, starvation, or ketogenic diets, endogenous synthesis of KBs is amplified resulting in a state of NK. Orally administered exogenous ketone supplements rapidly elevate circulating KBs and produce a similar, but far from identical, metabolic state. NK results in a number of convergent features regardless of endogenous or exogenous induction; however, important differences also are observed. The implications of NK across health, disease, and performance is rapidly becoming more evident, thus acknowledging the convergent and divergent features of NK is critical for fully understanding the potential utility of this metabolic state.

Urine dipsticks are not accurate for detecting mild ketosis during a severely‐energy restricted diet

Article

Full-text available

May 2020

Background Detection of the mild ketosis induced by severely energy‐restricted diets may be a clinically‐useful way to monitor and promote dietary adherence. Mild ketosis is often assessed using urine dipsticks, but accuracy for this purpose has not been tested. Objective To determine the accuracy of urine dipsticks to detect mild ketosis during adherence to a severely energy‐restricted diet. Methods Two hundred and sixty three (263) fasting urine and 263 fasting blood samples were taken from 50 women (mean (SD) age 58.0 (4.3) years and body mass index 34.3 (2.4) kg/m²) before and at 6 time points during or for up to 10 weeks after 16 weeks of severe energy restriction, achieved with a total meal replacement diet. The amount of ketones (acetoacetate) in the urine was classified as “0 (Negative)”, “+/‐ (Trace)”, “+ (Weak)”, or “++ (Medium)” by urine dipsticks (Ketostix®, Bayer). The concentration of ketones (β‐hydroxybutyrate) in the blood was measured with our reference method, a portable ketone monitor (FreeStyle Optium, Abbott). The diagnostic accuracy of the urine dipsticks was assessed from the percent of instances when a person was actually “in ketosis” (as defined by a blood β‐hydroxybutyrate concentration at or above three different thresholds) that were also identified by the urine dipsticks as being from a person in ketosis (the percent “true positives” or sensitivity), as well as the percent of instances when a person was not in ketosis (as defined by the blood monitor result) was correctly identified as such with the urine dipstick (the percent “true negatives” or specificity). Thresholds of ≥ 0.3 mM, ≥ 0.5 mM or ≥ 1.0 mM were selected, because mean blood concentrations of β‐hydroxybutyrate during ketogenic diets are approximately 0.5 mM. Sensitivity and specificity were then used to generate receiver operating characteristic curves, with the area under these curves indicating the ability of the dipsticks to correctly identify people in ketosis (1 = perfect results, 0.5 = random results). Results At threshold blood β‐hydroxybutyrate concentrations of ≥ 0.3 mM, ≥ 0.5 mM and ≥ 1.0 mM, the sensitivity of the urine dipsticks was 35%, 52% and 76%, the specificity was 100%, 97% and 78%, and the area under the receiver operating characteristic curves was 0.67, 0.74 and 0.77, respectively. These low levels of sensitivity mean that 65%, 48% or 24% of the instances when a person was in ketosis were not detected by the urine dipsticks. Conclusion Urine dipsticks are not an accurate or clinically‐useful means of detecting mild ketosis in people undergoing a severely energy‐restricted diet, and should thus not be recommended in clinical treatment protocols. If monitoring of mild ketosis is indicated (eg, to monitor or help promote adherence to a severely energy‐restricted diet), then blood monitors should be used instead.

Exogenous Ketones as Therapeutic Signaling Molecules in High-Stress Occupations: Implications for Mitigating Oxidative Stress and Mitochondrial Dysfunction in Future Research

Article

Dec 2020

High-stress occupations (ie, firefighters, military personnel, police officers, etc.) are often plagued by cardiometabolic diseases induced by exposure to chronic stressors. Interrupted sleep cycles, poor dietary patterns, lack of physical activity, and smoke exposure along with simultaneous psychological stressors promote chronic low-grade inflammation and excessive oxidative stress. Collectively, these data suggest that practical interventions which might mitigate the underlying pathologies of these cardiometabolic diseases are warranted. Ketones, specifically R-βHB, modulates intracellular signaling cascades such as the cellular redox ratios of NAD+/NADH, the activity of NAD dependent deacetylases SIRT1 and SIRT3, and promotes a robust mitochondrial environment which favors reductions in oxidative stress and inflammation. To date, the literature examining R-βHB as a signaling metabolite has mostly been performed from endogenous R-βHB production achieved through nutritional ketosis or cell culture and mouse models using exogenous R-βHB. To the authors knowledge, only 1 study has attempted to report on the effects of exogenous ketones and the mitigation of oxidative stress/inflammation. Therefore, the scope of this review is to detail the mechanisms of R-βHB as a signaling metabolite and the role that exogenous ketones might play in mitigating diseases in individuals serving in high-stress occupations.

A bibliometric and visual analysis of low carbohydrate diet

Article

Full-text available

Feb 2023

Introduction Numerous studies have confirmed the effects of low carbohydrate diet (LChD) on metabolism and chronic diseases. However, there were no bibliometric studies on LChD. This study was conducted through a bibliometric analysis to investigate the current status, hotspots and frontiers trends. Methods We searched all research publications related to LChD from 2002 to 2021 on the Web of Scientific Core Collection (WoSCC). CiteSpace and VOSviewer software was used to analyze countries/regions, institutions, journals, authors, references, and keywords. Results A total of 6938 papers were included, with an increasing trend of annual publication. LChD categories mainly included nutrition, endocrinology, and neurosciences which reflected the interdisciplinary characteristics. USA was with the largest number and the world science center in LChD field. Universities were main research institutions and five of the top 10 institutions were from USA. Eric Heath Kossoff had 101 publications and ranked first. Nutrients was the leading journal. “A randomized trial of a low-carbohydrate diet for obesity” and “ Obesity ” were considered to be the most co-cited and cited reference respectively. The hotspots of LChD are four aspects, “ketogenic diet”, “metabolism disease”, “cardiovascular disease” and “cancer”. We summarized that “oxidative stress”, “gut microbiota”, and “inflammation factors” are becoming frontiers trends of LChD research in the future and deserve further study. Discussion Over the past 20 years research on LChD has gained great attention. To better explore LChD field, multilevel mechanism studies will be required in the future.

Relationship between Ketones, Ghrelin, and, Appetite on Isocaloric Diets with Varying Carbohydrate Quality and Amount: Results from a Randomized Controlled Trial in People with Obesity (CARBFUNC)

Article

Dec 2022
J NUTR

Background: Low-carbohydrate high-fat (LCHF) diets may suppress the increase in appetite otherwise seen after diet-induced fat loss. However, studies of diets without severe energy restriction are lacking, and the effects of carbohydrate quality relative to quantity have not been directly compared. Objectives: To evaluated short- (3 mo) and long-term (12 mo) changes in fasting plasma concentrations of total ghrelin, β-hydroxybutyrate (βHB), and subjective feelings of appetite on 3 isocaloric eating patterns within a moderate caloric range (2000-2500 kcal/d) and with varying carbohydrate quality or quantity. Methods: We performed a randomized controlled trial of 193 adults with obesity, comparing eating patterns based on "acellular" carbohydrate sources (e.g., flour-based whole-grain products; comparator arm), "cellular" carbohydrate sources (minimally processed foods with intact cellular structures), or LCHF principles. Outcomes were compared by an intention-to-treat analysis using constrained linear mixed modeling. This trial was registered at clinicaltrials.gov as NCT03401970. Results: Of the 193 adults, 118 (61%) and 57 (30%) completed 3 and 12 mo of follow-up. Throughout the intervention, intakes of protein and energy were similar with all 3 eating patterns, with comparable reductions in body weight (5%-7%) and visceral fat volume (12%-17%) after 12 mo. After 3 mo, ghrelin increased significantly with the acellular (mean: 46 pg/mL; 95% CI: 11, 81) and cellular (mean: 54 pg/mL; 95% CI: 21, 88) diets but not with the LCHF diet (mean: 11 pg/mL; 95% CI: -16, 38). Although βHB increased significantly more with the LCHF diet than with the acellular diet after 3 m (mean: 0.16 mmol/L; 95% CI: 0.09, 0.24), this did not correspond to a significant group difference in ghrelin (unless the 2 high-carbohydrate groups were combined [mean: -39.6 pg/mL; 95% CI: -76, -3.3]). No significant between-group differences were seen in feelings of hunger. Conclusions: Modestly energy-restricted isocaloric diets differing in carbohydrate cellularity and amount showed no significant differences in fasting total ghrelin or subjective hunger feelings. An increase in ketones with the LCHF diet to 0.3-0.4 mmol/L was insufficient to substantially curb increases in fasting ghrelin during fat loss.

Effect of D-β-hydroxybutyrate-(R)-1,3 Butanediol on Appetite Regulation in People with Prediabetes

Article

Dec 2022
MOL NUTR FOOD RES

Scope: The primary aim of the present study was to study the effect of acute ketosis on parameters of appetite regulation in prediabetes. The secondary aim was to investigate whether the effect is influenced by eating behaviours. Methods and results: This was a randomised controlled trial. After an overnight fast, 18 adults with prediabetes (defined in line with the American Diabetes Association criteria) were assigned to consume either a ketone monoester (D-β-hydroxybutyrate-(R)-1,3 butanediol) drink (energy content 123 kcal) or a placebo drink (containing virtually no calories) in cross-over fashion. Blood samples were collected every 30 mins, from baseline to 150 minutes. Paired t-test was used to compare the total area under the curve (AUC) for the changes in parameters of appetite regulation (acylated ghrelin, peptide YY (PYY), and hunger) following both drinks. Eating behaviours were determined with the use of the three-factor eating questionnaire. Significant elevation in blood β-hydroxybutyrate from 0.2 mmol/L to 3.5 mmol/L (p < 0.001) was achieved within 30 minutes. Acute ketosis did not result in statistically significant differences in the AUCs for ghrelin, PYY, and hunger. No statistically significant difference in the AUCs was also observed when participants were stratified by their eating behaviours. Conclusion: Acute ketosis consistently did not affect both objective and subjective parameters of appetite regulation in prediabetes. No subset of people with prediabetes according to eating behaviours had a significant effect of acute ketosis on appetite regulation. This article is protected by copyright. All rights reserved.

Does exercise during a ketogenic diet effectively alter appetite sensation, appetite-regulating hormones, and body composition?

Article

Aug 2022

Exercise and diet are two essential interventions in weight control. The purpose of this study was to compare the effectiveness of two exercise training types during a ketogenic diet (KD) on appetite sensation, appetite-regulating hormones, and body composition in overweight or obese man. Thirty-six men, overweight or with obesity, voluntarily participated in this study. The participants were randomly assigned into three groups, including KD ( n = 12), aerobic training during KD (AT-KD) ( n = 12), and resistance training during KD (RT-KD) ( n = 12) groups. The participants followed a low-carbohydrate diet for 6 weeks. Exercise training programs consisted of three sessions per week over 6 weeks. Appetite sensation was analyzed using a visual analogue scale (VAS) in fasting and postprandial states. The Enzyme-Linked Immunosorbent Assay (ELISA) method analyzed appetite-regulating hormones, including spexin, leptin, and acylated ghrelin, in a fasting state. Body composition was measured using bioelectrical impedance analysis (BIA). Furthermore, the ketosis state was monitored by measuring urinary ketones weekly. The results indicated that in both AT-KD and RT-KD groups, spexin and acylated ghrelin increased while leptin decreased without any between-group differences. Hunger and prospective food consumption (PFC) declined while satiety and fullness increased in all groups. The AT-KD group experienced a significant decrease in hunger and PFC, while fullness increased compared with the KD group. Fat mass, weight, and body mass index (BMI) decreased in all groups. Lean body mass increased in the RT-KD group (+2.66 kg) compared with both AT-KD and KD groups (−1.71 and −1.33 kg, respectively). This study demonstrated that AT-KD and RT-KD effectively altered appetite-regulating hormones and suppressed appetite sensation. In addition, both interventions had a favorable effect on weight loss and body fat reduction, with a more pronounced effect of RT-KD on maintaining lean body mass in overweight or obese men.

Biochemistry and metabolic pathways of polysaccharides, lipids, and proteins

Article

Full-text available

Dec 2021

The eukaryotic cells are complex structures, capable of replication and performing a wide range of tasks in multicellular organisms. However, they also obey the laws of chemistry and physics that determine the metabolism of living systems. Consequently, cell biology seeks to understand metabolic processes in terms of reactions of anabolism and molecular catabolism. This review considers the chemical composition and properties of polysaccharides, lipids, and proteins as ultimately responsible for all cellular activities. The atoms and biochemical bonds of these macromolecules determine all cell dynamics, which is why the first part of each chapter reviews the nature of the functional group’s hydroxyl, amino and carboxyl, responsible for the formation of monosaccharides, amino acids and fatty acids. The rest of each chapter analyzes the genesis and lysis of these molecules within each cell organelle, for the formation of acetyl-coenzyme A and the liberation of energy in the Krebs cycle. Thus, the biochemistry of cell metabolism can be understood in terms of the structures and functions of three main organic molecules polysaccharides, lipids and proteins.

Could very low-calorie ketogenic diets turn off low grade inflammation in obesity? Emerging evidence

Article

Apr 2022

Obesity is an emerging non-communicable disease associated with chronic low-grade inflammation and oxidative stress, compounded by the development of many obesity-related diseases, such as cardiovascular disease, type 2 diabetes mellitus, and a range of cancers. Originally developed for the treatment of epilepsy in drug non-responder children, the ketogenic diet (KD) is being increasingly used in the treatment of many diseases, including obesity and obesity-related conditions. The KD is a dietary pattern characterized by high fat intake, moderate to low protein consumption, and very low carbohydrate intake (<50 g) that has proved to be an effective and weight-loss tool. In addition, it also appears to be a dietary intervention capable of improving the inflammatory state and oxidative stress in individuals with obesity by means of several mechanisms. The main activity of the KD has been linked to improving mitochondrial function and decreasing oxidative stress. β-hydroxybutyrate, the most studied ketone body, has been shown to reduce the production of reactive oxygen species, improving mitochondrial respiration. In addition, KDs exert anti-inflammatory activity through several mechanisms, e.g., by inhibiting activation of the nuclear factor kappa-light-chain-enhancer of activated B cells, and the inflammatory nucleotide-binding, leucine-rich-containing family, pyrin domain-containing-3, and inhibiting histone deacetylases. Given the rising interest in the topic, this review looks at the underlying anti-inflammatory and antioxidant mechanisms of KDs and their possible recruitment in the treatment of obesity and obesity-related disorders.

Intermittent Exogenous Ketosis for Athletic Performance, Recovery, and Adaptation

Chapter

Apr 2022

Sports nutrition science seeks to determine optimal dietary protocols for athletes pushing the limits of human physiology in power, endurance, and skill. Traditionally, dietary interventions aimed to stimulate performance have focused on strategic intake of carbohydrates, protein, and fat. However, recent development of oral ketone supplements has increased the popularity of intermitted exogenous ketosis (IEK) as a potential nutritional strategy to stimulate training adaptation and performance in athletes. Several physiologic mechanisms are implicated in acute modulation of exercise performance by IEK. These include use of ketone bodies as an alternative substrate for oxidative ATP production in contracting muscles and ketone-mediated inhibition of glycolytic flux. The latter could lead to glycogen sparing, which may increase endurance; on the other hand, glycolytic inhibition in conjunction with ketoacidosis could be ergolytic in short maximal exercise bouts. Furthermore, preliminary evidence suggests that acute and chronic post-exercise ketosis may stimulate recovery from training. Acute IEK could stimulate muscle protein synthesis and glycogen repletion, and chronic ketone ester intake blunted overreaching symptoms during short-term endurance training overload. This protection could be attributed to improved autonomic neural balance, appetite and stress hormone regulation, and possibly attenuation of exercise-induced inflammation and oxidative stress. Such effects could conceivably either down- or upregulate training adaptation. However, research to date describing both acute and chronic exogenous ketosis in exercise and training is limited and inconclusive. Further studies are required to elucidate the specific contexts and mechanisms whereby IEK could maximally benefit athletes.

Perceptions of appetite do not match hormonal measures of appetite in trained competitive cyclists and triathletes following a ketogenic diet compared to a high-carbohydrate or habitual diet: A randomized crossover trial

Article

Aug 2021
NUTR RES

Endurance athletes may implement rigid dietary strategies, such as the ketogenic diet (KD), to improve performance. The effect of the KD on appetite remains unclear in endurance athletes. This study analyzed the effects of a KD, a high-carbohydrate diet (HCD), and habitual diet (HD) on objective and subjective measures of appetite in trained cyclists and triathletes, and hypothesized that the KD would result in greater objective and subjective appetite suppression. Six participants consumed the KD and HCD for two-weeks each, in a random order, following their HD. Fasting appetite measures were collected after two-weeks on each diet. Postprandial appetite measures were collected following consumption of a ketogenic meal after the KD, high-carbohydrate meal after the HCD, and standard American/Western meal after the HD. Fasting total ghrelin (GHR) was lower and glucagon-like peptide-1 (GLP-1) and hunger were higher following the KD versus HD and HCD. Fasting insulin was not different. Mixed-effects model repeated measures analysis and effect sizes and 95% confidence intervals showed that postprandial GHR and insulin were lower and GLP-1 was higher following the ketogenic versus the standard and high-carbohydrate meals. Postprandial appetite ratings were not different across test meals. In conclusion, both fasting and postprandial concentrations of GHR were lower and GLP-1 were higher following the KD than the HC and HD, and postprandial insulin was lower on the KD. Subjective ratings of appetite did not correspond with the objective measures of appetite in trained competitive endurance athlete. More research is needed to confirm our findings.

Ketogenic diets, physical activity, and body composition: A review

Article

Full-text available

Jul 2021

Obesity remains a serious relevant public health concern throughout the world despite related countermeasures being well understood (i.e., mainly physical activity and an adjusted diet). Among different nutritional approaches, there is a growing interest in ketogenic diets (KDs) to manipulate body mass (BM) and to enhance fat mass (FM) loss. KDs reduce the daily amount of carbohydrate intake drastically. This results in increased fatty acid utilization, leading to an increase in blood ketone bodies (KBs) (acetoacetate [AcAc], 3-β-hydroxybutyrate [BHB], and acetone), and therefore metabolic ketosis. For many years, nutritional intervention studies have focused on reducing dietary fat with little or conflicting positive results over the long-term. Moreover, current nutritional guidelines for athletes propose carbohydrate-based diets to augment muscular adaptations. This review discusses the physiological basis of KDs and their effects on BM reduction and body composition improvements in sedentary individuals combined with different types of exercise (resistance training [RT] or endurance training [ET]) in individuals with obesity and athletes. Ultimately, we discuss the strengths and the weaknesses of these nutritional interventions together with precautionary measures that should be observed in both individuals with obesity and athletic populations. A literature search from 1921 to April 2021 using MEDLINE, GOOGLE SCHOLAR, PUBMED, WEB OF SCIENCE, SCOPUS, and SPORTDISCUS databases were used to identify relevant studies. In summary, based on the current evidence, KDs are an efficient method to reduce BM and body fat in both individuals with obesity and athletes. However, these positive impacts are mainly because of the appetite suppressive effects of KDs, which can decrease daily calorie intake. Therefore, KDs do not have any superior benefits to non-KDs in BM and body fat loss in individuals with obesity and athletic populations in an isocaloric situation. In sedentary individuals with obesity, it seems that fat-free mass (FFM) changes appear to be as great, if not greater, than decreases following a low-fat diet (LFD). In terms of lean mass, it seems that following a KD can cause FFM loss in resistance-trained individuals. In contrast, the FFM-preserving effects of KDs are more efficient in endurance-trained compared to resistance-trained individuals.

Very-low-calorie ketogenic diet for the management of obesity, overweight and related disorders

Article

Jun 2021

iNTrodUcTioN: Very-low-calorie ketogenic diet (VlcKd) is a promising lifestyle intervention for the management of overweight and obesity. it is characterized by a restriction of both calories and carbohydrates, while assuring the adequate proteins, fats and micronutrients intake. Significant results in terms of excess body weight loss have been reported and this strategy considered also in the preoperative settings. improvements in hypertension, type 2 diabetes and dyslipidemia follows. eVideNce acQUiSiTioN: PubMed and google Scholar were searched for papers reporting data on VlcKd as a strategy for the management of overweight, obesity and related disorders in adults. eVideNce SyNTHeSiS: Four main documents are available in the literature and were included in the present narrative review. coNclUSioNS: The present review discusses available evidence and provides practical recommendations for the management of VlcKd.

Ketogenic diets and appetite regulation

Article

Full-text available

Apr 2021
CURR OPIN CLIN NUTR

Purpose of review: The popularity of ketogenic diets in the treatment of obesity has increased dramatically over the last years, namely due to their potential appetite suppressant effect. The purpose of this review was to examine the latest evidence regarding the impact of ketogenic diets on appetite. Recent findings: The majority of the studies published over the last 2 years adds to previous evidence and shows that ketogenic diets suppress the increase in the secretion of the hunger hormone ghrelin and in feelings of hunger, otherwise see when weight loss is induced by non-ketogenic diets. Research done using exogenous ketones point out in the same direction. Even though the exact mechanisms by which ketogenic diets suppress appetite remain to be fully determined, studies show that the more ketotic participants are (measured as β-hydroxybutyrate plasma concentration), the smaller is the increase in ghrelin and hunger and the larger is the increase in the release of satiety peptides. Further evidence for a direct effect of ketones on appetite comes from studies using exogenous ketones. Summary: The appetite suppressant effect of ketogenic diets may be an important asset for improving adherence to energy restricted diets and weight loss outcomes.

Benefit and concern of ketogenic and vegan diets: A revisit to pathophysiology

Chapter

Jan 2021

The ketogenic diet has in normal healthy individuals no metabolic advantages over diets with normal composition (more carbohydrates). It comes with a risk to lose fat free (muscle) mass in inflammatory conditions including obesity. In this condition more glucose is required, which needs in part to be produced from muscle derived amino acids in view of the low glucose content of the diet. The vegan diet is a truly unbalanced diet, containing protein with low biological value. It is deficient in a number of vitamins and trace elements and contains excessive amounts of vegetables. It decreases body weight and consequently, diminishes the severity of the metabolic syndrome, cardiovascular disease cancer. In pregnancy and children, the diet stalls growth, so that a number of food components need to be supplemented. This may also apply in aged people.

Implicating the effect of ketogenic diet as a preventive measure to obesity and diabetes mellitus

Article

Jan 2021
LIFE SCI

Obesity and diabetes are the two major metabolic complications linked with bad eating habits and the sedentary (lazy) lifestyle. In the worst-case situation, metabolic problems are a causative factor for numerous other conditions. There is also an increased demand to control the emergence of such diseases. Dietary and lifestyle improvements contribute to their leadership at an elevated level. The present review, therefore, recommends the use of the ketogenic diet (KD) in obesity and diabetes treatment. The KD involves a diet that replaces glucose sugar with ketone bodies and is effective in numerous diseases, such as metabolic disorders, epileptic seizures, autosomal dominant polycystic disease of the kidney, cancers, peripheral neuropathy, and skeletal muscle atrophy. A lot of high profile pathways are available for KD action, including sustaining the metabolic actions on glucose sugar, suppressing insulin-like growth factor-1 (IGF1) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways, altering homeostasis of the systemic ketone bodies, contributing to lowering diabetic hyperketonemia, and others. The KD regulates the level of glucose sugar and insulin and can thus claim to be an effective diabetes approach. Thus, a stopgap between obesity and diabetes treatment can also be evidenced by KD.

From Fad to Fact: Evaluating the Impact of Emerging Diets on the Prevention of Cardiovascular Disease

Article

Jun 2020
AM J MED

Cardiovascular disease remains one of the most prevalent and preventable chronic conditions worldwide. Diet modification is the foundation of cardiovascular disease prevention. Several dietary approaches have emerged to promote better cardiovascular health. The rapid dissemination of anecdotal and observational data through the internet and social media has caused confusion amongst providers and patients. The aim of this comprehensive review is to present objective insights into two of today's most popular fad diets, ketogenic diet and intermittent fasting. We will evaluate the performance of these diets based on their impact on cardiovascular risk factors. •The ketogenic dietary pattern and intermittent fasting are new approaches that have been touted as diets that have a potential to reduce the risk for cardiovascular disease. •Current evidence indicates that the ketogenic diet results in short-term weight loss and improvements in glucose metabolism. However there remains a concern about its dyslipidemic potential. •Intermittent fasting has more a better impact on the cardiometabolic profile with much less risk for dyslipidemia.

Investigating the effect of sex and ketosis on weight-loss-induced changes in appetite

Article

Full-text available

May 2019
AM J CLIN NUTR

Background: Diet-induced weight loss (WL) is usually accompanied by increased appetite, a response that seems to be absent when ketogenic diets are used. It remains unknown if sex modulates the appetite suppressant effect of ketosis. Objective: The aim of this study was to examine if sex modulates the impact of WL-induced changes in appetite and if ketosis alters these responses. Methods: Ninety-five individuals (55 females) with obesity (BMI [kg/m 2]: 37 ± 4) underwent 8 wk of a very-low-energy diet, followed by 4 wk of refeeding and weight stabilization. Body composition, plasma concentration of β-hydroxybutyrate (β-HB) and appetite-related hormones (active ghrelin, active glucagon-like peptide 1 [GLP-1], total peptide YY [PYY], cholecystokinin and insulin), and subjective feelings of appetite were measured at baseline, week 9 in ketosis, and week 13 out of ketosis. Results: The mean WL at week 9 was 17% for males and 15% for females, which was maintained at week 13. Weight, fat, and fat-free mass loss were greater in males (P < 0.001 for all) and the increase in β-HB at week 9 higher in females (1.174 ± 0.096 compared with 0.783 ± 0.112 mmol/L, P = 0.029). Basal and postprandial GLP-1 and postprandial PYY (all P < 0.05) were significantly different for males and females. There were no significant sex × time interactions for any other appetite-related hormones or subjective feelings of appetite. At week 9, basal GLP-1 was decreased only in males (P < 0.001), whereas postprandial GLP-1 was increased only in females (P < 0.001). No significant changes in postprandial PYY were observed over time for either sex. Conclusions: Ketosis appears to have a greater beneficial impact on GLP-1 in females. However, sex does not seem to modulate the changes in the secretion of other appetite-related hormones, or subjective feelings of appetite, seen with WL, regardless of the ketotic state. This trial was registered at clinicaltrials.gov as NCT01834859.

Concentration-Dependent Effects of a Dietary Ketone Ester on Components of Energy Balance in MiceTable_1.pdf

Article

Full-text available

May 2019

Objectives: Exogenous ketones may provide therapeutic benefit in treatment of obesity. Administration of the ketone ester (KE) R,S-1,3-butanediol acetoacetate diester (BD-AcAc2) decreases body weight in mice, but effects on energy balance have not been extensively characterized. The purpose of this investigation was to explore concentration-dependent effects of BD-AcAc2 on energy intake and expenditure in mice. Methods: Forty-two male C57BL/6J mice were randomly assigned to one of seven isocaloric diets (n = 6 per group): (1) Control (CON, 0% KE by kcals); (2) KE5 (5% KE); (3) KE10 (10% KE); (4) KE15 (15% KE); (5) KE20 (20% KE); (6) KE25 (25% KE); and (7) KE30 (30% KE) for 3 weeks. Energy intake and body weight were measured daily. Fat mass (FM), lean body mass (LBM), and energy expenditure (EE) were measured at completion of the study. Differences among groups were compared to CON using ANOVA and ANCOVA. Results: Mean energy intake was similar between CON and each concentration of KE, except KE30 which was 12% lower than CON (P < 0.01). KE25 and KE30 had lower body weight and FM compared to CON, while only KE30 had lower LBM (P < 0.03). Adjusted resting and total EE were lower in KE30 compared to CON (P < 0.03), but similar for all other groups. Conclusions: A diet comprised of 30% energy from BD-AcAc2 results in lower energy intake, coincident with lower body weight and whole animal adiposity; while KE20 and KE25 have significantly lower body weight and adiposity effects independent of changes in energy intake or expenditure.

Ketone ester supplementation blunts overreaching symptoms during endurance training overload

Article

Full-text available

Apr 2019
J PHYSIOL-LONDON

Key points: •Overload training is required for sustained performance gain in athletes (functional overreaching). However, excess overload may result in a catabolic state which causes performance decrements for weeks (non-functional overreaching) up to months (overtraining). •Blood ketone bodies can attenuate training- or fasting-induced catabolic events. Therefore, we investigated whether increasing blood ketone levels by oral ketone ester (KE) intake can protect against endurance training-induced overreaching. •We show for the first time that KE intake following exercise markedly blunts the development of physiological symptoms indicating overreaching, and at the same time significantly enhances endurance exercise performance. •We provide preliminary data to indicate that growth differentiation factor 15 (GDF15) may be a relevant hormonal marker to diagnose the development of overtraining. •Collectively, our data indicate that ketone ester intake is a potent nutritional strategy to prevent the development of non-functional overreaching and to stimulate endurance exercise performance. Abstract: It is well known that elevated blood ketones attenuate net muscle protein breakdown, as well as negate catabolic events, during energy deficit. Therefore, we hypothesized that oral ketones can blunt endurance training-induced overreaching. Fit male subjects participated in two daily training sessions (3 weeks, 6 days/week) while receiving either a ketone ester (KE, n = 9) or a control drink (CON, n = 9) following each session. Sustainable training load in week 3 as well as power output in the final 30 min of a 2-h standardized endurance session were 15% higher in KE than in CON (both P < 0.05). KE inhibited the training-induced increase in nocturnal adrenaline (P < 0.01) and noradrenaline (P < 0.01) excretion, as well as blunted the decrease in resting (CON: -6 ± 2 bpm; KE: +2 ± 3 bpm, P < 0.05), submaximal (CON: -15 ± 3 bpm; KE: -7 ± 2 bpm, P < 0.05) and maximal (CON: -17 ± 2 bpm; KE: -10 ± 2 bpm, P < 0.01) heart rate. Energy balance during the training period spontaneously turned negative in CON (-2135 kJ/day), but not in KE (+198 kJ/day). The training consistently increased growth differentiation factor 15 (GDF15), but ∼2-fold more in CON than in KE (P < 0.05). In addition, delta GDF15 correlated with the training-induced drop in maximal heart rate (r = 0.60, P < 0.001) and decrease in osteocalcin (r = 0.61, P < 0.01). Other measurements such as blood ACTH, cortisol, IL-6, leptin, ghrelin and lymphocyte count, and muscle glycogen content did not differentiate KE from CON. In conclusion, KE during strenuous endurance training attenuates the development of overreaching. We also identify GDF15 as a possible marker of overtraining.

Dietary R , S -1,3-butanediol diacetoacetate reduces body weight and adiposity in obese mice fed a high-fat diet

Article

Full-text available

Oct 2018

The dietary R-3-hydroxybutyrate- R-1,3-butanediol monoester increases resting energy expenditure (REE) and markers of brown and white adipose thermogenesis in lean mice. The purpose of this investigation was to determine whether the ketone ester, R, S-1,3-butanediol diacetoacetate (BD-AcAc2), increases energy expenditure and markers of adipose tissue thermogenesis in the context of high-fat diet (HFD)-induced obesity. Thirty-five-week-old male C57BL/6J mice were placed on an ad libitum HFD (45% kcal) for 10 wk. The mice were then randomized to 1 of 3 groups ( n = 10 per group) for an additional 12 wk: 1) control (Con), continuous HFD, 2) pair-fed (PF) to ketone ester (KE); and 3) KE: HFD+30% energy from BD-AcAc2. Mean energy intake throughout the study was ∼26% lower in the KE compared to the Con group (8.2 ± 0.5 vs. 11.2 ± 0.7 kcal/d; P < 0.05). Final body weight (26.8 ± 3.6 vs. 34.9 ± 4.8 g; P < 0.001) and fat mass (5.2 ± 1.2 vs. 11.3 ± 4.5 g; P < 0.001) of the KE group was significantly lower than PF, despite being matched for energy provisions. Differences in body weight and adiposity were accompanied by higher REE and total energy expenditure in the KE group compared to PF after adjustment for lean body mass and fat-mass ( P = 0.001 and 0.007, respectively). Coupled or uncoupled mitochondrial respiratory rates in skeletal muscle were not different among groups, but markers of mitochondrial uncoupling and thermogenesis (uncoupling protein-1, deiodinase-2, and peroxisome proliferator-activated receptor γ coactivator-1α) were higher in interscapular brown adipose tissue (BAT) of mice receiving the KE diet. The absence of mitochondrial uncoupling in skeletal muscle and increased markers of mitochondrial uncoupling in BAT suggest that BD-AcAc2 initiates a transcriptional signature consistent with BAT thermogenesis in the context of HFD-induced obesity.-Davis, R. A. H., Deemer, S. E., Bergeron, J. M., Little, J. T., Warren, J. L., Fisher, G., Smith, D. L., Jr., Fontaine, K. R., Dickinson, S. L., Allison, D. B., Plaisance, E. P. Dietary R, S-1,3-butanediol diacetoacetate reduces body weight and adiposity in obese mice fed a high-fat diet.

Defining the Optimal Dietary Approach for Safe, Effective and Sustainable Weight Loss in Overweight and Obese Adults

Article

Full-text available

Jun 2018

Various dietary approaches with different caloric content and macronutrient composition have been recommended to treat obesity in adults. Although their safety and efficacy profile has been assessed in numerous randomized clinical trials, reviews and meta-analyses, the characteristics of the optimal dietary weight loss strategy remain controversial. This mini-review will provide general principles and practical recommendations for the dietary management of obesity and will further explore the components of the optimal dietary intervention. To this end, various dietary plans are critically discussed, including low-fat diets, low-carbohydrate diets, high-protein diets, very low-calorie diets with meal replacements, Mediterranean diet, and diets with intermittent energy restriction. As a general principle, the optimal diet to treat obesity should be safe, efficacious, healthy and nutritionally adequate, culturally acceptable and economically affordable, and should ensure long-term compliance and maintenance of weight loss. Setting realistic goals for weight loss and pursuing a balanced dietary plan tailored to individual needs, preferences, and medical conditions, are the key principles to facilitate weight loss in obese patients and most importantly reduce their overall cardiometabolic risk and other obesity-related comorbidities.

Investigation of the long-term sustainability of changes in appetite after weight loss

Article

Full-text available

Aug 2018
INT J OBESITY

Background/objective: Diet-induced weight loss (WL) leads to a compensatory increase in appetite and changes in the plasma concentration of appetite-regulating hormones are likely to play a role. Whether these changes are transient or sustained remains unclear. This study aimed to assess if changes in subjective and objective appetite markers observed with WL are sustained after 1 year (1Y). Subjects/methods: In total 100 (45 males) individuals with obesity (BMI: 37 ± 4 kg/m2, age: 43 ± 10 years) underwent 8 weeks (wks) of a very-low energy diet (VLED), followed by 4 wks refeeding, and a 1Y maintenance program. Fasting/postprandial subjective ratings of hunger, fullness, desire to eat, and prospective food consumption (PFC) were assessed, and plasma concentration of active ghrelin (AG), total peptide YY (PYY), active glucagon-like peptide 1, cholecystokinin (CCK), and insulin measured, at baseline, week 13 (Wk13) and 1Y. Results: At Wk13, 16% WL (-18 ± 1 kg, P < 0.001) was associated with a significant increase in fasting and postprandial hunger ratings (P < 0.01 and P < 0.05, respectively), and postprandial fullness (P < 0.01) combined with a reduction in PFC (P < 0.001). These were accompanied by a significant rise in basal and postprandial AG concentrations (P < 0.001, for both), a reduction in postprandial CCK (P < 0.01) and in basal and postprandial insulin (P < 0.001). At 1Y follow-up, with sustained WL (15%; -16 ± 1 kg, P < 0.001), fasting hunger and postprandial fullness ratings remained increased (P < 0.05 for both), and postprandial PFC reduced (P < 0.001). Basal and postprandial AG remained elevated and insulin reduced (P < 0.001, for all), while postprandial CCK was increased (P < 0.01) and PYY decreased (P < 0.001). Conclusion: With a 15% sustained WL at 1Y, the drive to eat in the fasting state is increased, but this may be balanced out by raised postprandial feelings of fullness. To assist with WL maintenance, new strategies are required to manage increased hunger and drive to eat.

Timeline of changes in adaptive physiological responses, at the level of energy expenditure, with progressive weight loss

Article

Full-text available

May 2018

Diet-induced weight loss (WL) is associated with reduced resting and non-resting energy expenditure (EE), driven not only by changes in body composition but also potentially by adaptive thermogenesis (AT). When exactly this happens, during progressive WL, remains unknown. The aim of this study was to determine the timeline of changes in RMR and exercise-induced EE (EIEE), stemming from changes in body composition v . the presence of AT, during WL with a very-low-energy diet (VLED). In all, thirty-one adults (eighteen men) with obesity (BMI: 37 ( sem 4·5) kg/m ² ; age: 43 ( sem 10) years) underwent 8 weeks of a VLED, followed by 4 weeks of weight maintenance. Body weight and composition, RMR, net EIEE (10, 25 and 50 W) and AT (for RMR (AT RMR ) and EIEE (AT EIEE )) were measured at baseline, day 3 (2 ( sem 1) % WL), after 5 and 10 % WL and at weeks 9 (16 ( sem 2) %) and 13 (16 ( sem 1) %). RMR and fat mass were significantly reduced for the first time at 5 % WL (12 ( sem 8) d) ( P <0·01 and P <0·001, respectively) and EIEE at 10 % WL (32 ( sem 8) d), for all levels of power ( P <0·05), and sustained up to week 13. AT RMR was transiently present at 10 % WL (−460 ( sem 690) kJ/d, P <0·01). A fall in RMR should be anticipated at ≥5 % WL and a reduction in EIEE at ≥10 % WL. Transient AT RMR can be expected at 10 % WL. These physiological adaptations may make progressive WL difficult and will probably contribute to relapse.

A Ketone Ester Drink Lowers Human Ghrelin and Appetite

Article

Full-text available

Nov 2017
OBESITY

Objective: The ketones d-β-hydroxybutyrate (BHB) and acetoacetate are elevated during prolonged fasting or during a "ketogenic" diet. Although weight loss on a ketogenic diet may be associated with decreased appetite and altered gut hormone levels, it is unknown whether such changes are caused by elevated blood ketones. This study investigated the effects of an exogenous ketone ester (KE) on appetite. Methods: Following an overnight fast, subjects with normal weight (n = 15) consumed 1.9 kcal/kg of KE, or isocaloric dextrose (DEXT), in drinks matched for volume, taste, tonicity, and color. Blood samples were analyzed for BHB, glucose, insulin, ghrelin, glucagon-like peptide 1 (GLP-1), and peptide tyrosine tyrosine (PYY), and a three-measure visual analogue scale was used to measure hunger, fullness, and desire to eat. Results: KE consumption increased blood BHB levels from 0.2 to 3.3 mM after 60 minutes. DEXT consumption increased plasma glucose levels between 30 and 60 minutes. Postprandial plasma insulin, ghrelin, GLP-1, and PYY levels were significantly lower 2 to 4 hours after KE consumption, compared with DEXT consumption. Temporally related to the observed suppression of ghrelin, reported hunger and desire to eat were also significantly suppressed 1.5 hours after consumption of KE, compared with consumption of DEXT. Conclusions: Increased blood ketone levels may directly suppress appetite, as KE drinks lowered plasma ghrelin levels, perceived hunger, and desire to eat.

On the Metabolism of Exogenous Ketones in Humans

Article

Full-text available

Oct 2017

Background and aims: Currently there is considerable interest in ketone metabolism owing to recently reported benefits of ketosis for human health. Traditionally, ketosis has been achieved by following a high-fat, low-carbohydrate “ketogenic” diet, but adherence to such diets can be difficult. An alternative way to increase blood D-β-hydroxybutyrate (D-βHB) concentrations is ketone drinks, but the metabolic effects of exogenous ketones are relatively unknown. Here, healthy human volunteers took part in three randomized metabolic studies of drinks containing a ketone ester (KE); (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, or ketone salts (KS); sodium plus potassium βHB. Methods and Results: In the first study, 15 participants consumed KE or KS drinks that delivered ~12 or ~24 g of βHB. Both drinks elevated blood D-βHB concentrations (D-βHB Cmax: KE 2.8 mM, KS 1.0 mM, P < 0.001), which returned to baseline within 3–4 h. KS drinks were found to contain 50% of the L-βHB isoform, which remained elevated in blood for over 8 h, but was not detectable after 24 h. Urinary excretion of both D-βHB and L-βHB was <1.5% of the total βHB ingested and was in proportion to the blood AUC. D-βHB, but not L-βHB, was slowly converted to breath acetone. The KE drink decreased blood pH by 0.10 and the KS drink increased urinary pH from 5.7 to 8.5. In the second study, the effect of a meal before a KE drink on blood D-βHB concentrations was determined in 16 participants. Food lowered blood D-βHB Cmax by 33% (Fed 2.2 mM, Fasted 3.3 mM, P < 0.001), but did not alter acetoacetate or breath acetone concentrations. All ketone drinks lowered blood glucose, free fatty acid and triglyceride concentrations, and had similar effects on blood electrolytes, which remained normal. In the final study, participants were given KE over 9 h as three drinks (n = 12) or a continuous nasogastric infusion (n = 4) to maintain blood D-βHB concentrations greater than 1 mM. Both drinks and infusions gave identical D-βHB AUC of 1.3–1.4 moles.min. Conclusion: We conclude that exogenous ketone drinks are a practical, efficacious way to achieve ketosis.

Ketone Diester Ingestion Impairs Time-Trial Performance in Professional Cyclists

Article

Full-text available

Oct 2017

We investigated the effect of pre- “race” ingestion of a 1,3-butanediol acetoacetate diester on blood ketone concentration, substrate metabolism and performance of a cycling time trial (TT) in professional cyclists. In a randomized cross-over design, 10 elite male cyclists completed a ~31 km laboratory-based TT on a cycling ergometer programmed to simulate the 2017 World Road Cycling Championships course. Cyclists consumed a standardized meal [2 g/kg body mass (BM) carbohydrate (CHO)] the evening prior to a trial day and a CHO breakfast (2 g/kg BM CHO) with 200 mg caffeine on the morning of a trial day. Cyclists were randomized to consume either the ketone diester (2 × 250 mg/kg) or a placebo drink, followed immediately by 200 mL diet cola, given ~ 30 min before and immediately prior to commencing a 20 min incremental warm-up. Blood samples were collected prior to and during the warm-up, pre- and post- TT and at regular intervals after the TT. Urine samples were collected pre- and post- warm-up, immediately post TT and 60 min post TT. Pre-exercise ingestion of the diester resulted in a 2 ± 1% impairment in TT performance that was associated with gut discomfort and higher perception of effort. Serum β-hydroxybutyrate, serum acetoacetate, and urine ketone concentrations increased from rest following ketone ingestion and were higher than placebo throughout the trial. Ketone ingestion induces hyperketonemia in elite professional cyclists when in a carbohydrate fed state, and impairs performance of a cycling TT lasting ~50 min.

Timeline of changes in appetite during weight loss with a ketogenic diet

Article

Full-text available

Apr 2017

Background/objective: Diet-induced weight loss (WL) leads to increased hunger and reduced fullness feelings, increased ghrelin and reduced satiety peptides concentration (glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK) and peptide YY (PYY)). Ketogenic diets seem to minimise or supress some of these responses. The aim of this study was to determine the timeline over which changes in appetite occur during progressive WL with a ketogenic very-low energy diet (VLED). Subjects/methods: Thirty-one sedentary adults (18 men), with obesity (BMI: 37±4.5 kg/m(2)) underwent 8 weeks (wks) of a VLED followed by 4 wks of weight maintenance. Body weight and composition, subjective feelings of appetite and appetite related hormones (insulin, active ghrelin (AG), active GLP-1, total PYY and CCK) were measured in fasting and postprandially, at baseline, on day 3 of the diet, 5 and 10% WL, and at wks 9 and 13.Data shown as mean±s.d. Results: A significant increase in fasting hunger was observed by day 3 (2±1% WL), (P<0.01), 5% WL (12±8 days) (P<0.05) and wk 13 (17±2% WL) (P<0.05). Increased desire to eat was observed by day 3 (P<0.01) and 5% WL (P<0.05). Postprandial prospective food consumption was significantly reduced at wk 9 (16±2% WL) (P<0.01). Basal total PYY was significantly reduced at 10% WL (32±8 days) (P<0.05). Postprandial active GLP-1 was increased at 5% WL (P<0.01) and CCK reduced at 5 and 10% WL (P<0.01, for both) and wk 9 (P<0.001). Basal and postprandial AG were significantly increased at wk 13 (P<0.001, both). Conclusion: WL with a ketogenic VLED transiently increases the drive to eat up to 3 weeks (5% WL). After that, and while participants are ketotic, a 10-17% WL is not associated with increased appetite. However, hunger feelings and AG concentrations increase significantly from baseline, once refeeding occurs.International Journal of Obesity accepted article preview online, 25 April 2017. doi:10.1038/ijo.2017.96.

The impact of rate of weight loss on body composition and compensatory mechanisms during weight reduction: A randomized control trial

Article

Full-text available

Apr 2017

Background & aims: Rapid weight loss (WL) has been associated with a larger loss of fat free mass and a disproportional reduction in resting metabolic rate (RMR), but the evidence is inconclusive. We aimed to evaluate the impact of WL rate on body composition and compensatory mechanisms activated with WL (reduced RMR, increased exercise efficiency (ExEff) and appetite), both during negative and neutral energy balance (EB). Methods: Thirty-five participants with obesity were randomized to lose a similar weight rapidly (4 weeks) or gradually (8 weeks), and afterwards to maintain it (4 weeks). Body weight and composition, RMR, ExEff (10, 25 and 50 W), appetite feelings and appetite-regulating hormones (active ghrelin, cholecystokinin, total peptide YY (PYY), active glucagon-like peptide-1 and insulin), in fasting and every 30 min up to 2.5 h, were measured at baseline and after each phase. Results: Changes in body weight (≈9%) and composition were similar in both groups. With WL, RMR decreased and ExEff at 10 W increased significantly in the rapid WL group only. However, fasting hunger increased significantly with gradual WL only, while fasting and postprandial prospective food consumption, and postprandial hunger decreased (and postprandial fullness increased) significantly with rapid WL only. Basal total PYY, and basal and postprandial insulin decreased significantly, and similarly in both groups. After weight stabilization and no ketosis no differences between groups were found. Conclusions: Despite differences while under negative EB, WL rate does not seem to have a significant impact on body composition or on compensatory mechanisms, once EB is reestablished. Clinical trial registration number: NCT01912742 (the study was registered in clinicaltrial.gov).

Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation

Article

Full-text available

May 2017
J PHYSIOL-LONDON

Optimising training and performance through nutrition strategies is central to supporting elite sportspeople, much of which has focussed on manipulating the relative intake of carbohydrate and fat and their contributions as fuels for energy provision. The ketone bodies, namely acetoacetate, acetone, and β-hydroxybutyrate (βHB), are produced in the liver during conditions of reduced carbohydrate availability and serve as an alternative fuel source for peripheral tissues including brain, heart and skeletal muscle. Ketone bodies are oxidised as a fuel source during exercise, are markedly elevated during the post-exercise recovery period, and the ability to utilise ketone bodies is higher in exercise-trained skeletal muscle. The metabolic actions of ketone bodies can alter fuel selection through attenuating glucose utilisation in peripheral tissues, anti-lipolytic effects on adipose tissue, and attenuation of proteolysis in skeletal muscle. Moreover, ketone bodies can act as signalling metabolites with βHB acting as an inhibitor of histone deacetylases, an important regulator of the adaptive response to exercise in skeletal muscle. Recent development of ketone esters facilitates acute ingestion of βHB that results in nutritional ketosis without necessitating restrictive dietary practices. Initial reports suggest this strategy alters the metabolic response to exercise and improves exercise performance, while other lines of evidence suggest roles in recovery from exercise. The present review focuses on the physiology of ketone bodies during and after exercise and in response to training, with specific interest in exploring the physiological basis for exogenous ketone supplementation and potential benefits for performance and recovery in athletes.

Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague–Dawley rats

Article

Full-text available

Feb 2016
NUTR METAB

Nutritional ketosis induced by the ketogenic diet (KD) has therapeutic applications for many disease states. We hypothesized that oral administration of exogenous ketone supplements could produce sustained nutritional ketosis (>0.5 mM) without carbohydrate restriction. We tested the effects of 28-day administration of five ketone supplements on blood glucose, ketones, and lipids in male Sprague–Dawley rats. The supplements included: 1,3-butanediol (BD), a sodium/potassium β-hydroxybutyrate (βHB) mineral salt (BMS), medium chain triglyceride oil (MCT), BMS + MCT 1:1 mixture, and 1,3 butanediol acetoacetate diester (KE). Rats received a daily 5–10 g/kg dose of their respective ketone supplement via intragastric gavage during treatment. Weekly whole blood samples were taken for analysis of glucose and βHB at baseline and, 0.5, 1, 4, 8, and 12 h post-gavage, or until βHB returned to baseline. At 28 days, triglycerides, total cholesterol and high-density lipoprotein (HDL) were measured. Exogenous ketone supplementation caused a rapid and sustained elevation of βHB, reduction of glucose, and little change to lipid biomarkers compared to control animals. This study demonstrates the efficacy and tolerability of oral exogenous ketone supplementation in inducing nutritional ketosis independent of dietary restriction.

Ketosis, ketogenic diet and food intake control: A complex relationship

Article

Full-text available

Feb 2015

Though the hunger-reduction phenomenon reported during ketogenic diets is well-known, the underlying molecular and cellular mechanisms remain uncertain. Ketosis has been demonstrated to exert an anorexigenic effect via cholecystokinin (CCK) release while reducing orexigenic signals e.g., via ghrelin. However, ketone bodies (KB) seem to be able to increase food intake through AMP-activated protein kinase (AMPK) phosphorylation, gamma-aminobutyric acid (GABA) and the release and production of adiponectin. The aim of this review is to provide a summary of our current knowledge of the effects of ketogenic diet (KD) on food control in an effort to unify the apparently contradictory data into a coherent picture.

Ketosis, ketoacidosis and very-low-calorie diets: Putting the record straight

Article

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Sep 2011
Nutr Bull

Very-low-calorie diets (VLCDs) are used to treat obesity, often in a non-clinical setting, and the typical formulation of a minimum of 50 g carbohydrates daily can induce a mild dietary ketosis. This clinically benign state is sometimes confused with the non-metabolically adapted state of ketoacidosis, and this misunderstanding may lead to the rejection of VLCDs as a suitable obesity treatment. This paper summarises and discusses the difference between physiological ketosis and pathological ketoacidosis, the benefits of ketosis-inducing weight-loss regimen such as VLCDs and why ketoacidosis should never be the diagnosis in a non-type 1 diabetic on a carbohydrate-restricted diet.

Ketosis and appetite-mediating nutrients and hormones after weight loss

Article

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May 2013

Background/objectives: Diet-induced weight loss is accompanied by compensatory changes, which increase appetite and encourage weight regain. There is some evidence that ketogenic diets suppress appetite. The objective is to examine the effect of ketosis on a number of circulating factors involved in appetite regulation, following diet-induced weight loss. Subjects/methods: Of 50 non-diabetic overweight or obese subjects who began the study, 39 completed an 8-week ketogenic very-low-energy diet (VLED), followed by 2 weeks of reintroduction of foods. Following weight loss, circulating concentrations of glucose, insulin, non-esterified fatty acids (NEFA), β-hydroxybutyrate (BHB), leptin, gastrointestinal hormones and subjective ratings of appetite were compared when subjects were ketotic, and after refeeding. Results: During the ketogenic VLED, subjects lost 13% of initial weight and fasting BHB increased from (mean±s.e.m.) 0.07±0.00 to 0.48±0.07 mmol/l (P<0.001). BHB fell to 0.19±0.03 mmol/l after 2 weeks of refeeding (P<0.001 compared with week 8). When participants were ketotic, the weight loss induced increase in ghrelin was suppressed. Glucose and NEFA were higher, and amylin, leptin and subjective ratings of appetite were lower at week 8 than after refeeding. Conclusions: The circulating concentrations of several hormones and nutrients which influence appetite were altered after weight loss induced by a ketogenic diet, compared with after refeeding. The increase in circulating ghrelin and subjective appetite which accompany dietary weight reduction were mitigated when weight-reduced participants were ketotic.

Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats

Article

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Apr 2013
AM J PHYSIOL-REG I

Central nervous system oxygen toxicity (CNS-OT) seizures occur with little or no warning, and no effective mitigation strategy has been identified. Ketogenic diets (KD) elevate blood ketones and have successfully treated drug-resistant epilepsy. We hypothesized that a ketone ester given orally as R,S-1,3-butanediol acetoacetate diester (BD-AcAc2), would delay CNS-OT seizures in rats breathing hyperbaric oxygen (HBO2). Adult male rats (n = 60) were implanted with radio-telemetry units to measure electroencephalogram (EEG). Rats were administered a single oral dose of BD-AcAc2, 1,3-butanediol (BD) or water 30 min before being placed into a hyperbaric chamber and pressurized to 5 ATA O2. Latency to seizure (LS) was measured from the time maximum pressure was reached until the onset of increased EEG activity and tonic-clonic contractions. Blood was drawn from an arterial catheter in an additional 18 animals that were administered the same compounds, and levels of glucose, pH, pO2, pCO2, β-hydroxybutyrate (BHB), AcAc and acetone were analyzed. BD-AcAc2 caused a rapid (30 min) and sustained (>4 h) elevation of BHB (>3 mM) and AcAc (>3 mM), which exceeded values reported with a KD or starvation. BD-AcAc2 increased LS by 574 ± 116 % compared to control (water), and was due to the effect of AcAc and acetone, but not BHB. BD produced ketosis in rats by elevating BHB (>5 mM), but AcAc and acetone remained low or undetectable. BD did not increase LS. In conclusion, acute oral administration of BD-AcAc2 produced sustained ketosis and significantly delayed CNS-OT seizures by elevating AcAc and acetone.

Low-carbohydrate diets: What are the long-term health implications?

Article

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Feb 2003
ASIA PAC J CLIN NUTR

Low-carbohydrate diets for weight loss are receiving a lot of attention of late. Reasons for this interest include a plethora of low-carbohydrate diet books, the over-sensationalism of these diets in the media and by celebrities, and the promotion of these diets in fitness centres and health clubs. The re-emergence of low-carbohydrate diets into the spotlight has lead many people in the general public to question whether carbohydrates are inherently 'bad' and should be limited in the diet. Although low-carbohydrate diets were popular in the 1970s they have resurged again yet little scientific fact into the true nature of how these diets work or, more importantly, any potential for serious long-term health risks in adopting this dieting practice appear to have reached the mainstream literature. Evidence abounds that low-carbohydrate diets present no significant advantage over more traditional energy-restricted, nutritionally balanced diets both in terms of weight loss and weight maintenance. Studies examining the efficacy of using low-carbohydrate diets for long-term weight loss are few in number, however few positive benefits exist to promote the adoption of carbohydrate restriction as a realistic, and more importantly, safe means of dieting. While short-term carbohydrate restriction over a period of a week can result in a significant loss of weight (albeit mostly from water and glycogen stores), of serious concern is what potential exists for the following of this type of eating plan for longer periods of months to years. Complications such as heart arrhythmias, cardiac contractile function impairment, sudden death, osteoporosis, kidney damage, increased cancer risk, impairment of physical activity and lipid abnormalities can all be linked to long-term restriction of carbohydrates in the diet. The need to further explore and communicate the untoward side-effects of low-carbohydrate diets should be an important public health message from nutrition professionals.

Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet

Article

Full-text available

Feb 2012
FASEB J

We measured the effects of a diet in which D-β-hydroxybutyrate-(R)-1,3 butanediol monoester [ketone ester (KE)] replaced equicaloric amounts of carbohydrate on 8-wk-old male C57BL/6J mice. Diets contained equal amounts of fat, protein, and micronutrients. The KE group was fed ad libitum, whereas the control (Ctrl) mice were pair-fed to the KE group. Blood d-β-hydroxybutyrate levels in the KE group were 3-5 times those reported with high-fat ketogenic diets. Voluntary food intake was reduced dose dependently with the KE diet. Feeding the KE diet for up to 1 mo increased the number of mitochondria and doubled the electron transport chain proteins, uncoupling protein 1, and mitochondrial biogenesis-regulating proteins in the interscapular brown adipose tissue (IBAT). [(18)F]-Fluorodeoxyglucose uptake in IBAT of the KE group was twice that in IBAT of the Ctrl group. Plasma leptin levels of the KE group were more than 2-fold those of the Ctrl group and were associated with increased sympathetic nervous system activity to IBAT. The KE group exhibited 14% greater resting energy expenditure, but the total energy expenditure measured over a 24-h period or body weights was not different. The quantitative insulin-sensitivity check index was 73% higher in the KE group. These results identify KE as a potential antiobesity supplement.

Long-Term Persistence of Hormonal Adaptations to Weight Loss

Article

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Oct 2011
NEW ENGL J MED

After weight loss, changes in the circulating levels of several peripheral hormones involved in the homeostatic regulation of body weight occur. Whether these changes are transient or persist over time may be important for an understanding of the reasons behind the high rate of weight regain after diet-induced weight loss. We enrolled 50 overweight or obese patients without diabetes in a 10-week weight-loss program for which a very-low-energy diet was prescribed. At baseline (before weight loss), at 10 weeks (after program completion), and at 62 weeks, we examined circulating levels of leptin, ghrelin, peptide YY, gastric inhibitory polypeptide, glucagon-like peptide 1, amylin, pancreatic polypeptide, cholecystokinin, and insulin and subjective ratings of appetite. Weight loss (mean [±SE], 13.5±0.5 kg) led to significant reductions in levels of leptin, peptide YY, cholecystokinin, insulin (P<0.001 for all comparisons), and amylin (P=0.002) and to increases in levels of ghrelin (P<0.001), gastric inhibitory polypeptide (P=0.004), and pancreatic polypeptide (P=0.008). There was also a significant increase in subjective appetite (P<0.001). One year after the initial weight loss, there were still significant differences from baseline in the mean levels of leptin (P<0.001), peptide YY (P<0.001), cholecystokinin (P=0.04), insulin (P=0.01), ghrelin (P<0.001), gastric inhibitory polypeptide (P<0.001), and pancreatic polypeptide (P=0.002), as well as hunger (P<0.001). One year after initial weight reduction, levels of the circulating mediators of appetite that encourage weight regain after diet-induced weight loss do not revert to the levels recorded before weight loss. Long-term strategies to counteract this change may be needed to prevent obesity relapse. (Funded by the National Health and Medical Research Council and others; ClinicalTrials.gov number, NCT00870259.).

High-protein, reduced-carbohydrate weight-loss diets promote metabolite profiles likely to be detrimental to colonic health

Article

Full-text available

Mar 2011
AM J CLIN NUTR

Diets that are high in protein but reduced in carbohydrate contents provide a common approach for achieving weight loss in obese humans. However, the effect of such diets on microbiota-derived metabolites that influence colonic health has not been established. We designed this study to assess the effect of diets with reduced carbohydrate and increased protein contents on metabolites considered to influence long-term colonic health, in particular the risk of colorectal disease. We provided 17 obese men with a defined weight-maintenance diet (85 g protein, 116 g fat, and 360 g carbohydrate/d) for 7 d followed by 4 wk each of a high-protein and moderate-carbohydrate (HPMC; 139 g protein, 82 g fat, and 181 g carbohydrate/d) diet and a high-protein and low-carbohydrate (HPLC; 137 g protein, 143 g fat, and 22 g carbohydrate/d) diet in a crossover design. Fecal samples were analyzed to determine concentrations of phenolic metabolites, short-chain fatty acids, and nitrogenous compounds of dietary and microbial origin. Compared with the maintenance diet, the HPMC and HPLC diets resulted in increased proportions of branched-chain fatty acids and concentrations of phenylacetic acid and N-nitroso compounds. The HPLC diet also decreased the proportion of butyrate in fecal short-chain fatty acid concentrations, which was concomitant with a reduction in the Roseburia/Eubacterium rectale group of bacteria, and greatly reduced concentrations of fiber-derived, antioxidant phenolic acids such as ferulate and its derivatives. After 4 wk, weight-loss diets that were high in protein but reduced in total carbohydrates and fiber resulted in a significant decrease in fecal cancer-protective metabolites and increased concentrations of hazardous metabolites. Long-term adherence to such diets may increase risk of colonic disease.

A Ketone Ester Diet Increases Brain Malonyl-CoA and Uncoupling Proteins 4 and 5 while Decreasing Food Intake in the Normal Wistar Rat

Article

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Aug 2010
J BIOL CHEM

Three groups of male Wistar rats were pair fed NIH-31 diets for 14 days to which were added 30% of calories as corn starch, palm oil, or R-3-hydroxybutyrate-R-1,3-butanediol monoester (3HB-BD ester). On the 14th day, animal brains were removed by freeze-blowing, and brain metabolites measured. Animals fed the ketone ester diet had elevated mean blood ketone bodies of 3.5 mm and lowered plasma glucose, insulin, and leptin. Despite the decreased plasma leptin, feeding the ketone ester diet ad lib decreased voluntary food intake 2-fold for 6 days while brain malonyl-CoA was increased by about 25% in ketone-fed group but not in the palm oil fed group. Unlike the acute effects of ketone body metabolism in the perfused working heart, there was no increased reduction in brain free mitochondrial [NAD(+)]/[NADH] ratio nor in the free energy of ATP hydrolysis, which was compatible with the observed 1.5-fold increase in brain uncoupling proteins 4 and 5. Feeding ketone ester or palm oil supplemented diets decreased brain L-glutamate by 15-20% and GABA by about 34% supporting the view that fatty acids as well as ketone bodies can be metabolized by the brain.

Long-term weight loss maintenance in the United States

Article

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Nov 2010
INT J OBESITY

Although the rise in overweight and obesity in the United States is well documented, long-term weight loss maintenance (LTWLM) has been minimally explored. The aim of this study is to estimate the prevalence and correlates of LTWLM among US adults. We examined weight data from 14 306 participants (age 20-84 years) in the 1999-2006 National Health and Nutrition Examination Survey (NHANES). We defined LTWLM as weight loss maintained for at least 1 year. We excluded individuals who were not overweight or obese at their maximum weight. Among US adults who had ever been overweight or obese, 36.6, 17.3, 8.5 and 4.4% reported LTWLM of at least 5, 10, 15 and 20%, respectively. Among the 17.3% of individuals who reported an LTWLM of at least 10%, the average and median weight loss maintained was 19.1 kg (42.1 pounds) and 15.5 kg (34.1 pounds), respectively. LTWLM of at least 10% was higher among adults of ages 75-84 years (vs ages 20-34, adjusted odds ratio (OR): 1.5; 95% confidence interval (CI): 1.2, 1.8), among those who were non-Hispanic white (vs Hispanic, adjusted OR: 1.6; 95% CI: 1.3, 2.0) and among those who were female (vs male, adjusted OR: 1.2; 95% CI: 1.1, 1.3). More than one out of every six US adults who has ever been overweight or obese has accomplished LTWLM of at least 10%. This rate is significantly higher than those reported in clinical trials and many other observational studies, suggesting that US adults may be more successful at sustaining weight loss than previously thought.

A controlled comparison of three very-low-calorie diets: Effects on weight, body composition, and symptoms

Article

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May 1992

To determine the optimal energy intake of very-low-calorie diets (VLCDs), 76 obese women were randomly assigned, in a double-blind fashion, to one of three liquid-formula diets: 1758 kJ/d (420 kcal/d), 2763 kJ/d (660 kcal/d), or 3349 kJ/d (800 kcal/d). Weight, body composition, symptoms, mood, and acceptability of the diet were assessed throughout the 6-mo study. There were no significant differences in weight losses or changes in body composition among the three dietary conditions at the end of treatment, nor were there significant differences among conditions in acceptability of the diet, symptoms, or mood. These results suggest that there is no clinical advantage to using VLCDs that provide less than 3349 kJ/d (800 kcal/d).

Metabolism of R- and S-1,3-butanediol in perfused livers from meal-fed and starved rats

Article

Full-text available

Aug 1992

The metabolism of millimolar concentrations of R- or S-1,3-butanediol has been studied in perfused livers from fed and starved rats. Protocols were designed to measure in the same experiment (i) uptake of the diol, (ii) the contribution of the diol to ketogenesis, (iii) the contribution of the diol to total fatty acid plus sterol synthesis, and (iv) conversion of S-1,3-butanediol into S-3-hydroxybutyrate. Our data show that R- and S-1,3-butanediol are taken up by the liver at the same rate. Most of the metabolism of R-1,3-butanediol is accounted for by conversion to the physiological ketone bodies R-3-hydroxybutyrate and acetoacetate. Only 29-38% of S-1,3-butanediol uptake is accounted for by conversion into physiological ketone bodies. The balance of S-1,3-butanediol metabolism is conversion to S-3-hydroxybutyrate, lipids and CO2.

Impact of ketosis on appetite regulation – A review

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