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Concept: Ketone bodies

207

Ketone bodies are the most energy-efficient fuel and yield more ATP per mole of substrate than pyruvate and increase the free energy released from ATP hydrolysis. Elevation of circulating ketones via high-fat, low-carbohydrate diets has been used for the treatment of drug-refractory epilepsy and for neurodegenerative diseases, such as Parkinson’s disease. Ketones may also be beneficial for muscle and brain in times of stress, such as endurance exercise. The challenge has been to raise circulating ketone levels by using a palatable diet without altering lipid levels. We found that blood ketone levels can be increased and cholesterol and triglycerides decreased by feeding rats a novel ketone ester diet: chow that is supplemented with ®-3-hydroxybutyl ®-3-hydroxybutyrate as 30% of calories. For 5 d, rats on the ketone diet ran 32% further on a treadmill than did control rats that ate an isocaloric diet that was supplemented with either corn starch or palm oil (P < 0.05). Ketone-fed rats completed an 8-arm radial maze test 38% faster than did those on the other diets, making more correct decisions before making a mistake (P < 0.05). Isolated, perfused hearts from rats that were fed the ketone diet had greater free energy available from ATP hydrolysis during increased work than did hearts from rats on the other diets as shown by using [(31)P]-NMR spectroscopy. The novel ketone diet, therefore, improved physical performance and cognitive function in rats, and its energy-sparing properties suggest that it may help to treat a range of human conditions with metabolic abnormalities.-Murray, A. J., Knight, N. S., Cole, M. A., Cochlin, L. E., Carter, E., Tchabanenko, K., Pichulik, T., Gulston, M. K., Atherton, H. J., Schroeder, M. A., Deacon, R. M. J., Kashiwaya, Y., King, M. T., Pawlosky, R., Rawlins, J. N. P., Tyler, D. J., Griffin, J. L., Robertson, J., Veech, R. L., Clarke, K. Novel ketone diet enhances physical and cognitive performance.

Concepts: Metabolism, Nutrition, Adenosine triphosphate, Fatty acid, Lipid, Ketone, Ketone bodies, Carbohydrate

65

In patients with cancer, the wasting syndrome, cachexia, is associated with caloric deficiency. Here, we describe tumor-induced alterations of the host metabolic response to caloric deficiency that cause intratumoral immune suppression. In pre-cachectic mice with transplanted colorectal cancer or autochthonous pancreatic ductal adenocarcinoma (PDA), we find that IL-6 reduces the hepatic ketogenic potential through suppression of PPARalpha, the transcriptional master regulator of ketogenesis. When these mice are challenged with caloric deficiency, the resulting relative hypoketonemia triggers a marked rise in glucocorticoid levels. Multiple intratumoral immune pathways are suppressed by this hormonal stress response. Moreover, administering corticosterone to elevate plasma corticosterone to a level that is lower than that occurring in cachectic mice abolishes the response of mouse PDA to an immunotherapy that has advanced to clinical trials. Therefore, tumor-induced IL-6 impairs the ketogenic response to reduced caloric intake, resulting in a systemic metabolic stress response that blocks anti-cancer immunotherapy.

Concepts: Immune system, Metabolism, Immunology, Colorectal cancer, Cachexia, Ketone bodies, Suppression, Suppression of dissent

55

The ketogenic diet (KD) is a very low-carbohydrate, high-fat and adequate-protein diet that without limiting calories induces different metabolic adaptations, eg, increased levels of circulating ketone bodies and a shift to lipid metabolism. Our objective was to assess the impact of a 6-week non-energy-restricted KD in healthy adults beyond cohorts of athletes on physical performance, body composition, and blood parameters.

Concepts: Protein, Metabolism, Nutrition, Fat, Lipid, Ketone bodies, Carbohydrate, Ketosis

44

High levels of ketone bodies are associated with improved survival as observed with regular exercise, caloric restriction, and-most recently-treatment with sodium-glucose linked transporter 2 inhibitor antidiabetic drugs. In heart failure, indices of ketone body metabolism are upregulated, which may improve energy efficiency and increase blood flow in skeletal muscle and the kidneys. Nevertheless, it is uncertain how ketone bodies affect myocardial glucose uptake and blood flow in humans. Our study was therefore designed to test whether ketone body administration in humans reduces myocardial glucose uptake (MGU) and increases myocardial blood flow.

Concepts: Metabolism, Heart, Positron emission tomography, Muscle, Cardiac muscle, Glycogen, Ketone bodies, Carbohydrate

42

Elite athletes and coaches are in a constant search for training methods and nutritional strategies to support training and recovery efforts that may ultimately maximize athletes' performance. Recently, there has been a re-emerging interest in the role of ketone bodies in exercise metabolism, with considerable media speculation about ketone body supplements being routinely used by professional cyclists. Ketone bodies can serve as an important energy substrate under certain conditions, such as starvation, and can modulate carbohydrate and lipid metabolism. Dietary strategies to increase endogenous ketone body availability (i.e., a ketogenic diet) require a diet high in lipids and low in carbohydrates for ~4 days to induce nutritional ketosis. However, a high fat, low carbohydrate ketogenic diet may impair exercise performance via reducing the capacity to utilize carbohydrate, which forms a key fuel source for skeletal muscle during intense endurance-type exercise. Recently, ketone body supplements (ketone salts and esters) have emerged and may be used to rapidly increase ketone body availability, without the need to first adapt to a ketogenic diet. However, the extent to which ketone bodies regulate skeletal muscle bioenergetics and substrate metabolism during prolonged endurance-type exercise of varying intensity and duration remains unknown. Therefore, at present there are no data available to suggest that ingestion of ketone bodies during exercise improves athletes' performance under conditions where evidence-based nutritional strategies are applied appropriately.

Concepts: Metabolism, Nutrition, Fat, Glycogen, Ketone, Ketone bodies, Carbohydrate, Ketosis

40

Diabetes is a common chronic condition and as of 2015, approximately 30 million persons in the United States had diabetes (23 million with diagnosed and 7 million with undiagnosed) (1). Diabetic ketoacidosis (DKA) is a life-threatening but preventable complication of diabetes characterized by uncontrolled hyperglycemia (>250 mg/dL), metabolic acidosis, and increased ketone concentration that occurs most frequently in persons with type 1 diabetes (2). CDC’s United States Diabetes Surveillance System* (USDSS) indicated an increase in hospitalization rates for DKA during 2009-2014, most notably in persons aged <45 years. To explore this finding, 2000-2014 data from the Agency for Healthcare Research and Quality's National Inpatient Sample (NIS)†were assembled to calculate trends in DKA hospitalization rates and in-hospital case-fatality rates. Overall, age-adjusted DKA hospitalization rates decreased slightly from 2000 to 2009, then reversed direction, steadily increasing from 2009 to 2014 at an average annual rate of 6.3%. In-hospital case-fatality rates declined consistently during the study period from 1.1% to 0.4%. Better understanding the causes of this increasing trend in DKA hospitalizations and decreasing trend in in-hospital case-fatality through further exploration using multiple data sources will facilitate the targeting of prevention efforts.

Concepts: Diabetes mellitus, Diabetes mellitus type 1, Diabetes, Ketone bodies, Hyperglycemia, Ketoacidosis, Diabetic ketoacidosis, Maturity onset diabetes of the young

30

Low-carbohydrate, high-fat diets (ketogenic diets) might prevent tumor progression and could be used as supportive therapy; however, few studies have addressed the effect of such diets on colorectal cancer. An infant formula with a ketogenic composition (ketogenic formula; KF) is used to treat patients with refractory epilepsy. We investigated the effect of KF on cancer and cancer cachexia in colon tumor-bearing mice. Mice were randomized into normal (NR), tumor-bearing (TB), and ketogenic formula (KF) groups. Colon 26 cells were inoculated subcutaneously into TB and KF mice. The NR and TB groups received a standard diet, and the KF mice received KFad libitum. KF mice preserved their body, muscle, and carcass weights. Tumor weight and plasma IL-6 levels were significantly lower in KF mice than in TB mice. In the KF group, energy intake was significantly higher than that in the other two groups. Blood ketone body concentrations in KF mice were significantly elevated, and there was a significant negative correlation between blood ketone body concentration and tumor weight. Therefore, KF may suppress the progression of cancer and the accompanying systemic inflammation without adverse effects on weight gain, or muscle mass, which might help to prevent cancer cachexia.

Concepts: Immune system, Cancer, Oncology, Metabolism, Colorectal cancer, Muscle atrophy, Ketone bodies, Ketogenic diet

28

To explore the relationship between family history of diabetes and frequency of diabetic ketoacidosis (DKA) at diagnosis and to analyze the possible association between HLA genotypes and DKA.

Concepts: Diabetes mellitus, Diabetes mellitus type 1, Diabetes, Ketone bodies, Hyperglycemia, Ketoacidosis, Diabetic ketoacidosis, Maturity onset diabetes of the young

28

To evaluate the effect of a diabetes awareness campaign on the incidence of diabetic ketoacidosis (DKA) at the first presentation of type 1 diabetes in children (0-18 yr).

Concepts: Insulin, Diabetes mellitus, Diabetes mellitus type 1, Diabetes, Ketone bodies, Ketoacidosis, Diabetic ketoacidosis, Maturity onset diabetes of the young

27

A new method for ketone enolate C-acylation is described which utilizes alkyl pentafluorophenylcarbonates, thiocarbonates, and thionocarbonates as the reactive acylating agents, and MgBr(2)·Et(2)O, DMAP, and i-Pr(2)NEt as the reagents for enolization. A wide range of ketones have been observed to undergo clean C-acylation via this protocol.

Concepts: Carbonyl, Ketone, Ketone bodies, Functional groups, Alkane, Aldehyde, Keto-enol tautomerism, Enol