An increasing amount of people have their work hours displaced to the night and there are indications that shift work and other irregular working schedules are associated with an increased risk of developing the metabolic syndrome and other pathological conditions. It is therefore important to address the consequences of eating at irregular hours, especially nighttime. Papers I-III refer to a study in which 7 males were given a high-carbohydrate diet (HC) or a high-fat diet (HF), using a cross-over design. Subjects were kept awake for 24 h and food was provided as 6 equally spaced isocaloric meals. Higher energy expenditure and non-esterified fatty acids (NEFA) concentration, as well as lower glucose and triacylglycerol (TAG) concentrations were observed with the HF-diet, compared to the HC-diet. With the HF-diet, fat oxidation, heat release, heart rate, glucose, NEFA and TAG concentrations differed depending on time of day. The highest postprandial TAG concentrations were seen after the 04.00 meal with both diets. Insulin and leptin responses to meal intake differed with respect to diet and time of day. Time of day affected glucagon, thyroid stimulating hormone, free thyroxin, total triiodothyronine (tT3), cortisol, chromogranin A and pancreatic polypeptide (PP) concentrations. PP’s postprandial increase was greater during 08.00 – 16.00 compared to 20.00 – 08.00. Furthermore, the subjects felt less irritated when eating the HF-diet but hunger was not related to macronutrient composition. Hunger and thirst decreased throughout the 24 h period despite constant activity and energy intake; and were correlated with several endocrine and metabolic variables. In paper IV 7 males were studied twice during 24-h either given 6 isocaloric meals throughout the 24-h period, or 4 isocaloric meals from 08.00 to 20.00, followed by a nocturnal fast. Energy expenditure, glucose, TAG, insulin and glucagon concentrations were lower; and NEFA concentrations were higher during the nocturnal fast compared to nocturnal eating; although no 24 h differences between the protocols were apparent. The subjects were more passive during the fasting period compared to when food was given. Stepwise regression showed that correlations between metabolic variables and hormones differed between daytime and nighttime. The decreased evening/nocturnal responses of cortisol and PP to meal intake suggest that nocturnal eating might have health implications and that the body reacts unfavorably to nocturnal eating. Smaller meals around the clock, however, showed marginally better effects on postprandial TAG concentrations and mental energy compared to larger meals during daytime. Further studies (long term) are needed before dietary guidelines can be given to shift workers, especially regarding the impact of nocturnal eating on gastrointestinal response and cortisol.

Ovarian cancer is the fifth leading cause of all cancer deaths in women and the most lethal gynecologic cancer in the United States. During metastasis, cancer cells exfoliate from the primary tumor and aggregate to form spheroids, enhancing their survival within the peritoneal cavity during dissemination to a secondary outgrowth site. The inability of removal of these aggregates by traditional surgical interventions may contribute to the high recurrence and mortality rate of ovarian cancer diagnosed at late stages. Obesity, particularly abdominal obesity, has been shown to increase ovarian cancer risk and decrease survival. The recruitment of stromal vascular fraction (SVF) present in adipose tissue represents a growth and proliferation advantage to ovarian tumors, and endogenous sphingolipids like sphingosine-1-phosphate are increased in ovarian cancer patients. These conditions, combined with the physiological conditions within malignant ascites (hypoxia and low glucose), represent a physiological environment that can impact the metabolic responses of ovarian cancer spheroids. Here, we investigated the metabolic adaptations of serous ovarian cancer cells across the metastatic cycle and in conditions that mimic those of the peritoneal cavity and malignant ascites. We first investigated the different in metabolic responses between adherent monolayers and 3D spheroids. We confirmed that spheroids have a reduced metabolic rate and drug response that is affected by the incorporation of obese SVF into aggregates. To investigate these changes in the next stages of the metastatic cycle, we used time trials to observe how adherence of spheroids to a secondary site changes metabolic response and substrate utilization in physiological conditions. Adhesion of spheroids showed changes in energy metabolism and substrate utilization, switching from mainly glutamine oxidation to glucose oxidation that could support successful outgrowth. Spheroids also were resilient to culture conditions, even non-permissive conditions such as those found in the peritoneal cavity. Finally, we utilized human malignant ascites from ovarian cancer patients as a further investigation into conditions that imitate in vivo characteristics that could affect spheroid metabolism. Exposure to malignant ascites reduced spheroid viability as well as basal respiration and ATP synthesis. However, spare respiratory capacity was increased, and human spheroids changed their substrate utilization in response to ascites. Taken together, these studies provide an identification of metabolic switches across different stages of ovarian cancer metastasis that contribute to their survival, which represents an emerging target for prevention and treatment for individuals with ovarian cancer. / Doctor of Philosophy / Ovarian cancer is the deadliest reproductive cancer in women, and most women who are diagnosed will die from the disease because of its high recurrence rate and because it is typically detected at late stages. When ovarian cancer metastasizes, cells or cell clusters from the original tumor aggregate together to form balls of cells called spheroids, which move through the abdominal cavity to other sites to grow additional tumors. These spheroids are thought to contribute to recurrence of this cancer, since they cannot be removed by surgery. As these spheroids move through the abdominal cavity, they are exposed to an environment that has a low amount of oxygen and glucose. These spheroids may also be exposed to bioactive lipids and cells from the adipose tissue called stromal vascular fraction, both of which are related to obesity and may help cancer spheroids survive. The survival of these spheroids is in part related to how their metabolism functions, which may help them make energy and the building blocks needed to continue growing and form successful secondary tumors. Identifying how these spheroids change their metabolism at different points during the disease may help identify points that can be targeted to prevent changes in metabolism that could support their growth. This dissertation identified metabolic changes that occur in spheroids, in conditions that are similar to those spheroids would be exposed to in an abdominal cavity. First, we compared single layers of cells to spheroids and found that spheroids had a lower metabolic rate and lower drug response, which may help them survive in the abdominal cavity. Next, we allowed the spheroids to lay down and grow out, like they would when they found a new location during metastasis, to see how their metabolism changed and what substances they used to make energy in conditions that mimicked the abdominal cavity. As spheroids adhered, they changed their energy metabolism and switched the substances they used to make energy, all while continuing to survive and grow out even in conditions that were not supportive. These switches could help them grow out and successfully metastasize. Lastly, we used ascites fluid from human ovarian cancer patients and treated spheroids with this to see how their metabolism changed in response. While some aspects of metabolism and survival was reduced, their ability to increase their metabolism when stressed increased and human spheroids used nutrients to make energy differently. Overall, we show that across the stages of metastasis, ovarian cancer spheroids can change their metabolism in response to their environment. Identifying these metabolic switches helps us understand how successful metastasis happens, and can inform future targets to slow or prevent metastasis, prolonging the life of women who have been diagnosed with ovarian cancer.

abstract: ABSTRACT Vitamin C plays an important role in fatty acid metabolism because it is required for carnitine synthesis. Vitamin C has been shown to have an inverse relationship with weight and body fat percent in a number of studies. However, there has been limited research exploring the relationship between vitamin C status and fat oxidation. This cross-sectional study investigates the relationship between plasma vitamin C and fat oxidation in 69 participants and between plasma vitamin C and body fatness in 82 participants. Participants were measured for substrate utilization via indirect calorimetry while at rest and measured for body fatness via DEXA scan. Participants provided a single fasting blood draw for analysis of plasma vitamin C. Results did not show a significant association between vitamin C and fat oxidation while at rest, therefore the data do not support the hypothesis that vitamin C status affects fat oxidation in a resting state. However, a significant inverse association was found between vitamin C and both total body fat percent and visceral fat. / Dissertation/Thesis / M.S. Nutrition 2014

There is a common belief that children compared with adults are at a greater risk for exercise-induced heat illness. However, a limitation of previous studies involves different exercise intensities used in the comparison between children and adults. Dehydration impairs aerobic performance, but its effects on strength are not well understood. Sports drinks are often used as ergogenic aids. There is some evidence to suggest children have a greater reliance on exogenous carbohydrate compared to adults, which could require special considerations when children exercise in the heat. The overall purpose of this thesis was to compare physiological and metabolic responses during exercise in the heat between boys and men. Three studies were conducted to 1) compare the thermoregulatory responses of boys and men exercising in the heat at a fixed absolute metabolic heat production or a fixed metabolic heat production per unit of body mass; 2) compare the effects of 2% hypohydration or, euhydration with and without carbohydrate ingestion during exercise in the heat on subsequent strength in boys and men; and 3) examine the effects of exogenous carbohydrate on endogenous metabolism in boys and men exercising in the heat. Age and body size differences between boys and men did not influence thermoregulatory responses at a fixed metabolic heat production per unit of body mass. No differences in strength were observed among trials. When exercising in the heat, the relative contribution of ingested carbohydrate and endogenous substrate to total energy yield were not different between groups. These findings together have practical implications for boys and men who exercise in the heat. Specifically, moderate exercise in the heat is equally safe for boys and men. The effects of hypohydration and a carbohydrate drink compared to water on muscle strength performance following exercise in the heat are minimal. An important practical application is that carbohydrate intake spared endogenous fuels during exercise in the heat in both groups. / Thesis / Doctor of Philosophy (PhD) / Children may not adapt to temperature extremes as effectively as adults. Thermoregulatory differences may be due to variable exercise intensities prescribed in available child-adult comparisons. Dehydration affects aerobic performance, but its effects on strength are not well understood. Sports drinks are often used to offset dehydration and improve performance; however, the body may have a harder time using sugar drinks when exercising in the heat. The purpose of this thesis was to compare bodily responses of boys and men during exercise in the heat. Our findings have important practical implications for boys and men who exercise and play sports in hot temperatures. Specifically, exercise in the heat is equally safe for boys and men. The effects of hypohydration and a sports drink on muscle strength performance following exercise in the heat are minimal. Finally, although exercise in the heat may affect the use of a sugar drink, boys and men may use this drink to improve aerobic performance, while maintaining hydration levels.

No description available.

L’utilisation du glucose exogène est un déterminant de la performance sportive, particulièrement lors d’épreuves de plus d’une heure. Les caractéristiques des sujets, les conditions d’exercice et d’ingestion du glucose sont tous des facteurs pouvant affecter l’oxydation de glucose exogène (OGE). De plus, la co-ingestion d’autres substrats et l’environnement dans lequel l’activité est pratiquée peuvent également avoir un impact sur l’OGE et sa contribution à la fourniture d’énergie. Il est souvent difficile, voire impossible, de comparer les résultats des études qui ont examiné l’OGE due au manque d’uniformité dans la méthodologie. Afin de clarifier l’effet de ces facteurs sur le taux d’OGE, ainsi que sa contribution à la fourniture d’énergie lors de l’exercice prolongé, une revue de littérature et une méta-analyse ont été effectuées. Le sexe, l’âge, la masse corporelle, le VO2max des participants, le moment d’ingestion, le taux d’ingestion, la concentration de la solution, la puissance absolue et relative de l’exercice, et la durée de l’exercice ont été utilisés comme modérateurs. Les facteurs pouvant influencer le taux d’OGE et sa contribution à la fourniture d’énergie pendant l’exercice prolongé rapportés dans cette méta-analyse confirment une relation dose-réponse curvilinéaire. D’autres facteurs, tels le VO2 et le %VO2max de l’exercice, ainsi que le moment d’ingestion, permettent également d’expliquer la relation observée dans le taux d’oxydation exogène et sa contribution à la fourniture d’énergie. La grande majorité des études ayant été effectuées sur une population restreinte (hommes sportifs ou en santé, âgés entre 20 et 30 ans), davantage de travaux sont nécessaires chez les femmes et les sujets d’âge et de masse corporelle différents afin d’éviter les biais d’interprétation dus à au sexe ou aux caractéristiques physiques. Les résultats de cette méta-analyse pourront aider à améliorer les recommandations sur l’ingestion de glucides au cours de l’exercice prolongé. / Exogenous glucose oxidation is a determinant of sports performance especially in activities lasting over 1 hour. Many factors concerning the subjects, the substrate and the exercise itself could influence the capacity of the human body to oxidize exogenous glucose. Furthermore, the co-ingestion of other substrates, as well as the environment in which the activity is performed, could also influence the rate of exogenous glucose oxidation (EGO) and its contribution to the energy yield. The lack of uniformity in methodologies used to investigate EGO makes it very difficult, and in some cases even impossible, to make direct comparisons between study results. In an attempt to shed some light on the impact of those various factors on the rate of EGO and its contribution to the energy yield, the literature was reviewed and a meta-analysis was done. The sex, age, body mass, VO2max, timing of ingestion, rate of ingestion, solution concentration, exercise’s absolute and relative intensity, and exercise duration were used as moderators. Many factors can contribute to EGO and its contribution to the energy yield and the results from this meta-analysis confirm a dose-response relationship. Additional factors, such as exercise VO2 or %VO2max, and ingestion timing also have a significant effect. Further studies might be needed with women and subjects with different age and body mass to avoid bias due to an unbalanced number of studies when comparing subject characteristics. These results should help improve nutritional recommendations for carbohydrate ingestion during prolonged exercise.

La production endogène ou la prise exogène d’hormones sexuelles chez la femme génère un climat hormonal qui lui est propre. Ces particularités endocriniennes influent sur la composition corporelle et modifient les sécrétions et/ou la sensibilité de certaines hormones clés du métabolisme énergétique pouvant conduire à une utilisation spécifique des substrats énergétiques à l’exercice. L’objectif de ce travail était d’étudier l’influence d’une contraception orale (CO : mini dosée monophasique), de la prise alimentaire pré-exercice et de la localisation des graisses sur les réponses métaboliques et hormonales de la femme préménopausée et normo-pondérée à l’exercice (45 min à 65% de O2max). Nos résultats ont montré que la prise d’une CO ne modifiait pas les réponses métaboliques et hormonales et l’utilisation des substrats énergétiques à l’exercice quel que soit le statut nutritionnel des sujets (exercice à jeun ou en situation postprandiale). Cependant, à l’exercice, une situation de jeûne a favorisé une augmentation de l’oxydation lipidique et cela quel que soit le statut hormonal des sujets (CO+ ou CO-). En situation postprandiale, l’exercice physique a stimulé l’activité lipolytique chez des femmes CO+ et CO- sans distinction entre les deux groupes. Enfin, quand l’utilisation des substrats énergétiques à l’exercice est appréhendée en fonction du rapport de la masse grasse abdominale/masse grasse des membres inférieurs (A/MI), nos travaux ont montré une augmentation de la mobilisation et de l’oxydation des lipides chez les femmes présentant un plus faible rapport A/MI (malgré des masses corporelles et des tours de taille normaux). Ainsi, au sein d’une population féminine normo-pondérée, les CO minidosées monophasiques ne semblent pas influer sur l’utilisation des substrats énergétiques à l’exercice, alors que la prise alimentaire pré-exercice et la localisation des graisses semblent avoir un impact plus important sur le métabolisme énergétique à l’exercice. / In the female population, sexual hormones (endogen production or exogenous consumption) induce particular hormonal status leading to specific body composition and metabolic and hormonal responses at rest and during exercise. The aim of this work was to determine the influence of oral contraception (low dose monophasic combined OC), pre-exercise food intake and body fat mass localization on metabolic and hormonal responses during exercise (45 min at 65% of O2max) in normal weight premenopausal women. Our results showed that OC did not alter substrate mobilization and oxidation during exercise (in fast and postprandial conditions). However, during exercise performed in fast condition, women exhibited greater lipid oxidation rates whatever their hormonal status (OC+ vs OC-). In postprandial condition, exercise increased lipolytic activity in OC+ and OC- women without differences between both groups. Finally, it has been observed that abdominal to lower body (A/LB) fat mass ratio influenced substrate mobilization and oxidation in premenopausal women with normal weights and waist circumferences. Subjects with a lower ratio exhibited greater lipid mobilization and oxidation than those with a higher ratio. Therefore, in normal weight women, low dose monophasic combined OC do not appear to influence substrate oxidation whereas pre-exercise food intake and body fat mass localization may have an important impact on substrate metabolism during exercise.

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Student: Terezie Poláková Supervisor of master thesis: PharmDr. Miroslav Kovařík, Ph.D. Title of master thesis: Assessment of energy metabolism in patients with chronic obstructive pulmonary disease. Chronic obstructive pulmonary disease (COPD) is the name for lung disease with systemic consequences. Besides the respiratory symptoms there are also described changes in body metabolism, which could lead to the development of serious metabolic syndrome called cachexia. The main aim of this study was to compare the resting energy expenditure (REE) and nutrition substrate utilization in 12 patients with advanced form of COPD from the Czech Multicentre Research Database of COPD (5 females and 7 males, mean age 68 ± 6 years) and in 9 patients of control group without respiratory impairment (5 females and 4 males, 62 ± 4 years). Assessment of body metabolism was determined by method of indirect calorimetry. Measured REE was then compared with prediction based on Harris-Benedict equation. The utilization of main nutrition substrates was determined from the respiratory quotient and urea nitrogen loss in urine. We found that measured REE in COPD patients was about 20 % higher than in control group....