The hypothesis that high multivitamin gestational (HV) diets affect the development of central serotonergic regulatory systems in female offspring, and that this is due to its high folic acid content, was investigated. Dams were fed the AIN-93G diet containing the recommended multivitamin mix (RV), 10-fold the RV amount (HV), or the RV diet with 10-fold the folic acid (Hfol). Serotonergic control of food intake and macronutrient selection was assessed by measuring long-term intake and selection, short-term intake and selection following injections of serotonin receptor agonists, and hypothalamic serotonin receptor expression. Offspring from Hfol dams selected more protein and were less responsive to agonist injections, but showed no altered serotonin receptor expression. In contrast, those born to HV fed dams were not different from the RV controls in any measure. In conclusion, the Hfol, but not HV gestational diet affects serotonergic regulation of food intake in female rat offspring.

Vitamin D plays a critical role in bone metabolism and many cellular and immunological processes, and low vitamin D levels have been associated with several chronic and infectious diseases. Previous studies have reported that many otherwise healthy adults of European ancestry living in Canada have low vitamin D concentrations during the wintertime. However, individuals of non-European ancestry are at a higher risk of having low vitamin D levels. This thesis examined vitamin D status in a sample of young adults of diverse ancestry living in the Greater Toronto Area. In my research I found that: 1) vitamin D levels (measured as 25(OH)D concentrations) are low in Canadian young adults, particularly in those of non-European ancestry; 2) vitamin D intakes, which were estimated to be on average higher than current Health Canada recommendations of 200 International Units (IU) per day, were inadequate to maintain optimal vitamin D levels year-round; 3) vitamin D levels undergo large seasonal changes. Winter 25(OH)D concentrations are substantially lower than those observed during the fall; 4) vitamin D intake is an important year-round predictor of 25(OH)D concentrations, but skin pigmentation and sun exposure are also important predictors during the times when UVB is adequate for cutaneous synthesis; and 5) vitamin D binding protein (VDBP) polymorphisms are significant predictors of 25(OH)D concentrations, but their effects vary by ancestry and season, indicating gene-environment interaction effects. My research shows that higher vitamin D intakes are needed to offset the seasonal drop in vitamin D levels and to ensure adequate vitamin D levels year-round for those at higher risk of insufficiency.

The hypothesis that source of protein in a nutritionally adequate diet during gestation, lactation and weaning alters food intake and characteristics of metabolic syndrome in the offspring was investigated. Pregnant Wistar rats were randomized to either the AIN 93-G casein (C) or soy protein (S) diets (n=12/group) during gestation only or during gestation and lactation. Male offspring in each dams’ diet group were weaned to either C or S diets (n=12/group). Food intake, body weight (BW), fat pad mass, systolic (SBP) and diastolic (DBP) blood pressure, and plasma homocysteine (p<0.05) were higher in offspring born to dams fed the S diet. Fasting blood glucose (BG), BG in response to a glucose gavage and Homeostatic Model of Assessment of Insulin Resistance (HOMA-IR) index were higher only in male offspring born to dams fed the S diet. Moreover, gene expression of Agouti Related Protein (AgRP) was higher in offspring born to dams fed the S diet at weaning. Extending the dams’ diet during gestation and lactation magnified the effect of the gestational S diet on BW and composition and glucose metabolism in male offspring. Although composition of the weaning diets interacted with that of the dams’ diets, the latter was the dominant factor in determining metabolic outcomes in the offspring. In conclusion, the soy protein diet, compared to the casein diet when consumed during gestation or throughout gestation and lactation increased food intake and the presence of characteristics of metabolic syndrome in the offspring.

Vitamin D plays a critical role in bone metabolism and many cellular and immunological processes, and low vitamin D levels have been associated with several chronic and infectious diseases. Previous studies have reported that many otherwise healthy adults of European ancestry living in Canada have low vitamin D concentrations during the wintertime. However, individuals of non-European ancestry are at a higher risk of having low vitamin D levels. This thesis examined vitamin D status in a sample of young adults of diverse ancestry living in the Greater Toronto Area. In my research I found that: 1) vitamin D levels (measured as 25(OH)D concentrations) are low in Canadian young adults, particularly in those of non-European ancestry; 2) vitamin D intakes, which were estimated to be on average higher than current Health Canada recommendations of 200 International Units (IU) per day, were inadequate to maintain optimal vitamin D levels year-round; 3) vitamin D levels undergo large seasonal changes. Winter 25(OH)D concentrations are substantially lower than those observed during the fall; 4) vitamin D intake is an important year-round predictor of 25(OH)D concentrations, but skin pigmentation and sun exposure are also important predictors during the times when UVB is adequate for cutaneous synthesis; and 5) vitamin D binding protein (VDBP) polymorphisms are significant predictors of 25(OH)D concentrations, but their effects vary by ancestry and season, indicating gene-environment interaction effects. My research shows that higher vitamin D intakes are needed to offset the seasonal drop in vitamin D levels and to ensure adequate vitamin D levels year-round for those at higher risk of insufficiency.

The hypothesis that source of protein in a nutritionally adequate diet during gestation, lactation and weaning alters food intake and characteristics of metabolic syndrome in the offspring was investigated. Pregnant Wistar rats were randomized to either the AIN 93-G casein (C) or soy protein (S) diets (n=12/group) during gestation only or during gestation and lactation. Male offspring in each dams’ diet group were weaned to either C or S diets (n=12/group). Food intake, body weight (BW), fat pad mass, systolic (SBP) and diastolic (DBP) blood pressure, and plasma homocysteine (p<0.05) were higher in offspring born to dams fed the S diet. Fasting blood glucose (BG), BG in response to a glucose gavage and Homeostatic Model of Assessment of Insulin Resistance (HOMA-IR) index were higher only in male offspring born to dams fed the S diet. Moreover, gene expression of Agouti Related Protein (AgRP) was higher in offspring born to dams fed the S diet at weaning. Extending the dams’ diet during gestation and lactation magnified the effect of the gestational S diet on BW and composition and glucose metabolism in male offspring. Although composition of the weaning diets interacted with that of the dams’ diets, the latter was the dominant factor in determining metabolic outcomes in the offspring. In conclusion, the soy protein diet, compared to the casein diet when consumed during gestation or throughout gestation and lactation increased food intake and the presence of characteristics of metabolic syndrome in the offspring.

The ‘Blood-Type’ diet advises individuals to eat according to their ABO blood group to optimize health without the support of science evidence. The objective of this study was to determine whether consumption of a diet in accordance with an individual’s ABO genotype is associated with various biomarkers of cardiometabolic health. Study subjects (n=1,455) were participants of the Toronto Nutrigenomics and Health study. Dietary intake was assessed using a one-month, 196-item food frequency questionnaire and a diet score was calculated to determine relative adherence to each of the four blood type diets. ABO blood group was determined by genotyping rs8176719 and rs8176746 in the ABO gene. The results show that adherence to the Type-A, Type-AB, and Type-O diets were associated with favourable profile of certain cardiometabolic risk factors (P<0.05); however, these dietary effects were not dependent on someone’s ABO blood group. Therefore, the findings do not support the “Blood-Type” diet hypothesis

The ‘Blood-Type’ diet advises individuals to eat according to their ABO blood group to optimize health without the support of science evidence. The objective of this study was to determine whether consumption of a diet in accordance with an individual’s ABO genotype is associated with various biomarkers of cardiometabolic health. Study subjects (n=1,455) were participants of the Toronto Nutrigenomics and Health study. Dietary intake was assessed using a one-month, 196-item food frequency questionnaire and a diet score was calculated to determine relative adherence to each of the four blood type diets. ABO blood group was determined by genotyping rs8176719 and rs8176746 in the ABO gene. The results show that adherence to the Type-A, Type-AB, and Type-O diets were associated with favourable profile of certain cardiometabolic risk factors (P<0.05); however, these dietary effects were not dependent on someone’s ABO blood group. Therefore, the findings do not support the “Blood-Type” diet hypothesis

Fatty acid synthase (FAS) is over-expressed in many human cancers and its activity is required for cancer cell survival. To understand why FAS is over-expressed, we compared in breast cancer cells the utilization of fatty acids synthesized endogenously by FAS to those supplied exogenously in the culture medium. We found that endogenously synthesized fatty acids are esterified to the same lipid and phospholipid classes in the same proportions as those derived exogenously and that some endogenous fatty acids are excreted. Thus, FAS over-expression in cancer does not fulfill a specific requirement for endogenously synthesized fatty acids. We next investigated whether lipogenic activity mediated by FAS was, instead, involved in the maintenance of high glycolytic activity in cancer cells. By culturing breast cancer and non-cancer cells in anoxic conditions, we increased glycolysis 2-3 fold but observed no concomitant increase in lipogenesis. More research is needed to understand why FAS is over-expressed in cancer.

La vitamine K fait l’objet d’un intérêt croissant en regard du rôle qu’elle peut jouer dans la santé humaine hormis celui bien établi dans la coagulation sanguine. De plus en plus d’études expérimentales lui confèrent des fonctions dans le système nerveux central, particulièrement dans la synthèse des sphingolipides, l’activation de la protéine vitamine K-dépendante Gas6 et la protection contre les dommages oxydatifs. Toutefois, il demeure beaucoup moins bien établi si la perturbation de ces fonctions peut conduire à des déficits cognitifs. L’objectif principal de cette thèse est de vérifier l’hypothèse selon laquelle le statut vitaminique K des personnes âgées en santé est un déterminant de la performance cognitive. En vue de la réalisation de cet objectif, une meilleure compréhension des indicateurs du statut vitaminique K s’avérait nécessaire. Chacune des études présentées vise donc un objectif spécifique : 1) évaluer le nombre de rappels alimentaires de 24 heures non consécutifs nécessaire pour mesurer l’apport habituel de vitamine K des personnes âgées; 2) évaluer la valeur d’une seule mesure de la concentration sérique de vitamine K comme marqueur de l’exposition à long terme; et 3) examiner l’association entre le statut vitaminique K et la performance cognitive des personnes âgées en santé de la cohorte québécoise NuAge. Trois dimensions cognitives ont été évaluées soient la mémoire épisodique verbale et non-verbale, les fonctions exécutives et la vitesse de traitement de l’information. Cette thèse présente la première étude appuyant l’hypothèse d’un rôle de la vitamine K dans la cognition chez les personnes âgées. Spécifiquement, la concentration sérique de vitamine K a été associée positivement à la performance en mémoire épisodique verbale, et plus particulièrement au processus de consolidation de la trace mnésique. En accord avec les travaux chez l’animal et l’action de la protéine Gas6 dans l’hippocampe, un rôle spécifique de la vitamine K à l’étape de consolidation est biologiquement plausible. Aucune association significative n’a été observée avec les fonctions exécutives et la vitesse de traitement de l’information. Parallèlement, il a été démontré qu’une mesure unique de la concentration sérique de vitamine K constitue une mesure adéquate de l’exposition à long terme à la vitamine K. De même, il a été établi que six à 13 rappels alimentaires de 24 heures sont nécessaires pour estimer précisément l’apport de vitamine K des personnes âgées en santé. Collectivement, les résultats de ces deux études fournissent des informations précieuses aux chercheurs permettant une meilleure interprétation des études existantes et une meilleure planification des études futures. Les résultats de cette thèse constituent une avancée importante dans la compréhension du rôle potentiel de la vitamine K dans le système nerveux central et renforce la nécessité qu’elle soit considérée en tant que facteur nutritionnel du vieillissement cognitif, en particulier chez les personnes traitées par un antagoniste de la vitamine K. / There is an increasing interest in the potential roles of vitamin K in human health aside from the one well established in blood clotting. Notably, a growing number of experimental studies show that vitamin K has biological functions in the central nervous system, particularly in the synthesis of sphingolipids, the activation of the vitamin K-dependent protein Gas6, and the prevention of oxidative damage. However, it remains uncertain whether the disruption of these functions can lead to cognitive deficits. The main objective of this thesis is to test the hypothesis that vitamin K status is a determinant of cognitive performance in healthy older adults. In order to achieve this goal, a better understanding of vitamin K status indicators was needed. Accordingly, three studies are presented each aiming at a specific objective: 1) estimate the number of non-consecutive 24-hour dietary recalls needed to assess usual vitamin K intake; 2) determine whether a single measurement of serum vitamin K concentration is an adequate indicator of long-term vitamin K exposure; and 3) examine the association between vitamin K status and cognitive performance in healthy older adults from the Québec NuAge Study. Three cognitive domains were assessed namely verbal and non-verbal episodic memory, executive functions, and speed of processing. This thesis presents the first study providing support for a role of vitamin K in cognition in older adults. Specifically, serum vitamin K concentration was positively associated with performance in verbal episodic memory, particularly in the consolidation process of the memory trace. Consistent with rodent studies and the action of the protein Gas6 in the hippocampus, a specific role of vitamin K in memory consolidation is biologically plausible. No significant association was observed with executive functions and speed of processing. Additionally, it was established that a single measurement of serum vitamin K concentration is adequate for assessing long-term vitamin K exposure in healthy older adults. Similarly, it was determined that six to 13 24-hour dietary recalls are needed to accurately assess usual vitamin K intake. Collectively, both studies provide valuable information to researchers for better interpretation of existing studies and planning future ones. Results from this thesis constitute an important step in the understanding of the potential role of vitamin K in the central nervous system, emphasizing the need to consider this micronutrient as a nutritional factor of cognitive aging, especially among those treated with vitamin K antagonists.

Previous findings have indicated that oxidative stress plays a role in the development of osteoporosis and that individual polyphenols, by virtue of their antioxidant properties, may mitigate these damaging effects. Nutritional supplements, greens+ bone builderTM, containing polyphenols and other micronutrients beneficial for bone health are of recent interest as complementary strategies in the management of osteoporosis. A randomized controlled study was conducted to explore the combined effects of the nutrients found within the supplement on bone health for 8 weeks. Total polyphenol content and antioxidant capacity increased whereas oxidative stress parameters and the bone resorption marker, crosslinked C-telopeptide of type I collagen decreased after supplementation. There was no significant change in the bone formation marker, procollagen type I N-terminal propeptide. This thesis shows an association of polyphenols with other micronutrients acts through their antioxidant capacity to decrease oxidative stress parameters and bone resorption, thus potentially reducing the risk for osteoporosis.