Le vieillissement de la population est le résultat de l’amélioration de la prise en charge des individus, en particulier des sujets âgés, conduisant à l’apparition d’une nouvelle catégorie démographique, le quatrième âge avec les plus de 75 ans. Cette population polypathologique présente de nombreuses spécificités, avec entre autres, une intolérance au glucose, un état de dénutrition et une altération des fonctions cardiovasculaires, les maladies cardiovasculaires restant la première cause de mortalité dans cette tranche d’âge. Comme évoqué dès les années 50 par Harman, le stress oxydant pourrait jouer un rôle important dans l’ensemble de ces comorbidités. Le resvératrol, un polyphénol anti-oxydant connu pour ses biens-faits cardiovasculaires pourrait ainsi être une molécule d’intérêt dans ce contexte. Nos objectifs dans ce travail ont donc été d’évaluer les effets d’un traitement chronique par le resvératrol accompagné ou non d’une prise en charge nutritionnelle chez la souris très âgée. Ces effets du resvératrol ont été étudiés aussi bien sur le plan métabolique que sur le phénotype cardiovasculaire. Nos résultats montrent qu’un régime riche en protéines et pauvre en glucides a des effets variables en fonction de l’âge. Sans effet sur la souris jeune, il devient délétère chez la souris adulte et très âgée avec une majoration de l’altération de l’homéostasie glucidique associée à une détérioration du bilan lipidique. Ces dysrégulations métaboliques ont pour conséquence une dégradation accrue des fonctions artérielles et cardiaques. Chez la souris très âgée, un traitement par le resvératrol amplifie les dommages liés à ce régime en accentuant les altérations métaboliques et cardiovasculaires, soulignant, et ce pour la première fois, de potentiels effets délétères du resvératrol dans le cadre du vieillissement. En revanche, chez la souris âgée dénutrie en l’absence de prise en charge nutritionnelle, le resvératrol présente des effets bénéfiques avec une amélioration de l’insulino-sensibilité et des fonctions artérielles, associée à une modification d’expression de TXNIP, protéine à l’interface de la régulation de l’homéostasie du glucose et de la balance oxydative, faisant d’elle une piste à explorer tant pour expliquer certains mécanismes impliqués dans le vieillissement que dans les effets du resvératrol. / The aging of the population is the result of the improvement of the care of individuals, especially the elderly, leading to the emergence of a new demographic category, the « fourth age » with people more than 75 years old. This polypathological population has many specificities, with among other things, glucose intolerance, a state of malnutrition and impaired cardiovascular function. Cardiovascular disease remains the leading cause of death in this age group. As mentioned in the 50s by Harman, oxidative stress may play an important role in all of these diseases. Resveratrol, an antioxidant polyphenol known for its properties on cardiovascular events could thus be a molecule of interest in this context. Our objectives in this study were therefore to assess the effects of chronic treatment with resveratrol with or without a nutritional care in the very old mice. These metabolic and cardiovascular effects of resveratrol have been studied. Our results show that a high protein and low carbohydrate diet has different effects depending on age. Despite no effect have been observed on young mice, this diet becomes deleterious in adult and very old mice with an increase of impaired glucose homeostasis associated with a deterioration of the lipid profile. These metabolic dysregulations result in a further deterioration of arterial and cardiac function. In the very old mice, treatment with resveratrol boosts the damage related to this plan by increasing the metabolic and cardiovascular alterations, highlighting, for the first time, potential deleterious effects of resveratrol in aging. However, in elderly malnourished mice in the absence of nutritional care, resveratrol has beneficial effects with improved insulin sensitivity and arterial functions associated with altered expression of TXNIP, protein regulating glucose homeostasis and oxidative balance, making it worth exploring as to explain some of the mechanisms involved in aging and in the effects of resveratrol.

L'encéphalopathie hépatique (EH) est une complication grave de la cirrhose, provoquant des troubles de mémoire, de coordination motrice et de sommeil, avec une progression vers le coma et la mort. Le stress oxydatif dû au foie défaillant et l'ammoniac provenant de la dégradation des protéines alimentaires sont des facteurs pathogènes connus. Simultanément, l'hyperammoniémie et la malnutrition protéino-calorique contribuent à la sarcopénie. Comme les muscles sont le principal mécanisme d'élimination de l'ammoniac pendant la cirrhose, il existe un cercle vicieux où l'hyperammonémie contribue à l'EH et à la sarcopénie, et la sarcopénie contribue à l'hyperammonémie et à l'EH. Notre objectif était de déterminer les effets d’un régime riche en protéines de lactosérum ou de soja administré à long terme, sur la masse musculaire, l'hyperammonémie, et l'EH chez les rats cirrhotiques. Ensuite, nous voulions déterminer les effets d’un gavage aigu de protéines sur l'hyperammonémie et l'EH. Nos résultats montrent qu'un apport élevé en protéines à long terme n'a pas maintenu la masse musculaire ou diminué l'ammoniac, mais que le stress oxydatif a été réduit, ce qui a conduit à la prévention de l'EH, améliorant la mémoire à court et à long terme, l'anxiété, et l'activité locomotrice. Un gavage aigu de protéines chez les rats cirrhotiques n’a pas augmenté l'ammoniac ni précipité l'EH. Cette étude est la première à évaluer l'effet d'un régime élevé en protéines chez des rats cirrhotiques pour observer la masse musculaire, l'ammoniac et l'EH. Nos résultats soutiennent la sécurité et l'efficacité d'une stratégie nutritionnelle riche en protéines dans la cirrhose. / Hepatic encephalopathy (HE) is a serious complication of liver disease, causing impairments in memory, motor coordination, sleep, with progression to coma and death. It affects up to 70% of patients, severely impacting quality of life. Oxidative stress from the failing liver and ammonia from the breakdown of dietary protein are known pathogenic factors. Concurrently, hyperammonemia and protein-calorie malnutrition contribute to muscle wasting, sarcopenia. As muscle is the main clearance mechanism for ammonia during cirrhosis, a vicious cycle exists where elevated ammonia contributes to HE and sarcopenia, and sarcopenia in turn contributes further to hyperammonemia and HE. Our aim was to determine whether long-term high protein whey or soy diets administered from the onset of liver disease in rats could maintain muscle mass, decrease hyperammonemia, and prevent symptoms of HE. Secondly, we wanted to determine the effects an acute load of high protein on hyperammonemia and HE in cirrhotic rodents. Our results show that long-term high protein intake did not maintain muscle mass or decrease ammonia, but oxidative stress was reduced, leading to HE prevention, as shown by the improvement of short- and long-term memory, anxiety, and locomotor activity. An acute load of protein was shown to be safe in cirrhotic rodents, with no increase in ammonia or precipitation of HE. This study is the first of its kind to evaluate the effect of high protein intake in cirrhotic rodents to observe muscle mass, ammonia, and HE. Our results support the safety and efficacy of a high protein nutritional strategy in cirrhosis.

No description available.

Dans l'alimentation des pays industrialisés, l'apport en protéines est bien supérieur à l'apport nutritionnel conseillé (ANC). De plus, cet apport peut être encore supérieur lors de la consommation de régimes riches en protéines utilisés à des fins de perte de poids par des personnes obèses ou en surpoids. Cependant, les conséquences des régimes riches en protéines au niveau de l'écosystème du gros intestin sont encore très mal connues. Dans la première partie de cette thèse, nous avons étudié l'impact d'un régime hyperprotéique sur le microbiote, le contenu endoluminal du gros intestin et le métabolisme des colonocytes. Les rats ont consommé pendant 15 jours soit un régime hyperprotéique (53% de protéines) soit un régime normoprotéique (14% de protéines). Nous avons observé que le régime hyperprotéique réduit la quantité des groupes bactériens majeurs comme Clostridium coccoides et Clostridium leptum, ainsi que Faecalibacterium prausnitzii dans le microbiote du gros intestin avec conjointement des modifications sur sa biodiversité. En même temps, les quantités des produits finaux de la fermentation des acides aminés par le microbiote, les acides gras à chaîne courte (AGCC) et les acides gras à chaîne branchée sont fortement augmentées. Cependant, l'expression des transporteurs des acides monocarboxyliques et l'oxydation du butyrate par les colonocytes ne sont pas modifiés en lien avec des modifications mineures des concentrations en AGCC dues à une augmentation des contenus du gros intestin après l'ingestion du régime hyperprotéique. Il en résulte une augmentation de l'excrétion des AGCC dans les fèces. Ces phénomènes permettraient une homéostasie du métabolisme du butyrate dans les colonocytes, en lien avec le rôle crucial de cet AGCC sur l'épithélium du côlon. Dans la deuxième partie de cette thèse, nous avons testé l'effet d'un mélange d'acides aminés (Thr, Met et Glu) sur la cicatrisation de la muqueuse colique après une colite induite par le DSS (dextran sodium sulfate) ; un modèle d'étude des maladies inflammatoires intestinales souvent utilisé. Une optimisation de la cicatrisation de la muqueuse intestinale émerge comme une cible thérapeutique, dans la prise en charge de ces maladies. La colite a été induite chez le rat avec 5% (w/v) de DSS pendant 6 jours, puis, à l'arrêt du traitement DSS, les animaux ont soit reçu le mélange d'acides aminé soit l'Ala comme témoin iso-azoté, pendant 3, 7 et 10 jours. Nous avons observé que 10 jours de complément en mélange d'acides aminés améliorent la cicatrisation post-colite, avec des modifications sur le taux de synthèse protéique dans la muqueuse colique, sans toutefois modifier la résolution de l'inflammation. Nos résultats suggèrent que l'utilisation des mélanges d'acides aminés améliore la cicatrisation de la muqueuse colique après colite chimio-induite. / In industrialized countries, protein intake is largely higher than the recommended dietary allowance (RDA). Furthermore, high protein diets are used for their slimming effect by obese or overweight people. However, little is known regarding to the consequences of a high protein diet on the large intestinal ecosystem. We thus study the influence of a high protein diet on the microbiota, on the endoluminal composition of the large intestine and on the butyrate metabolism by isolated colonocytes. Rats received during 15 days either a high protein diet (53% of proteins) or a normo protein diet (14% of proteins). We observed that the quantity of major bacterial groups Clostridium coccoides and Clostridium leptum, but also Faecalibacterium prausnitzii was reduced in the microbiota of the large intestine together with modifications of its biodiversity. In the same time, the quantities of short-chain fatty acids (SCFA) and branched-chain fatty acids, final products of bacterial fermentation of amino acids, were increased. However, the expression of monocarboxylic acid transporters and butyrate oxidation in colonocytes remained unchanged, in association with minor changes of the SCFA concentrations due to marked increase of the weight of the large intestine content. We then observed an increase in the amount of SCFA in the feces. These phenomena would allow homeostatic metabolism of butyrate in colonocytes, in relationship with its crucial role on the colonic epitheliumIn. In the second part of this thesis, we have tested the effects of a mixture of amino acids (Thr, Met and Glu) on the colonic mucosa healing after colitis induced by DSS (dextran sodium sulphate); a model to study intestinal inflammatory bowel diseases largely used. Optimization of intestinal mucosa healing is more and more considered as a therapeutic goal. Colitis was induced in rats by 5% (w/v) DSS during 6 days, then at the end of the treatment with DSS, animals received either the amino acid mixture or Ala as iso-nitrogenous control, during 3, 7 or 10 days. We observed that 10 days amino acid mixture supplementation was able to improve the colonic mucosal healing, with modification of the protein synthesis rate, without however changes in the resolution of inflammation. Our results suggest that the supplementation with the amino acid mixture improve the mucosal healing after experimental colitis.

Metabolic syndrome (MetS) and abdominal obesity (AbOb) increase the risk of developing cardiovascular disease and diabetes. Energy restriction (ER), highprotein (PRO) intake and high-intensity interval training (HIT) can independently improve MetS and AbOb. However, ER reduces metabolically active lean body mass (LBM) in addition to body fat (BF). Purpose: To determine the effects of a 16-wk ER diet with 2 levels of PRO (15% or 25% of energy), plus HIT, on MetS risk factors, AbOb, and body composition in women. Methods: Sedentary, premenopausal women (age=35±10y) with AbOb (waist circumference [WC] ≥80cm) were randomized to a 16-wk ER diet (-300kcals/d) with 15% (15PRO; n=17) or 25% (25PRO; n=18) of energy from PRO, plus 45min/d, 3d/wk HIT and 45min/d, 2d/wk continuous moderate-intensity exercise (CME) (-200kcals/d). Diet and physical activity (PA) were assessed using 4-d weighed food and PA records, respectively; diet and exercise compliance were assessed monthly with multiple-pass 24-h recalls and weekly tracking logs. Body weight (BW), WC, DXA-assessed body composition (BF [%], BF [kg], trunk fat [kg], and LBM [kg]), blood lipids (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], triglycerides [TG]), glycemic markers (fasting plasma glucose [FPG], insulin, and homeostatic model assessment for insulin resistance [HOMA-IR], beta cell function [HOMA-%β] and insulin sensitivity [HOMA-%S]) and resting blood pressure (BP) (systolic BP [SBP]; diastolic BP [DBP]) were assessed pre/post-intervention. Repeated measures analysis of variance and two sample t-tests were used at analyze the date. Results are reported as means±standard deviations. Results: There were significant time, but not group, differences in BW (-5.1±2.6kg, p=0.0141), WC (- 7.3±3.6cm, p<0.0001), TC (-18.1±17.4mg/dL, p<0.0001), LDL-C (12.2± 16.2mg/dL, p<0.0001), TG (-25.3±56.2mg/dL, p=0.0064), insulin (-2.1±4.2mg/dL, p=0.0048), HOMA-IR (-0.2±0.5, p=0.0062), HOMA-%β (-12.1±35.2%, p=0.0497), HOMA-%S (28.5±78.4%, p=0.0357), and SBP (-3±9mmHg, p=0.214). There were significant group x time differences in DBP (15PRO=-5±8mmHg, 25PRO=- 2±8mmHg; p=0.0024). There were no time or group differences in FPG or HDLC. There were significant time, but not group, effects on changes in BW (-5.1kg± 2.6, p<0.0001), BF (-3.3±1.6%, p<0.0001), and LBM (-0.6kg±1.5, p=0.0283). The 15PRO group lost more absolute whole BF (-5.2kg vs. -3.9kg, p=0.0355) and trunk fat (-3.1kg vs. -2.2kg) vs. the 25PRO group. Conclusion: Both diets significantly improved BW, AbOb, MetS risk factors, glycemic control, and BF (%); LBM (kg) loss was similar in both groups. Compared to the 15PRO diet had significantly greater absolute BF-kg and trunk fat-kg losses. Increased PRO intake did not improve AbOb or MetS risk beyond ER and HIT/CME. The impact of HIT/CME and the greater (-1.3kg) changes in BW in the 15PRO group may have contributed significantly to the changes in absolute BF and trunk fat. More research is needed to separate the impact of HIT/CME and weight loss from the impact of PRO during ER. / Graduation date: 2013 / Access restricted to the OSU Community at author's request from March 28, 2013 - March 28, 2014

Intermittent fasting (IF) is a recently popularized meal timing strategy whereby individuals abstain continuously from any energy intake for 16 to 20 hours each day, subsequently condensing energy intake into a short period spanning 4 to 8 hours. We aimed to test the effects of intermittent fasting in 10 individuals with Type 2 Diabetes Mellitus in conjunction with recommendations to consume a high protein diet in a 6 to 8 week withdrawal study. This study consisted of three phases: baseline, intervention, and follow-up. During the 2-week baseline and intervention phases participants consumed meals at regular times. Biochemical, anthropometric, and physical activity measurements were taken at the end of each phase. Participants reported morning, afternoon and evening self-monitored blood glucose and fasting duration on a daily basis, in addition to completing a remote food photography diary three times within each study phase. Despite the short duration of the intervention phase, intermittent fasting led to significant decreases in weight, BMI, morning SMBG, and overall reductions in waist circumference, C-reactive protein, energy intake, carbohydrate intake, and fat intake. There were significant variations between participants in response to intermittent fasting in respect to changes in lipids and insulin sensitivity, which could not be explained by baseline biochemical or anthropometric measures, fasting duration, energy intake, or physical activity. Upon cessation of intermittent fasting, biochemical changes regressed towards baseline values during the follow-up period. Intermittent fasting was well tolerated by most participants, and no severe adverse events were noted. Morning nausea was the most common complaint, which abruptly ceased when medication timing was changed.

Background: Higher protein diets, especially from animal sources, have seen a rise in popularity due to potential metabolic. This may have consequences for kidney function particularly in rising middle class populations who are allocating more income towards meat. The objective of this systematic review and meta-analysis was to evaluate the effects of higher versus lower protein intake on glomerular filtration rate (GFR) in adult populations without renal impairment. Methods: Search strategies were developed and electronic databases searched: MEDLINE and EMBASE. Data were extracted up until June 3, 2015. The main outcome measure was GFR and a random effect model (Cochrane’s Review Manager Version 5.3) was used to pool mean differences in GFR values. Results: Database searches yielded 25 trials from 1914 articles that were eligible for analysis based on inclusion/exclusion criteria. 12 studies were randomized controlled trials and 11 studies were crossover trials. As a result of data presented, 2 crossover studies were treated as 4 trials to result in 25 total trials. A total of 810 subjects from 25 trials were included in this systematic review and meta-analyses. The age of participants was 24-62 years and their BMI was 21-36 kg/m2. Higher protein compared to lower protein-containing diets were associated with increased GFR values [mean difference (MD): 8.33 ml/min (95% CI 4.87 to 11.79), P < 0.00001] but this was less pronounced when assessing change from baseline GFR values [MD: 4.71 ml/min (95% CI 0.06 to 9.36), P = 0.05]. Moreover, significant heterogeneity was present and funnel plot asymmetry indicated potential publication bias in both meta-analyses. Conclusion: Higher protein diets were associated with increased GFR, however, these results were inconclusive due to significant heterogeneity and overestimation by random effect analyses. There is still no clear evidence that high protein diets negatively impact renal function in healthy populations. / Thesis / Master of Science (MSc) / Globally, the leading causes of mortality in industrialized countries are cardiovascular disease (CVD), stroke, and type 2 diabetes (T2D). Deaths from these chronic diseases now outpace deaths due to malnutrition. Being overweight and obese increases the risk of both morbidity and mortality from CVD, stroke, and T2D. Global rates of overweight and obesity have now reached ‘epidemic’ proportions and the World Health Organization has stated that, “… [a] global epidemic of overweight and obesity – ‘globesity’ – is taking over many parts of the world. If immediate action is not taken, millions will suffer from an array of serious health disorders.” Over the past 20-30 years, the popularity of higher protein energy restricted diets have grown due to the potential benefits regarding weight loss, appetite regulation, and maintenance of lean (muscle) mass. Additionally, the expansion of the global ‘middle-class’ has resulted in families allocating more income towards meat products as a primary protein source in their diet. A health concern is that higher protein intake may have an adverse effect on kidney function. In individuals with chronic kidney disease, higher protein diets have been shown to result in further renal impairment. However, the effects of increased protein intake in healthy populations are unclear. The aim of this systematic review and meta-analysis was to compare higher versus lower protein diets on kidney function in healthy populations based on the literature to date. This was accomplished by looking at changes in glomerular filtration rate (the rate at which kidneys filter blood), which is the ‘gold standard’ marker of kidney function.

Weight gain due to poor diet and lack of exercise is responsible for over 300,000 deaths each year (U.S. Department of Health and Human Services, 2010). Obese adults have an increased risk for serious health conditions including high blood pressure and cholesterol, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea, respiratory problems, and certain cancers (National Cancer Institute, 2012). Participation in exercise can help control weight, strengthen muscles and bones, and reduce the incidence of cardiac events, stroke, hypertension, type 2 diabetes, colon and breast cancers, osteoporotic fractures, gallbladder disease, obesity, depression, anxiety, and delay mortality (ACSM, 2009). The purpose of this study was to determine the effectiveness of exercise participation during weight loss on a high protein-low carbohydrate diet plan during a 12-week span in females aged 15 to 25 years. Specifically, this research study was a comparison of markers of health such as weight, fat mass, percent body fat, and fat-free mass in females who consistently exercised during the diet (Exercisers) from those who did not participate in consistent exercise (Non- Exercisers). The population in this study was selected due to the transition from high school to college being a critical period because it is associated with many identity choices and lifestyle changes that can lead to weight gain (Anderson, Shapiro, & Lundgren, 2003). The data indicate participation in regular exercise, while consuming a high protein-low carbohydrate diet plan, increases the loss of body weight, fat mass, and percent body fat when compared to participating in the diet plan alone. There was no significant difference in fat-free mass reduction between the groups. One implication for practice is recommending moderate to vigorous exercise for a minimum of 30 minutes at a time, totaling a minimum of 150 minutes per week, for females trying to achieve weight loss. Based from the results of this research study, in order to achieve a greater amount of body weight, fat mass, and percent body fat reduction one should consider incorporating exercise participation and high protein-low carbohydrate dieting into their weight loss plan.