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Les bétaïne lipides (BL) sont des lipides polaires qui se distinguent des phospholipides (PL)par l’absence de phosphore (P). La réorientation métabolique induite par une limitation en P chez des microalgues produisant des BL (Tisochrysis lutea et Diacronema lutheri, Haptophytes) ou en produisant peu (Phaeodactylum tricornutum, Bacillariophyte) a été comparée à celle induite par une limitation en azote (N). Le devenir et le flux de carbone dans différentes voies de biosynthèse ont été étudiés par une approche pluridisciplinaire.La limitation nutritive en P ou en N affecte différemment le métabolisme du carbone selon les espèces microalgales. La limitation en P réduit fortement l’activité photosynthétique et la respiration chez P. tricornutum et T. lutea. Par conséquent, l’accumulation de carbone est plus élevée que sous limitation en N chez ces deux espèces. Les deux limitations stimulent en particulier la synthèse des lipides neutres et / ou des glucides. Le remplacement des PL par les BL a été observé chez P. tricornutum en condition de limitation en P. Ce résultat est en accord avec une augmentation de la transcription du gène codant la bétaïne lipide synthase. En revanche, cette limitation ne modifie pas les teneurs en BL rapportées au carbone chez T. lutea et D. lutheri. La composition en acides gras des différentes classes lipidiques est modifiée selon l’espèce microalgale et l’élément nutritif limitant. Une attention particulière a été portée aux acides gras de la série oméga-3, notamment l’acide eicosapentaénoïque (EPA, 20:5 ω3) et l’acide docosahexaénoïque (DHA, 22:6 ω3) dont les proportions varient en fonction de l’élément limitant,de l’espèce et de la classe lipidique. L’augmentation de la production des lipides neutres et / ou des lipides polaires, notamment des bétaïne lipides, riches en DHA et/ou EPA induite par un stress nutritif laisse envisager une valorisation de ces molécules d’intérêt dans différents domaines dont la nutrition et la santé. / Betaine lipids (BL) are P-free polar lipids, conversely to phospholipids (PL). The metabolic reorientation induced by phosphorus (P) limitation in microalgae producing BL (Tisochrysis lutea and Diacronema lutheri, Haptophyta) or producing low levels of BL (Phaeodactylum tricornutum, Bacillariophyta) was compared to that induced by nitrogen (N) limitation. The carbon destiny and flow in different biosynthetic pathways were studied with a multidisciplinary approach. P or N limitation differently affected carbon metabolism according to microalgal species. P limitation highly decreased photosynthetic activity and respiration of P. tricornutum and T. lutea. Consequently, carbon accumulation was higher than under N limitation in these two species. Both limitations stimulated the synthesis of neutral lipids and / or carbohydrates. Replacement of PL by BL was observed in P. tricornutum under P limitation. This result is in agreement with a transcription increase of the gene encoding BL synthase. On the other hand, this limitation did not modify BL contents in reference with carbon in T. lutea or D. lutheri. Fatty acid composition of the different lipid classes was modified according to the microalgal species and the limiting nutrient. Particular attention was paid to the fatty acids of the omega-3 series, notably eicosapentaenoic acid (EPA, 20:5 ω3) and docosahexaenoic acid (DHA, 22:6 ω3), the proportions of which vary according to the limiting element, species and lipid class. The increase in the production of neutral lipids and / or polar lipids, especially betaine lipids, rich in DHA and / or EPA induced by nutritive stress suggests a valorization of these molecules of interest in various areas including nutrition and health.

This thesis concerns the role of nutrients in cognitive and behaviour problems associated with child attention deficit hyperactivity disorder (ADHD). Study 1 investigated relationships between Conners' ADHD Index ratings, fatty acid deficiency symptoms (FADS), and cognitive performance in a normal population of children. Studies 2 and 3 comprised a 30 week intervention trial investigating effects of n-3 PUFA supplementation on ADHD symptoms in 7-12 year old children with high ADHD scores.

Obesity is a major health problem in the United States and worldwide. It increases the risk for type-2 diabetes and cardiovascular diseases. A chronic low-grade inflammation occurring in white adipose tissue (WAT) is causally linked to the development of insulin resistance (IR), metabolic syndrome and obesity-associated chronic diseases. The aim of this dissertation research was to elucidate the WAT function in metabolic syndrome using genetic (overexpression of an adipose pro-inflammatory hormone, angiotensinogen) and nutritional manipulations/approaches (caloric restriction and omega-3 fatty acids), with specific emphasis on the role of inflammation. Previous research indicates that WAT renin-angiotensin system (RAS) is overactivated in obesity. However, its role in the pathogenesis of IR is hitherto unknown. Using mice overexpressing angiotensinogen (Agt), the only precursor for the hypertensive hormone angiotensin (Ang) II, in WAT, we showed that adipose-specific RAS overactivation leads to systemic IR. This is at least in part due to Ang II, NADPH oxidase and NF-kB-dependent increases in WAT inflammation. Caloric restriction is the main dietary intervention to treat obesity-associated metabolic disorders. While most health agencies recommend a low-fat diet, energy-restricted high-fat diets (HFR) are also claimed to be effective in this regard. Here, we show that weight loss due to HFR is accompanied by improvements of IR but only partial resolution of WAT inflammation. Further, this diet negatively impacted the adipokine profile supporting the current recommendations for low-fat diets. Dietary interventions targeted at reducing WAT inflammation have not been explored in detail. Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid of marine origin with anti-inflammatory properties. We show that EPA is able to both prevent and reverse high-fat diet-induced IR and hepatic steatosis via modulation of WAT inflammation. In conclusion, primary changes occurring in WAT, such as overexpression of Agt, can lead to WAT inflammation and systemic IR. Moreover, nutritional interventions targeting at reducing adiposity (caloric restriction) and inflammation (EPA) can both lead to improvements in systemic IR. Our findings support the current recommendation of low-fat diets for improvement in metabolic profile and show that dietary modulation of WAT function can be used to improve metabolic derangements in obesity.

Colon cancer is one of the most commonly diagnosed cancers in the US, yet small intestine cancer is a rare event. While there are many similarities between these two tissues, inherent differences such as redox status, may contribute to the variation in cancer occurrence. We examined the difference in reactive oxygen species (ROS) generation, antioxidant enzyme activity and oxidative DNA damage in the small and large intestine of rats under normal conditions and following exposure to exogenous oxidative stress. Basal ROS and antioxidant enzyme activities were greater in the colon than the small intestine, and the balance of ROS to antioxidant enzymes in the colon was more pro-oxidant than in the small intestine. During oxidative stress, ROS and oxidative DNA damage were greater in the colon than the small intestine. Thus the colon responds to oxidative stress less effectively than the small intestine, possibly contributing to increased cancer incidence at this site. We next wanted to understand how diets containing a combination of fish or corn oil and pectin or cellulose may alter the redox environment of the colon. ROS, oxidative DNA damage, antioxidant enzyme activity and apoptosis were measured in colonocytes of rats fed one of four diets containing either corn oil or fish oil and cellulose or pectin. Measurements were madein rats untreated with carcinogen and rats exposed to a chemical carcinogen and radiation. In rats not treated with a carcinogen, fish oil enhanced ROS, and fish oil/pectin suppressed antioxidant enzymes as compared to corn oil/cellulose. Oxidative DNA damage was inversely related to ROS in the fish oil/pectin diet and apoptosis was enhanced relative to other diets. In carcinogen treated and irradiated rats, a similar protective effect was seen with fish oil/pectin as evidenced by a reduction in oxidative DNA damage and enhancement of apoptosis. This suggests that a diet containing fish oil/pectin may protect against colon carcinogenesis by modulation of the redox environment to promote apoptosis and minimize oxidative DNA damage.

The effect of fish consumption on the risk of cardiovascular disease has been extensively studied. Omega-3 fatty acids present in fish, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been found to have beneficial effects through several mechanisms. In addition, selenium, an antioxidant, may be protective. Fish also represents the main human exposure source to the pollutant methylmercury (MeHg), which is associated with elevated cardiovascular risk in previous studies. The aim of this thesis was to evaluate whether MeHg is associated with the risk of myocardial infarction (MI) or stroke, whether EPA+DHA or selenium (Se) have protective associations, and if the overall association between fish consumption and risk of stroke or MI is detrimental or protective. A prospective incident case-control study design was used to study effects on stroke or MI. Three hundred and sixty-nine cases with twice as many matched controls were included in the study on stroke, while 431 cases with 499 controls participated in the MI study, all from the Northern Sweden Health and Disease Study. The data was collected from health examinations of the population from 1986 until 1999. Also, time trends in burdens of mercury (Hg), lead (Pb) and cadmium (Cd) in erythrocytes (Ery) from 1990 to 1999 were examined. The food frequency questionnaire (FFQ) used in the case-control studies was correlated with measurements of fatty acids in erythrocyte membranes as biomarkers of intake. In this northern Swedish population, levels of Ery-Hg and Ery-Pb decreased during the 1990´s, but Ery-Cd decreased only in smoking men. No significant associations were found between Ery-Hg or levels of EPA+DHA and the risk of stroke. Men reporting fish consumption >3 meals/week had an elevated risk of stroke. In the MI study, higher levels of Ery-Hg were associated with lower risk of MI. No clear associations were found for reported fish consumption, levels of EPA+DHA or Ery-Se. The validated FFQ has a fair reliability in estimating intake of fatty acids EPA and DHA. However, the low variation in fish consumption in the general population in combination with different versions of the FFQ (with pre-defined, multiple choice alternatives) decreased the reliability of self-reported fish consumption in the case-control studies on risk of stroke or MI. In conclusion, MeHg has no harmful association regarding the risk of stroke or MI in this population with generally low exposure levels. The protective association regarding risk of MI is probably due to Ery-Hg being a biomarker for consumption of fish, a source of other beneficial nutrients. Thus, in this population the benefits of the nutrients in fish appear to overcome the potential harm of MeHg. The finding of elevated stroke risk related to high fish consumption in men will be investigated further. / PHIME; Public health impact of long-term, low-level mixed element exposure in susceptible population strata

Colon cancer is one of the most commonly diagnosed cancers in the US, yet small intestine cancer is a rare event. While there are many similarities between these two tissues, inherent differences such as redox status, may contribute to the variation in cancer occurrence. We examined the difference in reactive oxygen species (ROS) generation, antioxidant enzyme activity and oxidative DNA damage in the small and large intestine of rats under normal conditions and following exposure to exogenous oxidative stress. Basal ROS and antioxidant enzyme activities were greater in the colon than the small intestine, and the balance of ROS to antioxidant enzymes in the colon was more pro-oxidant than in the small intestine. During oxidative stress, ROS and oxidative DNA damage were greater in the colon than the small intestine. Thus the colon responds to oxidative stress less effectively than the small intestine, possibly contributing to increased cancer incidence at this site. We next wanted to understand how diets containing a combination of fish or corn oil and pectin or cellulose may alter the redox environment of the colon. ROS, oxidative DNA damage, antioxidant enzyme activity and apoptosis were measured in colonocytes of rats fed one of four diets containing either corn oil or fish oil and cellulose or pectin. Measurements were madein rats untreated with carcinogen and rats exposed to a chemical carcinogen and radiation. In rats not treated with a carcinogen, fish oil enhanced ROS, and fish oil/pectin suppressed antioxidant enzymes as compared to corn oil/cellulose. Oxidative DNA damage was inversely related to ROS in the fish oil/pectin diet and apoptosis was enhanced relative to other diets. In carcinogen treated and irradiated rats, a similar protective effect was seen with fish oil/pectin as evidenced by a reduction in oxidative DNA damage and enhancement of apoptosis. This suggests that a diet containing fish oil/pectin may protect against colon carcinogenesis by modulation of the redox environment to promote apoptosis and minimize oxidative DNA damage.

Il periparto è la parte più critica della vita della bovina da latte. I cambiamenti importanti ed improvvisi nel metabolismo e nelle condizioni di vita possono favorire l’insorgenza di problemi di salute e di uno stato infiammatorio. Una risposta eccessiva dell’organismo all’infiammazione può sottrarre risorse fondamentali, causando un peggioramento delle condizioni di salute e un calo della produzione di latte. Nella prima parte della tesi si propone un nuovo indice basato su alcuni parametri plasmatici utile a descrivere meglio la risposta all’infiammazione nel post-parto. Una identificazione rapida degli animali caratterizzati da una risposta eccessiva all’infiammazione, specialmente quelli senza sintomi esterni, permette un intervento efficace per evitare ulteriori conseguenze negative. La seconda e terza parte della tesi descrivono due prove sperimentali finalizzate a ridurre la risposta all’infiammazione impiegando acidi grassi ω-3 e/o acido acetilsalicilico. La somministrazione di acidi grassi ω-3 a cavallo del parto ha ridotto la risposta all’infiammazione e migliorato il bilancio energetico, mentre la loro somministrazione esclusivamente prima del parto ha evidenziato alcuni leggeri miglioramenti nella risposta all’infiammazione e nel bilancio energetico. La somministrazione prima del parto di acido acetilsalicilico ha causato l’insorgenza di alcuni problemi e pertanto dovrebbe essere somministrata solo dopo il parto. / The peripartum period is the most critical stage of the dairy cows. The sudden and major changes in metabolism and life conditions may favor the onset of health problems together with an inflammatory status. An excessive response by the organism to inflammation may subtract primary resources, resulting in a worsening of health status and in a lower milk yield. In the first part of the thesis a new index based on some plasma parameters is proposed to better describe the response to inflammation in the post-calving of dairy cows. An early identification of the animals characterized by a severe response to inflammation, especially without any external symptom, allows an effective intervention in order to avoid further negative consequences. The second and the third part of the thesis describe two experiments aiming to reduce the response to inflammation using ω-3 fatty acids and/or acetylsalicylic acid. The administration of ω-3 fatty acids around calving reduced the inflammatory response and improved the energy balance, while their pre-calving only administration highlighted some slight improvements in inflammatory response and energy balance. The pre-calving administration of acetylsalicylic acid caused the onset of some problems and should be used only after calving.

Salmon is a good source of long chain (LC) omega 3 fatty acids and selenium; these are well recognised for their health benefits. Recommendations for LC omega 3 fatty acid intakes presume equivalence between fish and fish oil. The aim of this research was to compare the effects of consuming salmon with salmon oil capsules on LC omega 3 fatty acid and selenium status. Forty four healthy subjects were randomly assigned to consume either two servings of 120 g farmed New Zealand King (FNZK) salmon/week or 2, 4 or 6 capsules of salmon oil/day for 8 weeks. Fasting blood samples, anthropometric measures, food consumption habits information and blood pressure (BP) measurements were obtained at the study commencement and ending. Each subject’s intake of LC omega 3 fatty acids and selenium was determined by analysing the fatty acid and selenium content of duplicate portions of cooked salmon and capsules. The amount of salmon consumed was then calculated by subtracting unconsumed amounts of salmon and then calculating the intake of LC omega 3 fatty acids as grams of LC omega 3 fatty acids consumed per day. Percentage of compliance to capsule intake, based on counts of unconsumed capsules, was calculated to determine the amount of LC omega 3 fatty acids consumed per day from capsules. Change in red blood cells (RBC) LC omega 3 fatty acid levels from equivalent amounts of LC omega 3 fatty acids consumed from capsules and salmon were compared using linear regression analysis predictive models fitted to the capsule data. Omega 3 index was calculated. LC omega 3 fatty acid intakes from salmon and 2, 4 and 6 capsules were 0.82, 0.24, 0.47 and 0.68 g/day, respectively. Equal amounts of LC omega 3 fatty acids consumed from salmon and capsules resulted in similar increases in RBC LC omega 3 fatty acids and omega 3 index (RBC eicosapentaenoic acid (EPA): 0.80 [0.58 – 1.02] vs. 1.00 [0.71 – 1.27] %; RBC docosahexaenoic acid (DHA): 0.93 [0.58 – 1.29] vs. 0.99 [0.68 – 1.31] %; omega 3 index: 1.92 [1.46 – 2.38] vs. 2.25 [1.65 – 2.83] %). The capsules did not contain selenium, but the salmon provided 6.84 µg selenium/day. Plasma selenium concentrations increased significantly in the salmon group compared to the capsule

Salmon is a good source of long chain (LC) omega 3 fatty acids and selenium; these are well recognised for their health benefits. Recommendations for LC omega 3 fatty acid intakes presume equivalence between fish and fish oil. The aim of this research was to compare the effects of consuming salmon with salmon oil capsules on LC omega 3 fatty acid and selenium status. Forty four healthy subjects were randomly assigned to consume either two servings of 120 g farmed New Zealand King (FNZK) salmon/week or 2, 4 or 6 capsules of salmon oil/day for 8 weeks. Fasting blood samples, anthropometric measures, food consumption habits information and blood pressure (BP) measurements were obtained at the study commencement and ending. Each subject’s intake of LC omega 3 fatty acids and selenium was determined by analysing the fatty acid and selenium content of duplicate portions of cooked salmon and capsules. The amount of salmon consumed was then calculated by subtracting unconsumed amounts of salmon and then calculating the intake of LC omega 3 fatty acids as grams of LC omega 3 fatty acids consumed per day. Percentage of compliance to capsule intake, based on counts of unconsumed capsules, was calculated to determine the amount of LC omega 3 fatty acids consumed per day from capsules. Change in red blood cells (RBC) LC omega 3 fatty acid levels from equivalent amounts of LC omega 3 fatty acids consumed from capsules and salmon were compared using linear regression analysis predictive models fitted to the capsule data. Omega 3 index was calculated. LC omega 3 fatty acid intakes from salmon and 2, 4 and 6 capsules were 0.82, 0.24, 0.47 and 0.68 g/day, respectively. Equal amounts of LC omega 3 fatty acids consumed from salmon and capsules resulted in similar increases in RBC LC omega 3 fatty acids and omega 3 index (RBC eicosapentaenoic acid (EPA): 0.80 [0.58 – 1.02] vs. 1.00 [0.71 – 1.27] %; RBC docosahexaenoic acid (DHA): 0.93 [0.58 – 1.29] vs. 0.99 [0.68 – 1.31] %; omega 3 index: 1.92 [1.46 – 2.38] vs. 2.25 [1.65 – 2.83] %). The capsules did not contain selenium, but the salmon provided 6.84 µg selenium/day. Plasma selenium concentrations increased significantly in the salmon group compared to the capsule