The aim of this thesis was to investigate how dietary fatty acids affect the risk for cardiometabolic disease, i.e. cardiovascular disease (CVD), type 2 diabetes and obesity. The overall hypothesis was that unsaturated fatty acids and especially the predominant polyunsaturated fatty acid (PUFA) linoleic acid (LA), 18:2n-6, would decrease cardiometabolic risk compared with saturated fatty acids (SFAs), in line with current recommendations to partly replace dietary SFA with PUFA. Papers I and V were observational studies based on the community-based cohort Uppsala Longitudinal Study of Adult Men (ULSAM). Adipose tissue fatty acid composition was determined as biomarker for dietary fat intake. Studies II, III and IV were randomised short-term interventions on human volunteers, in which different dietary fats were provided to the participants. In 71-year-old men, adipose tissue LA and α-linolenic acid (18:3n-3) were associated with insulin sensitivity (euglycaemic clamp), although this association was diminished for LA after adjusting for lifestyle variables. Different SFA displayed divergent associations; only palmitic acid (16:0) was inversely associated with insulin sensitivity (Paper I). In Cox regression analyses, LA was modestly associated with decreased all-cause mortality, but not CVD mortality during 15 years follow-up (Paper V). In a 3+3-week cross-over study on 20 weight-stable volunteers with dyslipidaemia, all foods were provided. A rapeseed oil-based diet distinctly lowered low-density lipoprotein cholesterol and triglycerides compared with a dairy-fat based diet (butter, cream and fatty cheese). Insulin sensitivity or coagulation factors were not affected (Paper II). In a 10-week randomised trial on 67 abdominally obese participants, PUFA (mostly sunflower oil) decreased liver fat compared with SFA (mostly butter) under isocaloric conditions. In individuals considered highly compliant to study diets, lipoproteins were also decreased during the PUFA diet (Paper III). In a 7-week double-blind randomised trial on 41 healthy volunteers, PUFA (sunflower oil) decreased the total:HDL cholesterol ratio compared with SFA (palm oil) during moderate weight gain (1.5 kg) (Paper IV). In conclusion, LA (PUFA) intake is associated with decreased cardiometabolic risk compared with higher SFA intake, overall supporting a beneficial role of non-tropical vegetable oils in place of solid fats in preventing fatty liver and cardiometabolic disorders.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Fatty acids (FA) are constituent important of the neuronal phospholipids membranes and they carry out important functions in the development and function of the brain During the last decades changes were observed in the feeding habits of western countries, with an increase of the trans FA and omega-6 (n-6) and detriment of omega-3 fatty acids (n-3) consumption, contributing to increase the oxidative stress (OS) generation and development of neuropsychiatric disorders. The influence of FA supplementation containing n-6 (soybean oil-SO), trans (hydrogenated vegetable fat-HVF) and n-3 (fish oil-FO) on behavioral parameters and OS were studied in an animal model of mania. Rats were orally treated for 8 weeks with suspensions of SO, HVF and FO in place of drinking water, and treated with seven daily administrations of amphetamine (AMPH-mg/kg, ip) or vehicle, in the last week of oral treatment. Locomotor activity, vitamin C (VIT C) levels, protein oxidation and mitochondrial slices in striatum and cortex were evaluated. HVF supplemented rats showed an increase in the locomotor activity, higher levels of carbonyl protein in the cortex, and lower mitochondrial viability in the striatum and cortex, showing harmful effects per se. AMPH treatment increased the locomotor activity of all groups, but this effect showed greater intensity in the rats orally treated with HVF (456%). Similarly, AMPH increased the carbonyl protein levels in striatum (39.5%) and cortex (78%) of the animals orally treated with HVF, while SO and FO prevented it in the cortex. AMPH treatment decreased the mitochondrial viability in cortex and striatum of supplemented rats with all the FA; however the HVF group showed greater damage (46 and 44% of viability in the striatum and cortex, respectively). AMPH reduced the VIT C plasma levels of the HVF and SO groups (22.5 and 22.4% respectively), and this antioxidant parameter has not been changed in the FO treated rats. Here, we suggest that the trans FA contained in the HVF may increase the oxidative damages per se, leaving the rats more vulnerable to AMPH damage. FA n-3 contained in the FO showed subtle protecting effects, which were observed by preservation of the VIT C levels and lower levels of carbonyl protein in the cortex. Further studies should be conducted to evaluate the influence of the trans fatty acids consumption on neuronal activity, and consequently on the susceptibility to psychiatric disorders development among them the bipolar disorder. / Ácidos graxos (AG) são constituintes importantes das membranas fosfolipídicas neuronais e desempenham importantes funções no desenvolvimento e funcionamento do cérebro. Durante as últimas décadas foram observadas mudanças nos hábitos alimentares de países ocidentais, com aumento do consumo de AG trans e ômega-6 (n-6) em detrimento do consumo de ácidos graxos ômega-3 (n-3), cujas conseqüências podem estar relacionadas a um aumento dos danos oxidativos, facilitando o desenvolvimento de doenças neuropsiquiátricas. A influência da suplementação com AG n-6 (óleo de soja-OS), trans (gordura vegetal hidrogenada-GVH) e n-3 (óleo de peixe-OP) sobre parâmetros comportamentais e de estresse oxidativo (EO) foram estudados em um modelo animal de mania. Ratos tratados oralmente com suspensões de OS, GVH e OP, junto à água de beber durante 8 semanas, receberam nos últimos sete dias administrações diárias de anfetamina (ANF-4mg/kg, ip) ou veículo. Atividade locomotora, os níveis de vitamina C (VIT C) plasmático, marcadores de oxidação de proteínas e a viabilidade de fatias do estriado e córtex foram determinados. Animais suplementados com GVH mostraram um aumento da atividade locomotora, maior nível de proteínas carbonil no córtex, e menor viabilidade nas fatias do estriado e córtex, demonstrando efeitos prejudiciais per se. O tratamento com ANF aumentou a atividade locomotora dos animais de todos os grupos experimentais, porém este efeito mostrou maior intensidade nos animais que receberam a suplementação com GVH (456%). Semelhante, a ANF aumentou a carbonilação de proteínas no estriado (39.5%) e córtex (78%) dos animais suplementados com GVH, enquanto OS e OP preveniram o dano causado pela ANF no córtex. O tratamento com ANF diminuiu a viabilidade mitocondrial nos tecidos cerebrais de todos os grupos, entretanto o grupo suplementado com GVH apresentou maiores danos (46 e 44% de viabilidade no estriado e córtex, respectivamente). A ANF diminuiu os níveis de VIT C no plasma dos animais suplementados com OS e GVH (22.5 e 22.4%, respectivamente), e este parâmetro antioxidante não foi alterado nos ratos tratados com OP. Os resultados do presente estudo sugerem que os ácidos graxos trans presentes na GVH podem aumentar os danos oxidativos per se, deixando os animais mais expostos aos danos da ANF. A suplementação com ácidos graxos n-3 presentes no OP mostraram efeitos protetores sutis, representados pela preservação dos níveis de VIT C plasmático e menor oxidação de proteínas no córtex. Maiores estudos devem ser realizados para determinar a influência do consumo de ácidos graxos trans sobre a atividade neuronal, e conseqüentemente sobre a suscetibilidade para o desenvolvimento de desordens psiquiátricas entre estas, o transtorno bipolar.