京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第22510号 / 農博第2414号 / 新制||農||1078(附属図書館) / 学位論文||R2||N5290(農学部図書室) / 京都大学大学院農学研究科食品生物科学専攻 / (主査)教授 井上 和生, 教授 佐々木 努, 准教授 後藤 剛 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

No description available.

Cancer is the second leading cause of death in the United States and is expected to become the primary cause of disease-related death within the next decade. There are significant country-to-country variations in cancer incidence, which suggests that nutrition and dietary factors are important to the carcinogenesis process. An increased risk of cancer is associated with obesity and a high body mass index demonstrating that nutrition has a central role in the promotion of cancer. Healthy eating habits protect against cancer, while unhealthy eating habits increase the risk of cancer. Mediterranean societies have a lower risk for many cancers than those of northern Europe and the Americas. Mediterranean diets consist of a high consumption of fruits, vegetables, grains, beans, nuts, and seeds, with olive oil as an important source of monounsaturated fat. These foods are rich in lipid soluble antioxidants such as vitamin E. Vitamin E may prevent cancer by decreasing the formation of mutagens arising from the oxidation of lipids, decreasing oxidative stress in the epithelial cells as well as modulating molecular mechanisms that influence cell death, cell cycle, and transcriptional events. Vitamin E is a major fat-soluble antioxidant and it occurs naturally as eight compounds (alpha-, beta gamma-, and delta-tocopherol or alpha-, beta-, gamma-, and delta-tocotrienol). Since the recognition of vitamin E in 1922 as an essential nutrient for reproduction, alphatocopherol has been considered the major form of vitamin E. It has the highest concentration in the plasma and has been studied more in epidemiological and clinical studies than any other form of vitamin E. Recent data suggests that other isoforms of vitamin E may be important in the control of cancer. These isoforms of vitamin E have varying anti-carcinogenic potencies. Data indicate that gamma-tocopherol may be a more effective anti-cancer agent than alpha-tocopherol. Our laboratories and others have demonstrated that tocotrienols are even more effective than tocopherols at inhibiting cell proliferation in cancer cells. Differences in apoptotic induction among the various vitamin E isoforms are reflective of different avenues of apoptotic signaling and may be tissue specific. Dietary fat has been linked to an increase in a number of cancers including colon, prostate, and breast cancer. Vitamin E modulates a number of molecular mechanisms involved in fat metabolism. These include: the peroxisome proliferator activator receptor (PPAR), arachidonic acid metabolism, de novo sphingolipid metabolism, and cholesterol metabolism. Vitamin E family members have demonstrated the potential to activate pathways involved in cell proliferation, differentiation, apoptosis, and cell cycle. This chapter reviews data that identify the molecular targets of vitamin E action against the development of cancer.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18159号 / 医博第3879号 / 新制||医||1003(附属図書館) / 31017 / 京都大学大学院医学研究科医学専攻 / (主査)教授 横出 正之, 教授 木村 剛, 教授 柳田 素子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Serotonin (5-hydroxytryptamine [5-HT]) is a key enteric signaling molecule that is implicated in many gastrointestinal (GI) disorders, including inflammatory bowel disease (IBD). Enterochromaffin (EC) cells are a key subgroup of enteric endocrine cells and produce the majority of 5-HT via tryptophan hydroxylase 1 (Tph1) in the gut. Recently, we have identified a pivotal role of 5-HT in the pathogenesis of experimental colitis, whereby 5-HT plays as a pro-inflammatory molecule. Gut function as well as pathology rely on interactions with gut microbiota. The intestinal epithelial cells produce antimicrobial peptides (AMPs), maintaining the mucosal barrier by shaping gut microbiota composition. Among the AMPs, β-defensins are the most well investigated subtype in the colon. Aberrant β-defensin expression has been reported in association with various GI disease pathogenesis including IBD. As EC cells are dispersed throughout the intestinal epithelium, it seems possible that 5-HT can modify β-defensin production which can regulate gut inflammation by influencing gut microbial composition. Colitis was induced with dextran sulfate sodium (DSS) in Tph1+/+ and Tph1-/- (which have lower amounts of 5-HT in gut). Tph1-/- mice exhibited higher levels of β-defensin in the colon, compared with wild-type littermates post-DSS. In addition, increased expression of β-defensin in Tph1-/- mice was suppressed by 5-hydroxytryptophan (5-HTP; precursor of 5-HT) treatment. 5-HT treatment resulted in decreased human β-defensin (hBD) 1 and hBD-2 expression in HT-29 cells. Peroxisome proliferator-activated receptor gamma (PPAR-γ) is essential for maintaining β-defensin expression in the colon. GW-9662, PPAR-γ antagonist, reduced mouse β-defensin (mBD) 1 and mBD-3 (orthologue of hBD-2). Furthermore, disrupting 5-HT7 receptors, but not 5-HT3 or 5-HT4, led to enhanced expression of PPAR-γ via ERK1/2-dependent mechanism. These observations provide us with novel information on pivotal role of gut-derived 5-HT in innate immune response and highlight the potential benefits of targeting 5-HT signaling in various GI disorders such as IBD. / Thesis / Master of Science (MSc)

Sirt3, une des sept sirtuines chez les mammifères, est une déacétylase mitochondriale NAD+-dépendante qui joue un rôle dans le contrôle des facteurs clés de plusieurs voies métaboliques. Sirt3 déacétyle et active un grand nombre d'enzymes mitochondriales impliquées dans l'activité de la chaîne respiratoire, la production d'ATP, le cycle de Krebs, ainsi que le cycle de l'urée. Parallèlement à son rôle dans le métabolisme énergétique, l'activité mitochondriale intervient également dans l'induction de l'apoptose ainsi que dans la régulation de la prolifération et la différenciation cellulaires. En particulier les travaux du laboratoire ont montré qu'il existe une véritable régulation de la différenciation myogénique par l'activité mitochondriale. Comme Sirt3 régule l'activité mitochondriale, nous nous sommes intéressés à étudier l'implication de cette sirtuine dans la différenciation des myoblastes. Dans une première partie, nous avons évalué l'expression endogène de Sirt3 au cours de la différenciation des myoblastes murins C2C12, puis étudié l'effet de son inhibition sur le processus de différenciation et sur l'activité mitochondriale. Nous avons montré que l'expression de Sirt3 endogène augmente après induction de la différenciation des C2C12. Une inhibition stable de l'expression de Sirt3 par interférence (Short hairpin Sirt3, shSirt3) entraîne : 1) un blocage de la différenciation terminale des C2C12 reflété par une chute significative de l'index de fusion ainsi que de l'expression des marqueurs myogéniques MyoD, Myogénine et troponine T ; 2) une diminution de l'activité mitochondriale reflétée par une altération de l'expression de PGC-1alpha, VDAC et citrate synthase, et une diminution des activités enzymatiques des complexes de la chaîne respiratoire et de la respiration maximale des myoblastes ; 3) une augmentation de la production de DROs. Ces résultats suggèrent un rôle important de Sirt3 dans la différenciation des myoblastes, en relation avec son influence sur l'activité mitochondriale.Dans une seconde partie, nous avons évalué l'importance de Sirt3 in vivo sur le développement et le métabolisme du tissu musculaire en étudiant le phénotype de souris surexprimant l'isoforme courte (MCK-SIRT3M3) ou l'isoforme longue (MCK-SIRT3M1) de Sirt3 spécifiquement dans le muscle squelettique. Nos premiers résultats obtenus à l'âge de 3 mois montrent que la capacité oxydative des souris MCK-SIRT3M1 est plus faible et celle des souris MCK-SIRT3M3 plus élevée par rapport aux souris sauvages. Les souris MCK-SIRT3M3 présentent une atrophie musculaire dès l'âge de trois mois alors que la capacité musculaire et l'activité mitochondriale dans les muscles de ces souris ne sont pas modifiées. Avec l'âge, le phénotype des souris surexprimant l'isoforme M3 dans le muscle est plus marqué : l'atrophie s'accentue, le nombre de mitochondries augmente, et l'expression de la myosine de type 1 augmente alors que l'expression des myosines de type II diminue. Ces données indiquent que l'isoforme courte de Sirt 3 aurait une influence dans le développement et le métabolisme du muscle squelettique de souris. / Sirt3, one of the seven mammalian sirtuins, is a mitochondrial nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, and has been shown to control multiple key metabolic pathways. Sirt3 deacetylates and activates a large number of mitochondrial enzymes implicated in the activity of respiratory chain and ATP production, TCA and Urea cycles. We have previously shown that mitochondrial activity is importantly involved in the regulation of myoblast differentiation. Since Sirt3 modulates mitochondrial activity, we have investigated its influence on myoblast differentiation. First, we have evaluated endogen Sirt3 expression during C2C12 myoblast differentiation and then we examined the effect of its inhibition on the differentiation processes and on mitochondrial activity. We have shown that Sirt3 protein expression increased after the induction of myoblast differentiation. A stable inhibition of Sirt3 expression, using short hairpin Sirt3 (shSirt3) in C2C12 myoblasts resulted in: 1) abrogation of terminal differentiation reflected by a sharp decrease of the fusion index and a significant decrease of Myogenin, MyoD and Troponin T protein expression; 2) a decrease in mitochondrial activity reflected by alterations in PGC1-alpha, VDAC and citrate synthase expression, and a decrease in respiratory chain complexes activity and myoblast maximal respiration, 3) an increase in ROS production. These data suggest that Sirt3 plays an important role in the regulation of myoblast differentiation through its influence on mitochondrial activity.In a second part, to investigate the role of Sirt3, in vivo, in myogenesis and in mitochondrial activity, we have studied the effect of Sirt3 isoforms (short and long, MCK-SIRT3M3 and MCK-SIRT3M1 respectively) overexpression exclusively in skeletal muscle tissue of transgenic mice. We show that basal metabolism is lower MCK-SIRT3M1 mice and higher in MCK-SIRT3M3 compared to WT mice at 3 months of age. In 3 month-old MCK-SIRT3M3 mice, skeletal muscle is atrophied while muscle capacity and mitochondrial activity are not altered. Skeletal muscle phenotype evolves with age, in MCK-SIRT3M3 mice : increase in muscle atrophy, mitochondrial content. These data suggest that Sirt3 short isoform plays an important role in skeletal muscle development and metabolism in mice.

Une croissance intra-utérine insuffisante représente, avec la prématurité et les malfor-mations congénitales, une des principales causes de morbidité et de mortalité néonatales. Ces pathologies sont liées entre elles, les nouveau-nés prématurés étant souvent atteints de RCIU (RCIU). Les études épidémiologiques récentes ont montré que le RCIU était associé à une augmentation de la morbidité respiratoire dès la période néonatale, avec, en particulier, une augmentation du risque de dysplasie broncho-pulmonaire (DBP), principale séquelle respira-toire de la prématurité. La DBP est caractérisée par des anomalies du développement alvéo-laire et vasculaire, considérées comme les conséquences d’agressions multiples sur un poumon immature. La physiopathologie exacte reste encore largement méconnue. Nous nous sommes intéressés dans ce travail au lien entre RCIU et DBP avec un abord expérimental et clinique. Alors que les études épidémiologiques sont relativement concordantes sur le lien entre RCIU et DBP, les études expérimentales, montrent des résultats divers tant sur le développement pulmonaire qu’au niveau moléculaire. Nous avons donc voulu identifier, dans un premier temps, un modèle de RCIU reproduisant les anomalies du développement alvéolaire observées chez l’Homme en utilisant trois modèles précédemment validés chez le rat : un modèle de res-triction protidique per-gestationnelle , un modèle de ligature unilatérale de l’artère utérine, un modèle d’injection d’un inhibiteur chimique de la NO synthase, le L NAME. Seule la restric-tion protidique anténatale permet de reproduire à long terme des lésions de l’alvéolisation proches de celles observées dans la DBP. En revanche, dans ce modèle, les modifications des principaux gènes identifiés précédemment dans les anomalies le développement alvéolaire ne sont pas observées, que ce soit avant, pendant ou après l’alvéolisation. Ce résultat nous a ame-né à entreprendre une étude multigénique qui a permis d’identifier plusieurs voies modifiées pendant l’alvéolisation dans ce modèle. Parmi celles-ci, les gènes impliqués dans la contractili-té et l’adhésion cellulaire, l’immunité ou la voie des « Peroxisome Proliferator-Activated Re-ceptor ». Dans la partie clinique de cette étude, nous avons évalué le risque de DBP chez les extrêmes prématurés atteints de RCIU dont les mères présentaient des signes de pathologie vasculaire de la grossesse (prééclampsie). Cette étude rétrospective unicentrique sur 184 en-fants a permis de comparer des enfants atteints de RCIU à des enfants eutrophes pris en charge de manière homogène. Le RCIU d’origine vasculaire multiplie le risque de DBP par 6. Un marqueur précoce de l’évolution vers une DBP est un taux de plaquettes bas à la naissance, évoquant le rôle d’un taux élevé de facteurs anti-angiogéniques circulants. Une étude est en cours pour corréler les facteurs anti-angiogéniques circulants présents chez les mères pré-éclamptiques au devenir respiratoire, en particulier à l’évolution vers une DBP, de leurs nou-veau-nés d’âge gestationnel inférieur à 30 semaines d’aménorrhée. En conclusion, nous avons montré expérimentalement que seule la restriction protidique anténatale chez le rat reproduisait les troubles de l’alvéolisation comparables à ceux observés dans la DBP. De nouvelles voies moléculaires potentiellement impliquées dans les anomalies de l’alvéolisation ont été mises en évidence. Par ailleurs, le rôle de facteurs anti-angiogéniques d’origine maternelle comme fac-teurs de développement d’une DBP est en cours d’évaluation. / Insufficient intrauterine growth is with prematurity and congenital malformations, a major cause of neonatal morbidity and mortality. These conditions are interrelated, the preterm infants often suffered of intrauterine growth restriction (IUGR). Recent epidemiological stud-ies showed that IUGR was associated with increased respiratory morbidity as soon as the ne-onatal period, with an increased risk of bronchopulmonary dysplasia (BPD), the main respira-tory sequelae of prematurity. BPD is characterized by impaired alveolar and vascular devel-opment and is the consequence of multiple insults on an immature lung. The exact pathophysi-ology is still largely unknown. We study in this work the relationship between IUGR and DBP with an experimental and clinical approach. While epidemiological studies are relatively concordant on the relationship between IUGR and BPD, experimental studies showed various results in lung development and molecular process. We wanted to identify, at first, a model of IUGR reproducing impaired alveolar development observed in humans using three previously validated models in rats: a model of per-gestational protein restriction, a model of unilateral ligation uterine artery, an injection pattern of a chemical inhibitor of NO synthase, L NAME. Only antenatal protein restriction can reproduce long-term impaired alveolarization as those observed in BPD. However, in this model, changes in key genes previously identified in pathological alveolar development are not observed before, during or after alveolarization. This result led us to perform a genome-wide analysis which identified several modified path-ways during alveolarization. Among these, the genes involved in the “cardiac contractility”, “cell adhesion molecules”, “immunity”, “molecular adhesion” or the "Peroxisome Proliferator-Activated Receptor" pathways. In the clinical part of this study, we evaluated the risk of BPD in extreme preterm infants with IUGR whose mothers had evidence of vascular disease of pregnancy (preeclampsia). This single-center retrospective study of 184 children was used to compare children with IUGR in adjusted for gestational age children. The vascular IUGR increases the risk of DBP by 6. An early marker of progression to BPD is a low platelet count at birth, referring to the role of high levels of circulating anti-angiogenic factors. A study is ongoing to correlate circulating anti-angiogenic factors present in preeclamptic mothers to res-piratory outcome and particularly BDP, in newborn younger than 30 weeks of gestational age at birth. In conclusion, we have shown experimentally that only prenatal protein restriction in rats reproduced impaired alveolarization comparable to those observed in the BPD. New mo-lecular pathways potentially involved in the impaired alveolarization were highlighted. More-over, the role of placental anti-angiogenic factors leading to development of BPD is evaluat-ed.

<p>Accumulating evidence is suggesting that exposure to some environmental contaminants may alter adipogenesis, resulting in accumulation of adipocytes, and often significant weight gain. Thus these types of contaminants are often referred to as obesogens. Many of these contaminants act via the activation (i.e. agonism) of the peroxisome proliferator activated receptor &#947; (PPAR&#947;) nuclear receptor. To date, very few chemicals have been identified as possible PPAR&#61543; ligands. In the thesis, our goal was to determine the PPAR&#947; ligand binding potency and activation of several groups of major semi-volatile organic compounds (SVOCs) that are ubiquitously detected in indoor environments, including flame retardants such as polybrominated diphenyl ethers (PBDEs) and Firemaster 550 (FM550), and other SVOCs such as phthalates, organotins, halogenated phenols and bisphenols. Additional attention was also given to the potential activity of the major metabolites of several of these compounds. Since the primary sink for many of these SVOCs is dust, and dust ingestion has been confirmed as an important pathway for SVOCs accumulation in humans, the potential PPAR&#61543; binding and activation in extracts from environmentally relevant dust samples was also investigated. </p><p> Previous studies have also shown that SVOCs sorbed to organic matrices (e.g., soil and sediment), were only partially bioaccessible (bioavailable), but it was unclear how bioaccessible these compounds are from indoor dust matrices. In addition, bioactivation of SVOCs (via metabolism) could exacerbate their PPAR&#61543; potency. Therefore, to adequately assess the potential risk of PPAR&#947; activation from exposure to SVOC mixtures in house dust, it is essential that one also investigates the bioaccessibility and bioactivation of these chemicals following ingestion. </p><p> In the first research aim of this thesis, the bioaccessibility and bioactivation of several important SVOCs in house dust was investigated. To accomplish this, Tenax beads (TA) encapsulated within a stainless steel insert were used as an infinite adsorption sink to estimate the dynamic absorption of a suite of flame retardants (FRs) commonly detected in indoor dust samples, and from a few polyurethane foam samples for comparison. Experimental results demonstrate that the bioaccessibility and stability of FRs following ingestion varies both by chemical and by matrix. Organophosphate flame retardants (OPFRs) had the highest estimated bioaccessibility (~80%) compared to brominated compounds (e.g. PBDEs), and values generally decreased with increasing Log Kow, with <30% bioaccessibility measured for the most hydrophobic compound tested, BDE209. In addition, the stability of the more labile SVOCs that contained ester groups (e.g. OPFRs and 2-ethylhexyl-tetrabromo-benzoate (TBB)) were examined in a simulated digestive fluid matrix. No significant changes in the OPFR concentrations were observed in this fluid; however, TBB was found to readily hydrolyze to tetrabromobenzoic acid (TBBA) in the intestinal fluid in the presence of lipases. </p><p> In research aims 2 and 3, two commercially available high-throughput bioassays, a fluorescence polarization PPAR&#61543; ligand binding assay (PolarScreenTM PPAR&#947;-competitor assay kit, Invitrogen, Aim 2) and a PPAR&#61543; reporter gene assay (GeneBLAzer PPAR&#947; non-DA Assay, Invitrogen, Aim 3) were used to investigate the binding potency and activation of several groups of SVOCs and dust extracts with human PPAR&#947; LBD; respectively. In the PPAR&#61543; binding assay (Aim 2), most of the tested compounds exhibited dose-dependent binding to PPAR&#947;. Mono(2-ethylhexyl) tetrabromophthalate (TB-MEHP), halogenated bisphenol/phenols, triphenyl phosphate and hydroxylated PBDEs were found to be potent or moderate PPAR&#947; ligands, based on the measured ligand binding dissociation constant (Kd). The most potent compound was 3-OH-BDE47, with an IC50 of 0.24 &#956;M. The extent of halogenation and the position of the hydroxyl group strongly affected binding. Of the dust samples tested, 21 of 24 samples showed significant PPAR&#61543; binding potency at a concentration of 3 mg dust equivalents (DEQ)/mL. In the PPAR&#61543; reporter assay (Aim 3), many SVOCs or their metabolites were either confirmed (based on previous reports) or for the first time were found to be potential PPAR&#947; agonists with various potency and efficacy. We also observed that 15 of 25 dust extracts examined showed an activation percentage more than 8% (calculated activation threshold) of the maximal activation induced by rosiglitazone (positive control). In some cases, activation was as high as 50% of the rosiglitazone activation for the dust extracts with the highest efficacy. Furthermore, the correlation between the reporter assay and the ligand binding assay among the house dust extracts was significant and positive (r = 0.7, p < 0.003), suggesting the binding potency was predicting activation. In research aim 2, the effect of bioactivation on the PPAR&#947; binding potency was also investigated. In vitro bioactivation of house dust extracts incubated with rat and human hepatic S9 fractions was used to investigate the role of in vivo biotransformation on PPAR gamma activity. The result showed that metabolism may lead to an increased binding affinity, as a 3-16% increase in PPAR&#947; binding activity was observed following bioactivation of the dust extracts.</p><p> In research aim 4, an effect-directed analysis (EDA) was used to identify compounds likely contributing to the observed PPAR&#61543; activity among the dust extract. Three dust extracts which showed significant PPAR&#61543; activity with approximately 25, 30, and 50% of the maximal response induced by rosiglitazone at the highest efficacy were fractionated using normal phase high-performance liquid chromatography (NP-HPLC) and each fraction was individually tested for PPAR&#61543; activity. Active fractions were then analyzed using gas-chromatography mass spectrometry (GC-MS) and possible compounds identified. Three dust extracts showed a similar PPAR&#61543; activity distribution among the NP-HPLC fractions. In the most active fractions, fatty acids (FAs) were identified as the most active chemicals. The concentrations of four FAs were measured in the house dust extracts, and the concentrations were found to be highly correlated with the observed PPAR&#61543; activity. These four FAs were also tested for PPAR&#61543; activity and found to be partial PPAR&#61543; agonists, particularly oleic and myristic acid. To tentatively identify sources of FAs, FAs in human/animal hair, dead skin cells, and two brands of cooking oil were analyzed. We found the same FAs in those samples and there concentrations were relatively abundant, ranging from 186 to 14,868 µg/g. Therefore, these results suggest that FAs are likely responsible for the observed PPAR&#61543; activity in indoor dust. Also, this is the first study reporting on the level of FAs in dust samples. The source of these FAs in dust may be either from the cooking or accumulation of human/animal cells in indoor dust.</p><p> In conclusion, this research demonstrates that many SVOCs ubiqutiously detected in house dust, and/or their metabolites, can be weak or moderate PPAR&#61543; ligands. In addition, chemical mixtures in house dust can effectively bind to and activate PPAR&#61543;. However, our results suggest FAs are probably responsible for these observations, and likely outcompeting the synthetic environmental contaminants present in the dust extract. Furthermore, bioactivation of contaminants present in house dust can potentially increase their affinity for PPAR&#61543;. And lastly, the bioaccessibility and stability of SVOCs in house dust after ingestion are likely to modulate the PPAR&#61543; activity in the environmental mixtures and should be considered in future risk assessments.</p> / Dissertation

Ácidos graxos ácidos saturados induzem resistência à insulina, enquanto ácidos graxos poliinsaturados ômega-3 previnem. Camundongos Swiss foram tratados com dieta controle e dietas contendo óleo de peixe a 4% (NFO) e 40% (HFO) ou banha de suínos a 4% (NL) e 40% (HL) por oito semanas. O grupo HFO apresentou menor massa gorda e peso corpóreo em relação ao HL. Nos grupos NFO e HFO, a insulinemia, glicemia basal e aquela durante o teste de tolerância à glicose foi menor em relação ao HL. Apesar de não haver diferenças no conteúdo de triacilgliceróis no músculo esquelético, o grupo HFO apresentou 60% menos triacilgliceróis no fígado que nos grupos NL e HL. O menor consumo de oxigênio associado ao aumento da oxidação parcial do ácido palmítico e da atividade da acil CoA oxidase no fígado dos animais HFO, indicam maior oxidação peroxissomal de AG. Este processo demanda a metabolização de maior número de moléculas de AG, contribuindo para o menor acúmulo de gordura e preservação da tolerância à glicose. / Saturated fatty acids induce insulin resistance, while omega-3 polyunsaturated fatty acids prevent it. Swiss mice were fed on diets containing fish oil at 4% (NFO) and 40% (HFO) or lard at 4% and 40% for eight weeks. The HFO group showed smaller fat mass and body weight compared to HL. In the groups NFO and HFO, basal insulinemia and glycemia and the area under the curve during glucose tolerance test were lower, compared to HL. Despite no differences on skeletal muscle triacylglycerol content, the HFO group had 60% less triacylglycerols in the liver, compared to NL and HL. The lower oxigen consumption associated to the increase in partial oxidation of palmitic acid and activity of acyl CoA oxidase in the liver of the HFO group, indicate increased peroxisomal oxidation of fatty acids. This process demands the metabolization of more fatty acid molecules, contributing to the decresed fat acumulation and preservation of glucose tolerance.