Orientador: Jose Barreto Campello Carvalheira / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-25T02:56:20Z (GMT). No. of bitstreams: 1 Mendes_MariaCarolinaSantos_D.pdf: 2658779 bytes, checksum: 153ed5344815e7e59a41c04c4a965670 (MD5) Previous issue date: 2014 / Resumo: A proteína mTOR é um proteína reguladora chave de vários processos celulares, dentre eles proliferação, crescimento e sobrevivência celular. Fatores de crescimento, oxigênio, status energético e a presença de aminoácidos são fundamentais para que todos esses processos ocorram normalmente. Descobertas realizadas nas últimas décadas mostraram que a via da mTOR encontra-se ativada em vários processos celulares, incluindo formação tumoral e angiogênese. A leucina é um aminoácido de cadeia ramificada que tem o maior potencial em ativar a via da mTOR. Devido sua capacidade de promover a síntese proteica e ganho de massa muscular, seu uso é constantemente estimulado em pacientes com câncer. No entanto, seus efeitos no crescimento tumoral não está claro. Dessa forma, realizamos um estudo cujo objetivo principal foi investigar os efeitos da dieta suplementada com leucina na modulação do crescimento tumoral em diferentes linhagens de células tumorais que se diferenciem em relação à ativação constitutiva da via IRS1/Akt/mTOR. Estudos in vivo e in vitro realizados demonstraram que as células que se diferenciam em relação à ativação da via IRS1/AKT/mTOR respondem de maneira distinta à suplementação com leucina. Linhagens de células tumorais que possuem a via da mTOR constitutivamente ativada, PC-3 e MCF-7, quando suplementadas com doses elevadas de leucina in vitro reduziram a proliferação celular e causaram retenção das células na fase G1 do ciclo celular. Já o xenoenxerto tumoral da PC-3 reduziu sua proliferação e aumentou a morte celular quando os animais foram suplementados com leucina na dieta. Nós também observamos aumento da atividade da mTOR e da p70S6K em todas as linhagens celulares quando suplementadas com leucina. O aumento da atividade da proteína mTOR foi acompanhado de redução na fosforilação de AKTser473 nas células que possuíam a via da PI3K hiperativada (PC-3 e MCF-7). Esse fato pode estar ocorrendo devido a ativação das alças de contraregulação ocasionadas pela estimulação excessiva provocada pela suplementação com leucina, naquelas linhagens celulares que já possuem a via hiperativada. Fato este comprovado pelo aumento da fosforilação em serina 307 da proteína IRS1. Dessa forma, nossos resultados sugerem que a ativação da via da mTOR é central para determinar a sensibilidade de tumores à dieta suplementada com leucina, podendo modular o desenvolvimento tumoral naquelas células que já possuem a via IRS1/AKT/mTOR constitutivamente ativada. O mecanismo pelo qual a leucina pode retardar o desenvolvimento tumoral em células que possuem a via da mTOR hiperativada parece estar relacionado com o eixo de regulação negativa p70S6K-PI3K, com consequente redução da fosforilação de AKT e liberação das vias apoptóticas nos tecidos tumorais / Abstract: mTOR is a key regulatory protein in various cellular processes including proliferation, cell growth and survival. Growth factors, oxygen, energy status and amino acids are all essential to these processes. New findings in the last few decades have shown that the mTOR pathway is activated in many cellular processes, including tumorigenesis and angiogenesis. The branched chain amino acid leucine has the greatest potential to activate the mTOR pathway. Due to its ability to promote protein synthesis and muscle mass gain, use of leucine is frequently utilized in patients with cancer. However, the effect of leucine on tumor growth is not clear. The aim of this study is therefore to investigate the effect of diet-supplemented leucine on the modulation of tumor growth in several tumor cell lines that differ in the constitutive activation status of the insulin receptor substrate 1 (IRS1)/AKT/mTOR pathway. Both in vitro and in vivo experiments demonstrated different cell proliferation responses when cells were exposed to high doses of leucine. Tumor cell lines PC-3 and MCF-7, which have a constitutively activated mTOR signaling, displayed reduced cell proliferation and G1 phase cell cycle arrest when supplemented with high doses of leucine in vitro. Likewise, leucine-supplemented PC-3 cell tumor xenografts displayed reduced proliferation and increased cell death. We also observed increased activity of mTOR and its downstream substrate p70S6K in all cell lines supplemented with leucine. Increased mTOR activity was accompanied by a reduction in AKT serine 473 (ser473) phosphorylation in cell lines with a hyperactivated PI3K pathway (PC-3 and MCF-7). This most likely occurred because leucine supplementation further increased mTOR and p70S6K activity, triggering the inhibitory p70S6K/IRS1 axis. In fact, we found increased IRS1 ser307 phosphorylation in hyperactivated cell lines (PC-3 and MCF-7) supplemented with high doses of leucine. Therefore, our results suggest that mTOR pathway activation is central to determining the sensitivity of tumors to leucine supplementation. Furthermore, this could affect the response to leucine-supplemented therapies of those tumors in which the PI3K pathway is constitutively activated. The mechanism for this appears to be related to the negative p70S6K/IRS1 regulation axis, with consequent reduction of AKT phosphorylation and the release of apoptotic pathways in tumor tissues / Doutorado / Fisiopatologia Médica / Doutora em Ciências

Orientador: Jaime Amaya-Farfán / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia de Alimentos / Made available in DSpace on 2018-08-19T15:34:35Z (GMT). No. of bitstreams: 1 Moura_CarolinaSoaresde_M.pdf: 1533232 bytes, checksum: 1141b4840c5a0f9342072967abfece65 (MD5) Previous issue date: 2012 / Resumo: As heat shock proteins (HSPs), ou proteínas do estresse, correspondem a um importante sistema de defesa celular que é capaz de proteger e reparar danos causados ao organismo, conferindo à célula maior tolerância e resistência contra situações de alteração na homeostase, sendo também consideradas como um sistema antioxidante complementar. A glutamina é conhecida pelo seu potencial em promover o aumento na HSP70 contra diversas situações agressoras. As proteínas do soro do leite (PSL) contêm concentrações elevadas de aminoácidos de cadeia ramificada (BCAAs), sendo estes substratos para a síntese de glutamina, por meio da enzima glutamina sintetase. Objetivo: o objetivo deste trabalho foi observar a influência do consumo das proteínas do soro do leite (PSL), na forma concentrada (PSLC) e hidrolisada (PSLH), na concentração da HSP70 em ratos exercitados em esteira rolante. Metodologia: foram utilizados 48 ratos Wistar machos (290g ± 8g) divididos primeiramente pelo regime de atividade física em sedentários (S) e exercitados (E), e cada um desses, subdividido em outros três grupos, segundo a dieta. As dietas foram baseadas na AIN93-G, com substituição da fonte protéica da seguinte forma: PSLC, PSLH e caseína (CAS), como controle. O período em dieta experimental foi de 3 semanas, e os animais exercitados foram submetidos a 5 sessões de exercício a 22m/min durante 30 minutos como fonte de estresse térmico, na última semana de vida. Resultados: os resultados revelaram que o consumo da PSLH no grupo exercitado promoveu o aumento da HSP70 em pulmão, e nos músculos sóleo e gastrocnêmio. O consumo da PSLH aumentou os níveis de glutamato, isoleucina e leucina livres no plasma dos animais sedentários. Quando exercitado, o grupo PLSH teve redução no glutamato, leucina e valina (substratos envolvidos na síntese de glutamina) plasmáticos e aumento da enzima glutamina sintetase (GS) no sóleo, sugerindo o provável uso desses aminoácidos para proporcionar o aumento na HSP70. Em adição à elevação da GS, houve também aumento concomitante da concentração de corticosterona no grupo PSLH exercitado, sugerindo a influência do hormônio na enzima. Em relação ao possível dano oxidativo, avaliado pela geração de proteínas carboniladas, os grupos que consumiram PSLC e PSLH reduziram seus valores no plasma e, somente a PSLH, no gastrocnêmio. Houve preservação das proteínas totais e albumina nos grupos PSLC, PSLH exercitados. O ácido úrico aumentou no grupo PSLH exercitado, enquanto que a creatinina aumentou na PSLC, independente do exercício. A glicose foi reduzida nos animais sedentários que consumiram PSLH, porém as variações dos parâmetros sempre permaneceram dentro da normalidade. Nenhum efeito adverso ao consumo das diferentes fontes protéicas foi observado no rim ou no fígado, oriundo da mensuração das enzimas AST, ALT e o metabólito ureia respectivamente. Conclusão: os resultados indicam que o consumo da PSLH pode potencializar a resposta da HSP70, sugerindo aumento na proteção endógena e antioxidante, e que a PSLH possa ser mais estresse-responsiva em ratos submetidos ao exercício / Abstract: The heat shock proteins (HSPs), or stress proteins, correspond to an important cell defense system, whose function is to protect and repair injuries caused to the body, conferring the cell greater tolerance and resistance against altered homeostasis states, and for this reason they have been considered as a complementary antioxidant system. Glutamine in turn has been found to promote the increase of HSPs associated to various situations of stress. The milk whey proteins contain elevated concentrations of branched-chain amino acids (BCAAs), which can participate in the synthesis of glutamine via glutamine synthetase. Objective: the objective of this work was to assess the influence of the intake of the whey proteins either in the form of a concentrate (WPC) or a hydrolyzate (WPH) in enhancing the concentration of HSP70 in rats exercised in the treadmill. Methods: Forty-eight male Wistar rats (290 ± 8g) were divided, first, into two categories according to the level of physical activity: sedentary (S) and exercised (E), and each one subdivided into three groups according to the source of protein in the diet. The diets were based on the standard AIN93-G, formulated containing either WPC, WPH or casein (CAS), as the sole source of protein. The animals consumed the experimental diets for three weeks and those belonging to the exercised group were submitted to training 5 sessions on the last week of life. Results: the results showed that consumption of the WPH promoted the increase of HSP70 in lung, soleus and gastrocnemius in the exercised animals. Increases in plasma free glutamate, isoleucine and leucine of the sedentary rats were also observed. When exercised, the WPH group exhibited a reduction in the plasma levels of glutamate, leucine and valine (all involved in the synthesis of glutamine), plus an increase in the enzyme glutamine synthetase (GS) in the soleus muscle, thus suggesting a probable utilization of this amino acids, as a substrate, in the increase of HSP70. Considering that there was also an elevation of the corticosterone levels in the exercised cohorts that consumed the WPH, the concomitant increase of GS, suggested that the hormone exerted an influence on the enzyme. With regard to a possible oxidative damage, as assessed by the presence of carbonyls proteins, the group that consumed both of the whey proteins (WPC, WPH) exhibited lower plasma levels, but only the WPH reduced the levels in the gastrocnemius. Both total plasma proteins and albumin were preserved in the exercised animals. Uric acid was found to increase in the WPH exercised group, while creatinine increased in the WPC group, regardless of the exercise. Plasma glucose levels were also lowered in the sedentary animals that consumed the WPH diet, but at no time, did the increased or decreased levels of these parameters extrapolated normality. Additionally, from the AST, ALT and urea data, no adverse effects on either liver or kidney could be detected with the intake of the different proteins sources. Conclusion: from these results, it can be concluded that consumption of the WPH, in contrast to WPC or CAS, can enhance the HSP70 response suggesting a magnified endogenous and antioxidant protection, and that the hydrolyzed whey protein can be more stress-responsive / Mestrado / Nutrição Experimental e Aplicada à Tecnologia de Alimentos / Mestre em Alimentos e Nutrição

No description available.

Afin de mieux comprendre la sensibilité du continent européen aux changements climatiques, le potentiel des tétraéthers de glycérol ramifiés (ou « méthylés »), supports de nouveaux indicateurs de température et du pH des sols, a été étudié dans 2 archives sédimentaires. Ces 2 carottes de sédiments marins prélevées à l’embouchure de grands fleuves (Danube et paléo fleuve Manche) de part et d’autre de l’ancienne calotte glaciaire fennoscandinave, offrent l’opportunité d’obtenir des enregistrements contenant une information intégrée à l’échelle de vastes bassins versants depuis le dernier cycle glaciaire. Des reconstitutions continues des températures glaciaires obtenues à partir de l’analyse des tétraéthers ramifiés dans ces carottes sont présentées. Ces enregistrements sont interprétés avec précaution du fait de la relative méconnaissance des organismes producteurs des tétraéthers ramifiés et leur possible production en milieu aquatique. La haute résolution temporelle des reconstitutions permet toutefois de mieux comprendre la variabilité climatique abrupte de la dernière période glaciaire, de part l’estimation des températures associées aux évènements de Heinrich et cycles de Dansgaard-Oeschger, notamment par une estimation quantitative en Europe centrale-est. De plus, l’apport des tétraéthers à la reconstitution du pH des paléosols de cette partie du continent est étudié. Par ailleurs, une méthode automatisée de purification des échantillons, préalable à l’analyse des tétraéthers par HPLC-MS a été mise au point, afin de faciliter le travail préparatoire et promouvoir l’analyse de paléo séquences à haute résolution temporelle utilisant les tétraéthers. / In order to better understand the sensibility of the European continent to climate changes, the potential of branched tetraether lipids, as bases of temperature and soil pH proxies, has been studied in two sedimentary archives. These two marine sediment cores have been chosen for their location at the mouth of major rivers (Danube and paleo Channel river) on both sides of the ancient Fennoscandian ice sheet. Indeed, they enable to get records containing information integrated at large drainage basin scale, since the last glacial cycle. Thus, continuous temperature reconstructions of the last glacial period in Europe, based on branched tetraethers extracted from these cores, are presented. These records are carefully interpreted, notably because of the uncertainties on the tetraether producers and their likely production in the aquatic environment. The high temporal resolution of the reconstruction however enables insights into the last glacial abrupt climate variability, with temperature estimates of Heinrich events and Dansgaard-Oeschger cycles, and especially, quantitative estimations in central eastern Europe. Moreover, the reconstruction of past soil pH in this part of the continent is investigated. Last, an automated purification method for archaeal and bacterial tetraethers in soils and sediments has been developed in order to contribute to enhancing the time resolution of paleosequences based on tetraether biomarkers.

Cette thèse est consacrée à l’étude de certains problèmes variationnels de type transition de phase vectorielle ou "phase-field" qui font intervenir une contrainte de divergence. Ces modèles sont généralement basés sur une énergie dépendant d’un paramètre qui peut représenter une grandeur physique négligeable ou qui est liée à une méthode d’approximation numérique par exemple. Une question centrale concerne alors le comportement asymptotique de ces énergies et des minimiseurs globaux ou locaux lorsque ce paramètre tend vers 0. Cette thèse présente différentes stratégies prenant en compte la contrainte de divergence. Elles seront illustrées à travers l’étude de deux modèles. Le premier est une approximation du modèle Eulérien pour le transport branché par un modèle de type phase-field avec divergence prescrite. Nous montrons comment une estimation uniforme de l’énergie, en fonction de la contrainte sur la divergence, permet d’établir un résultat de Gamma-convergence. Le second modèle, en lien avec la théorie du micromagnétisme, concerne des énergies de type Aviles-Giga dans un cadre vectoriel avec contrainte de divergence. Nous illustrerons dans quelle mesure la méthode d’entropie permet de caractériser les minimiseurs globaux. Dans certaines situations nous montrerons une conjecture de type De Giorgi concernant la symétrie 1D des minimiseurs globaux de l’énergie sous une contrainte au bord. / This thesis is devoted to the study of phase-field type variational models with divergence constraint. These models typically involve an energy depending on a parameter which represents a negligible physical quantity or is linked to some numerical approximation method for instance. A central question concerns the asymptotic behavior of these energies and of their global or local minimizers when this parameter goes to 0. We present different strategies which allow to take the divergence constraint into account. They will be illustrated in two models. The first one is a phase-field type approximation, involving a divergence constraint, of the Eulerian model for branched transportation. We illustrate how uniform estimates on the energy, depending on the constraint on the divergence, allow to establish a Gamma-convergence result. The second model, related to micromagnetics, concerns Aviles-Giga type energies for divergence-free vector fields. We use the entropy method in order to characterize global minimizers. In some situations, we will prove a De Giorgi type conjecture concerning the one-dimensional symmetry of global minimizers under boundary conditions.

This thesis analyses how users' mouse behaviour during a video stall gets influenced by the type of video, either branched or linear, and by the presence of a playback bar. An experiment was conducted with thirty-two participants divided into six groups. Each group was watching a different combination of four videos with stalls, the first two videos belonging to the same type of video and either with or without a playback bar, and the last two videos changed in one of the two aspects. With mouse-tracking, these aspects were studied through the variables of mouse activity, average speed, average distance between the cursor and the playback bar, and the total distance moved on the screen. The participants also filled in questionnaires about their mouse behaviour, after watching each video, and their answers were later analysed through a thematic analysis. The results showed no significant differences between the groups in any of the main dependent variables. In general, within all groups, the participants moved the mouse very scarcely, indicating that the results about mouse movement should be interpreted carefully. During videos with a playback bar, mouse movements appeared to be concentrated to the stalls, focusing the movements to the bottom of the screen where the playback bar is located. Mouse behaviour during videos without a playback bar was more evenly divided between the different parts of the video and of the screen, or the user were not moving the mouse at all. Watching branched or linear videos influenced the mouse behaviour in such a way that branched videos seemed to engage the user to interact with the video player more than the linear videos. However, no difference was noticed between these conditions for active users during stalls when a playback bar was present. The thematic analysis gave clear indications that the playback bar was an important component for understanding a stall. Based on these findings, conclusions are drawn that a stall is a situation of watching videos during which mouse behaviour may be less affected by the type of video, and more influenced by the access to a playback bar. The playback bar was shown to be a source of information about the system and the situation.

No description available.

No description available.

Duchenne Muscular Dystrophy (DMD) is an X-linked recessive, progressive muscle-wasting disease characterized by mutations in the dystrophin gene. Duchenne muscular dystrophy is the most common and most severe form of inherited muscle diseases, with an incidence of 1 in 3,500 male births1,2. Mutations in the dystrophin gene result in non-functional dystrophin or the complete absence of the protein dystrophin, resulting in necrosis and fibrosis in the muscle, loss of ambulation, cardiomyopathies, inadequate or failure of respiratory function, and decreased lifespan. Although there has been little research for effective nutritional strategies, dietary intervention may be effective as an adjuvant treatment. In this study, wild type (WT) and mdx animals were provided either a control or elevated branched chain amino acid (BCAA) diet nocturnally for 25 weeks to determine if the elevated BCAAs would attenuate muscle torque loss. Twenty-five weeks of chronic, elevated BCAA supplementation had no impact on muscle function measures. Interestingly, mdx and WT animals had the same torque responses in the low stimulation frequencies (1 Hz – 30 Hz) compared to higher stimulation frequencies. Tetanus was reached at a much lower stimulation frequency in mdx animals compared to WT animals (100 Hz vs +150 Hz). The mdx mouse consistently had more cage activity in the light cycle X- and Y-planes. Interestingly, animals on the BCAA diet increased X-, Y-, and Z-plane activity in the dark cycles at four weeks while animals on the control diet more Z-plane activity at 25 weeks, although not significant. All three BCAAs were elevated in the plasma at 25 weeks, although only Leu was significantly elevated. The BCAAs had no effect on. The diaphragm and skeletal muscle masses were larger in mdx animals, and WT animals had a significantly larger epididymal fat pad. The active state of BCKDC determined by phosphorylation of the E1α enzyme was greater in WT animals in white skeletal muscle, but not red skeletal muscle. Protein synthesis effectors of the mTORC1 signaling pathway and autophagy markers were similar among groups. Wild type animals had increased mTORC1 effectors and animals on the BCAA diet had decreased autophagy markers, although not significant. Although BCAAs did not affect muscle function, fibrosis, or protein synthesis effectors, this study illustrates the functionality of mdx muscles over time. It would be interesting to see how the different muscle fiber types are affected by DMD, noting the differences between the diaphragm, heart, red muscle, and white muscle fibrosis markers. Although there was no increase in mTORC1 effectors with an elevated BCAA diet, it would be interesting to determine muscle protein synthesis, myofibrillar protein synthesis, and total protein turnover in the mdx mouse with an elevated BCAA diet, although the dietary intervention started when mice arrived at 4 weeks of age, earlier intervention may be beneficial early in the disease process. / Doctor of Philosophy / Duchenne Muscular Dystrophy (DMD) is an X-linked recessive, progressive muscle-wasting disease characterized by mutations in the dystrophin gene. Duchenne muscular dystrophy is the most common and most severe form of inherited muscle diseases, with an incidence of 1 in 3,500 male births1,2. Mutations in the dystrophin gene result in non-functional dystrophin or the complete absence of the protein dystrophin, resulting in necrosis and fibrosis in the muscle, loss of movement and walking ability, cardiomyopathies, inadequate or failure of respiratory function, and decreased lifespan. Although there has been little research for effective nutritional strategies, dietary intervention may be effective as an adjuvant treatment and palliative care. The branched chain amino acids (BCAAs) are known to directly stimulate muscle protein synthesis by direct activation of the mechanistic target of rapamycin complex 1 (mTORC1). This study aimed to illustrate the differences between diseased and healthy mice and determine if BCAAs can reduce muscle torque loss. Twenty-five weeks of chronic, elevated BCAA supplementation had no impact on muscle function measures. Interestingly, mdx and WT animals had the same torque responses in the low stimulation frequencies (1 Hz – 30 Hz) compared to higher stimulation frequencies. Tetanus was reached at a much lower stimulation frequency in mdx animals compared to WT animals (100 Hz vs +150 Hz). The mdx mouse consistently had more cage activity in the light cycle X- and Y-planes. Interestingly, animals on the BCAA diet increased X-, Y-, and Z-plane activity in the dark cycles at four weeks while animals on the control diet more Z-plane activity at 25 weeks, although not significant. All three BCAAs were elevated in the plasma at 25 weeks, although only Leu was significantly elevated. The BCAAs had no effect on. The diaphragm and skeletal muscle masses were larger in mdx animals, and WT animals had a significantly larger epididymal fat pad. The active state of BCKDC determined by phosphorylation of the E1α enzyme was greater in WT animals in white skeletal muscle, but not red skeletal muscle. Protein synthesis effectors of the mTORC1 signaling pathway and autophagy markers were similar among groups. Wild type animals had increased mTORC1 effectors and animals on the BCAA diet had decreased autophagy markers, although not significant. Although BCAAs did not affect muscle function, fibrosis, or protein synthesis effectors, this study illustrates the functionality of mdx muscles over time. It would be interesting to see how the different muscle fiber types are affected by DMD, noting the differences between the diaphragm, heart, red muscle, and white muscle fibrosis markers. Although there was no increase in mTORC1 effectors with an elevated BCAA diet, it would be interesting to determine muscle protein synthesis, myofibrillar protein synthesis, and total protein turnover in the mdx mouse with an elevated BCAA diet, although the dietary intervention started when mice arrived at 4 weeks of age, earlier intervention may be beneficial early in the disease process.

Recent findings have shown an inverse association between the circulating levels of pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0) with the risk of pathological development in type 2 diabetes, cardio vascular disease and neurological disorders. From previously published research, it has been said that both these odd chain fatty acids are biomarkers of their dietary intake and are significantly correlated to dietary ruminant fat intake. However, there are profound studies that show the contrary where they do not display this biomarker correlation. Additionally, several astute studies have suggested or shown odd chain fatty acid endogenous biosynthesis, most often suggested via alpha oxidation; the cleavage of a single carbon unit from a fatty acid chain within the peroxisomes. To better understand the correlations and interactions between these two fatty acids with pathological development, the origin of these odd chain fatty acids needed to be determined, along with confirming their association with the disease aetiology. To minimise animal & human experimentation we made use of existing sample sets made available through institutional collaborations, which produced both animal and human interventional study samples suitable for odd chain fatty acid investigations. These sample collaborations allowed us to comprehensively investigate all plausible contributory sources of these odd chain fatty acids; including from the intestinal microbiota, from dietary contributions, and derived from novel endogenous biosynthesis. The investigations included two intestinal germ-free studies, two ruminant fat diet studies, two dietary fat studies and an ethanol intake study. Endogenous biosynthesis was assessed through: a stearic acid infusion, phytol supplementation, and an Hacl1 knockout mouse model. A human dietary intervention study was used to translate the results. Finally, a study comparing circulating baseline C15:0 and C17:0 levels with the development of glucose intolerance. We found that the circulating C15:0 and C17:0 levels were not significantly influenced by the presence or absence of intestinal microbiota. The circulating C15:0 levels were significantly and linearly increased when the C15:0 dietary composition increased; however, there was no significant correlation in the circulating C17:0 levels with intake. Circulating levels of C15:0 were affected by the dietary composition and factors affecting the dietary intake, e.g. total fat intake and ethanol, whereas circulating C17:0 levels were found to be independent of these variables. In our studies, the circulating C15:0 levels were not significantly affected by any expected variations in alpha oxidation caused by pathway substrate inhibition or gene knockout. However, C17:0 was significantly related, demonstrating it is substantially endogenously biosynthesised. Furthermore, we found that the circulating C15:0 levels, when independent of any dietary variations, did not correlate with the progression of glucose intolerance when induced, but the circulating C17:0 levels did significantly relate and linearly correlated with the development of glucose intolerance. To summarise, the circulating C15:0 and C17:0 levels were independently derived; the C15:0 levels substantially correlated with its dietary intake, whilst the C17:0 levels proved to be separately derived from its endogenous biosynthesis via alpha oxidation of stearic acid. C15:0 was found to be minimally endogenously biosynthesised via a single cycle of beta oxidation of C17:0 in the peroxisomes, however, this did not significantly contribute to the circulating levels of C15:0. Additionally, only the baseline levels of C17:0 significantly correlated with the development of glucose intolerance. These findings highlight the considerable differences between both of these odd chain fatty acids that were once thought to be homogeneous and similarly derived. On the contrary, they display profound dietary, metabolic, and pathological differences.