L’homéostasie énergétique ou ‘balance énergétique’ est l’équilibre qui s’établit chez l’Homme et l’animal adulte entre la prise quotidienne de nutriments sous la forme de glucides, de lipides ou de protéines et leur oxydation pour ne produire que la quantité énergétique strictement nécessaire. Pour maintenir cette balance l’organisme doit recueillir en permanence des signaux nerveux, métaboliques ou hormonaux de la part de cellules spécifiques. Ces senseurs des besoins énergétiques transmettent alors à des centres régulateurs leurs informations qui en retour, par voie hormonale ou nerveuse, informent les organes effecteurs des mesures à prendre pour stocker, produire ou consommer l’énergie. Les trois principaux centres de cette balance sont 1/ le cerveau, centre intégrateur de l’information ; 2/ un groupe d’organes effecteurs parmi lesquels le foie, le tissu adipeux, les muscles squelettiques, le pancréas et 3/ un centre senseur de la qualité et de la quantité des aliments, le tractus gastrointestinal (Migrenne 2006). En plus d’être la source d’énergie nécessaire à la vie des cellules, les nutriments tels que les acides gras, le cholestérol ou encore le glucose sont aussi des molécules de signalisation cellulaire à la fois par leur fixation à des récepteurs membranaires mais aussi via des récepteurs nucléaires. Un déséquilibre dans l’homéostasie énergétique dû à une alimentation déséquilibrée, à un manque d’exercice physique ou à des facteurs génétiques est une caractéristique de l’obésité et de complications telles que le diabète de type 2 et les maladies cardiovasculaires (Hill, 2006). Au cours de ma thèse je me suis intéressé à l’intestin pour son rôle de régulateur de l’homéostasie énergétique dans un contexte physiologique ou physiopathologique d’obésité via sa capacité à sécréter l’incrétine Glucagon-Like Peptide-1 (GLP-1) en réponse au glucose et aux acides biliaires. J’ai étudié plus particulièrement le rôle du récepteur nucléaire en tant que senseurs moléculaires des acides biliaires FXR dans les cellules sécrétrices de cette incrétine car à l’heure actuelle rien n’était connu quant à son rôle ni même quant à son expression dans la cellule L. Pour cela, j’ai utilisé des lignées cellulaires murines et humaines où j’ai mis au point les conditions expérimentales pour répondre aux questions posées. Grâce à des ARN d’intestins issus de différents modèles de souris la relevance chez le rongeur a été testée. La relevance de ces résultats sur des biopsies intestinales humaine a également été testée. Grâce à ces outils, j'ai pu montré que FXR dans les cellules L était fonctionnel et que son activation interférait avec la voie de la glycolyse entrainant moins de synthèse et de sécrétion de GLP-1. Cela nous a permis de proposer un nouveau mécanisme moléculaire par lequel les séquestrants des acides biliaires exercent leur effets bénéfiques chez des patients atteints de diabète de type 2. / Originally identified as dietary lipid detergents, bile acids (BA) are now recognized as signaling molecules which bind to the transmembrane receptor TGR5 and the nuclear receptor FXR (Farnesoid X Receptor). Upon binding to TGR5 at the surface of enteroendocrine L cells, bile acids (BA) promote the secretion of the incretin GLP-1 which potentiates the glucose-induced insulin secretion by pancreatic beta-cells. More than 50% of the insulin secretion in response to glucose is mediated by GLP-1 and the other incretin Glucose-dependent Insulinotropic Polypeptide (GIP). Once secreted, GLP-1 is rapidly (2-3 minutes) degraded by the endothelial enzyme Dipeptydil Peptidase 4 (DPP4). GLP-1 analogues and DPP4 inhibitors are successfully used for the treatment of T2D. FXR is a ligand-activated nuclear receptor highly expressed in the liver and in the distal intestine. FXR controls BA, lipid and glucose metabolism. Whether FXR is expressed, functional in intestinal enteroendocrine L cells and in which extend its activation affects GLP-1 production are not yet reported. Encouraging data were obtained during my M2 training course. The aim of my thesis was thus to assess whether FXR in enteroendocrines cells could participate in the control of the deregulation of glucose homeostasis. Multiple in vitro, ex vivo and in vivo human and murine models allowed us to show that FXR is present and functional in L cells. FXR activation decreases GLP-1 production and secretion in L cells by inhibiting glycolysis pathway through an interference with the carbohydrate responsive transcription factor ChREBP. Finally, I identified an additional mechanism of action of the bile acid sequestrant Colesevelam, a molecule currently successfully used in USA for treating type 2 diabetic patients.

The development of a bioartificial pancreas (BAP) has the potential to substantially improve the treatment of insulin-dependent diabetes. Composed of insulin-secreting cells encapsulated in a hydrogel material, a BAP may provide superior glycemic regulation compared with conventional exogenous insulin-delivery therapies. Towards this goal, β- cells or islets encapsulated in alginate microcapsules remain a promising approach. Due to the limited supply of human islets, alternative cell sources are under investigation for incorporation into a BAP, including porcine islets and β- cell lines. Several challenges remain to clinical implementation, including loss of islet or β- cell function and viability following transplantation and host response to the transplanted microcapsules. The objective of this work was to evaluate strategies to improve a BAP by supporting the function and survival of encapsulated islets and β -cells. Towards this goal, two areas were explored: 1) the provision of pro-survival and insulinotropic factors, namely, CXCL12 and GLP-1 (or a GLP-1 analog, Exendin-4), to encapsulated islets and β-cells and 2) modification of the alginate microcapsule to confer long-term resistance to host cell adhesion. To achieve the first objective, methods to deliver both pro-survival and insulinotropic factors to a BAP were developed and their effects on encapsulated β-cells and porcine islets were studied, both in vitro and in vivo. Results demonstrate that delivery of pro-survival and insulinotropic factors is a promising strategy to prolong the survival and function of a BAP. To reduce host cell adhesion to the microcapsule, we employed covalent conjugation of PEG to the surface of alginate-PLL capsules to replace the un-crosslinked layer of alginate used in traditional alginate-PLL-alginate (APA) microcapsules. Results demonstrate that while PEGylation of alginate-PLL microcapsules initially reduced host cell adhesion over 2 weeks in vivo compared with APA capsules, the PEG coating did not provide long-term protection over 3 months. Taken together, these studies represent a multipronged approach towards improving the duration of BAP function, with the ultimate goal of advancing this technology to the clinic.

The main topic of this thesis is based on multiple-input multiple-output (MIMO) wireless communications, which is a novel technology that has attracted great interest in the last twenty years. Conventional MIMO systems using up to eight antennas play a vital role in the urban cellular network, where the deployment of multiple antennas have significantly enhanced the throughput without taking extra spectrum or power resources. The massive MIMO systems “scales” up the benefits that offered by the conventional MIMO systems. Using sixty four or more antennas at the BS not only improves the spectrum efficiency significantly, but also provides additional link robustness. It is considered as a key technology in the fifth generation of mobile communication technology standards network, and the design of new algorithms for these two systems is the basis of the research in this thesis. Firstly, at the receiver side of the conventional MIMO systems, a general framework of bit error rate (BER) approximation for the detection algorithms is proposed, which aims to support an adaptive modulation scheme. The main idea is to utilize a simplified BER approximation scheme, which is based on the union bound of the maximum-likelihood detector (MLD), whereby the bit error rate (BER) performance of the detector for the varying channel qualities can be efficiently predicted. The K-best detector is utilized in the thesis because its quasi- MLD performance and the parallel computational structure. The simulation results have clearly shown the adaptive K-best algorithm, by applying the simplified approximation method, has much reduced computational complexity while still maintaining a promising BER performance. Secondly, in terms of the uplink channel estimation for the massive MIMO systems with the time-division-duplex operation, the performance of the Grassmannian line packing (GLP) based uplink pilot codebook design is investigated. It aims to eliminate the pilot contamination effect in order to increase the downlink achievable rate. In the case of a limited channel coherence interval, the uplink codebook design can be treated as a line packing problem in a Grassmannian manifold. The closed-form analytical expressions of downlink achievable rate for both the single-cell and multi-cell systems are proposed, which are intended for performance analysis and optimization. The numerical results validate the proposed analytical expressions and the rate gains by using the GLP-based uplink codebook design. Finally, the study is extended to the energy efficiency (EE) of the massive MIMO system, as the reduction carbon emissions from the information and communication technology is a long-term target for the researchers. An effective framework of maximizing the EE for the massive MIMO systems is proposed in this thesis. The optimization starts from the maximization of the minimum user rate, which is aiming to increase the quality-of-service and provide a feasible constraint for the EE maximization problem. Secondly, the EE problem is a non-concave problem and can not be solved directly, so the combination of fractional programming and the successive concave approximation based algorithm are proposed to find a good suboptimal solution. It has been shown that the proposed optimization algorithm provides a significant EE improvement compared to a baseline case.

Current methods of energy restriction are not successful for achieving long-term weight loss and maintenance for the majority of individuals. As a result, the prevalence of obesity and obesity related diseases continue to increase. This calls for the development of novel lifestyle interventions to combat the obesity epidemic. Hunger has been highlighted as a major factor influencing the long-term success of weight management methods and therefore how a given dietary intervention affects the appetite regulatory system may dictate the success of the diet by augmenting long-term adherence. In addition, the effect of a given dietary intervention on exercise may determine its suitability for exercising individuals and may influence the energy deficit that can be achieved by the diet. This thesis investigated the acute effects of two novel methods of dietary restriction; breakfast omission and severe energy restriction. The main aims for this thesis were to determine the effect of these methods of energy restriction on ad-libitum energy intake, subjective appetite sensations, and peripheral concentrations of hormones involved in appetite regulation. In addition, this thesis also investigated the effects of these methods of energy restriction on metabolism and glycaemic control at rest, and performance and perceived exertion during exercise. This work found that moderate and severe energy deficits induced by breakfast omission and 24 h of severe energy restriction, respectively, resulted in either no (Chapter VIII) or partial (Chapters IV and VII) energy intake compensation over the subsequent 24-48 h. Subjective appetite was increased during (Chapters IV, V, VII and VIII) and shortly after (Chapter VII) energy restriction, but this effect was transient and was offset after an ad-libitum (Chapters IV and VII) or standardised (Chapters V and VIII) meal. In addition, none of the work presented in this thesis demonstrated an appetite hormone response to energy restriction that was indicative of compensatory eating behaviour. Compared to breakfast omission, breakfast consumption resulted in an increased in resting energy expenditure and carbohydrate oxidation, with a concurrent reduction in fat oxidation during the morning. However, there were no differences after lunch (Chapter V). In response to a standardised breakfast, resting energy expenditure was suppressed (Chapter VII) or not different (Chapter VIII) the following morning, after 24 h severe energy restriction compared to energy balance. Plasma NEFA and fat oxidation was greater, carbohydrate oxidation was reduced, and postprandial insulin sensitivity was impaired in the after 24 h severe energy restriction (Chapter VI, VII and VIII). In Chapter IV, omission of breakfast in the morning was shown to reduce exercise performance in evening, even after provision of an ad-libitum lunch 4 h before. However, there was no difference in perception of effort during steady state exercise, independent of breakfast consumption or omission in the morning (Chapters IV and V). Collectively, breakfast omission and 24 h severe energy restriction reduce energy intake and promote an appetite regulatory response conducive to maintenance of a negative energy balance. Chronic intervention studies are now required to confirm whether these effects persist after long-term practice of these dietary interventions.

Made available in DSpace on 2015-05-14T13:21:51Z (GMT). No. of bitstreams: 1 parte1.pdf: 2341886 bytes, checksum: b60aeb9bdb2a2b38987ae190843fc008 (MD5) Previous issue date: 2010-10-10 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The search for new energy sources and concern about environmental problems has caused an increase in the use of gaseous fuels like natural gas (CNG) and liquefied petroleum gas (LPG). The main advantages of these fuels besides clean energy, are low production and processing costs, high efficiency and versatility. Given these realities, there is both growing need and demand for quality controls applicable to these types of fuel. This study proposes quality screening analysis of gaseous fuels using near infrared (NIR) absorption spectroscopy for verifying adulteration and/or nonconformity of LPG and CNG samples. The development of gas handling equipment made possible the construction of different classification models for screening analysis, such as SIMCA, SPA-SPA-LDA and SIMCA. To build and test these models, several samples were grouped as; tampered with, adulterated, and commercially certified standard. The results demonstrated the methodology as effective and robust for performing preliminary analysis of CNG and LPG quality, minimizing normal drawbacks of the quality control reference methods used for these fuels. / A busca por novas fontes de energia e a preocupação com problemas ambientais provocaram um aumento no uso de combustíveis gasosos como o gás natural veicular (GNV) e gás liquefeito de petróleo (GLP). Entre as principais vantagens desses combustíveis, destacam-se o baixo custo de produção e processamento, sua grande eficiência e versatilidade, além de ser uma fonte limpa de energia. Diante dessa realidade, cresce também a necessidade e a demanda pelo monitoramento da qualidade e fiscalização desse tipo de combustível. Esse trabalho propõe a utilização da análise de triagem da qualidade dos combustíveis gasosos por espectroscopia de absorção no infravermelho próximo (NIR) para verificação de adulterações ou nãoconformidades de amostras de GLP e GNV. O desenvolvimento de equipamentos de manipulação de gases possibilitou a construção de diferentes modelos de classificação para análise de triagem, tais como, SIMCA, SPA-LDA e o SPASIMCA. Para construir e testar esses modelos, foram agrupadas diversas amostras adulteradas, não-adulteradas e padrões certificados comercialmente. Os resultados demonstraram que a metodologia desenvolvida é bastante eficaz e robusta ao realizar análises preliminares da qualidade do GNV e GLP, minimizando alguns inconvenientes dos métodos de referência utilizados para o controle de qualidade desses combustíveis.

[pt] A preocupação com o esgotamento de recursos naturais, acrescida de legislações cada vez mais restritivas no descarte de materiais, fez com que modelos de negócio baseados na reutilização de itens ganhassem força em comparação aos baseados em descarte. Nas cadeias de distribuição do tipo closed-loop, a gestão de itens retornáveis permanece como ponto de grande preocupação para seus gestores, dados os altos investimentos realizados nestas populações, contrastando com a relativa baixa atenção dada ao desenvolvimento de técnicas de gestão. O controle individual de itens retornáveis com a utilização de tecnologias como identificação por radiofrequência (RFID) mostra-se como a solução para alguns destes desafios. O objetivo deste trabalho é avaliar a viabilidade desta aplicação dado o atual estágio de maturidade da tecnologia RFID, identificar os fatores críticos de sucesso através da análise de estudos de caso envolvendo aplicações similares, e propor uma abordagem integrada para a indústria de distribuição de gás liquefeito de petróleo (GLP) no mercado brasileiro. Tendo a tecnologia atingido um grau adequado de maturidade, com soluções integradas disponíveis no mercado, os principais desafios deste tipo de aplicação passam a envolver questões organizacionais, como a gestão da mudança, similarmente à implantação de tecnologias bastante maduras, como sistemas de gestão integrados. / [en] Concerns with the exhaustion of natural resources, combined with growing legal restrictions on waste disposal, has drawn attention to business models based on the reutilization of items, in comparison with the disposal-based models. In closed-loop supply chains, the management of returnable items remains as a major challenge for its leaders, due to the significant investments made on these populations, contrasting with the relatively low attention given to the development of management practices in this area. The individual control of returnable items with the use of the radio frequency identification (RFID) technology emerges as a possible solution for these challenges. The objectives of this research are to evaluate the current maturity level of the RFID technology, identify critical success factors through the analysis of related case studies, and propose an integrated approach for the liquefied petroleum gas (LPG) distribution industry in Brazil. Having reached a satisfactory maturity level, with integrated solutions available in the marketplace, the main challenges of such applications move towards organizational issues, as change management, similar to the implementation of more mature technologies, such as enterprise resource planning systems.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13429号 / 論医博第2233号 / 新制||医||1053(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 長船 健二, 教授 妹尾 浩, 教授 川口 義弥 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Thesis / Doctor of Philosophy (PhD)

Diabetes Mellitus has continued to drastically affect the health of the world and many complications can prove fatal. As long as this metabolic disease persist, research discoveries will need to continue to be made so that patient outcomes and healthcare are dramatically enhanced. In recent years, GLP-1 has been the topic of conversation for diabetes research, due to its promising effects in promoting insulin sensitivity. Furthermore, bile acids and their receptors (TGR5 & FXR) have shown promise in their actions in the regulation of GLP-1, and thus glucose homeostasis. Here we have shown the detection and increased expression of TGR5 and GLP-1, and decreased expression of FXR in diabetic mouse intestinal mucosa tissues. We have also shown the detection and increased expression of these receptors in STC-1 cells. More importantly we have linked the connection of increased glucose concentration (hyperglycemia) to increased TGR5 activation to increased GLP-1 release, thus leading to increased insulin sensitivity and altered diabetic outcomes.

The regulation of glucagon-like peptide-1 and peptide YY hormone levels are regulated based on different influential factors, but primarily levels are dependent upon ingested food content. As meals today become more fat-enriched, there is greater requirement for evaluation of these hormones that regulate insulin and satiety levels within the body. We have shown that the gene expression transcript production of glucagon-like peptide-1 and peptide YY are modulated by different concentrations, and times of short-chain fatty acids and long-chain fatty acids. Although the peptide hormone levels have the influential physiological role on effector tissue, the regulation of these hormones begins at the transcript levels. Recent research indicates that glucagon-like peptide-1 and peptide YY hormones are altered in response to different free-fatty acids. The present investigation generally demonstrated an overall decrease in both hormones after chronic exposure to fatty acids. Intestinal secretin tumor cell line (STC-1 cells) was used as a representative for intestinal L-cells. Quantitative real-time PCR analysis was used to determine the changes in RNA transcripts. Overall, there was a decrease in the 3-hour timeline, which continued to decrease in the 16-hour and 24-hour timelines for glucagon-like peptide-1. Peptide YY transcript expression in 3-hours increased significantly after exposure to propionate, a significant decrease after exposure to acetate, and no significant increase or decrease after exposure to butyrate. However, there was a significant decrease in peptide YY once reaching 24-hour exposure. It was determined there is a threshold for different concentrations of free-fatty acids to influence glucagon-like peptide-1 and peptide YY production, which was present in the different concentrations of butyrate. Lastly, exposure to both concentrations of linolenic acid caused a significant decrease in glucagon-like peptide-1 and peptide YY.