Effets comparatifs des acides gras omega-3 (ALA, EPA, DHA) sur la sensibilité à l’insuline des cellules musculaires C2C12 dans un contexte lipotoxique

Objectifs :Etudier le rôle des ω3 sur la lipotoxicité induite par l’acide gras saturé palmitate (PAL, C16:0) dans un modèle de cellule musculaire C2C12.Identifier les effets propres de chaque w3 (ALA, EPA et DHA) à dose équivalente sur la fluidité des membranes et la réponse à l’insuline.Suivre le devenir intracellulaire du [1-14C]-palmitate en présence d’un w3 et définir les classes de lipides altérées.Rechercher les voies de signalisation impliquées dans la modulation de la réponse à l’insuline

Loss of thymidine phosphorylase activity disrupts adipocyte differentiation and induces insulin-resistant lipoatrophic diabetes.

BACKGROUND: Thymidine phosphorylase (TP), encoded by the TYMP gene, is a cytosolic enzyme essential for the nucleotide salvage pathway. TP catalyzes the phosphorylation of the deoxyribonucleosides, thymidine and 2'-deoxyuridine, to thymine and uracil. Biallelic TYMP variants are responsible for Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE), an autosomal recessive disorder characterized in most patients by gastrointestinal and neurological symptoms, ultimately leading to death. Studies on the impact of TYMP variants in cellular systems with relevance to the organs affected in MNGIE are still scarce and the role of TP in adipose tissue remains unexplored. METHODS: Deep phenotyping was performed in three patients from two families carrying homozygous TYMP variants and presenting with lipoatrophic diabetes. The impact of the loss of TP expression was evaluated using a CRISPR-Cas9-mediated TP knockout (KO) strategy in human adipose stem cells (ASC), which can be differentiated into adipocytes in vitro. Protein expression profiles and cellular characteristics were investigated in this KO model. RESULTS: All patients had TYMP loss-of-function variants and first presented with generalized loss of adipose tissue and insulin-resistant diabetes. CRISPR-Cas9-mediated TP KO in ASC abolished adipocyte differentiation and decreased insulin response, consistent with the patients' phenotype. This KO also induced major oxidative stress, altered mitochondrial functions, and promoted cellular senescence. This translational study identifies a new role of TP by demonstrating its key regulatory functions in adipose tissue. CONCLUSIONS: The implication of TP variants in atypical forms of monogenic diabetes shows that genetic diagnosis of lipodystrophic syndromes should include TYMP analysis. The fact that TP is crucial for adipocyte differentiation and function through the control of mitochondrial homeostasis highlights the importance of mitochondria in adipose tissue biology

Jørn Utzon y Rafael Moneo: el mercado como lugar de encuentro

Este artículo analiza el papel que desempeña el mercado como lugar de encuentro en los proyectos de Jørn Utzon y Rafael Moneo a través de la voluntad de incidir y transformar el espacio urbano donde se sitúan, al relacionarlos con los precedentes históricos y contextualizarlos en la trayectoria profesional de los dos arquitectos, desde el organicismo de sus primeros proyectos a la agregación compositiva de la arquitectura aditiva, y al ilustrar, además, la influencia del maestro danés en la arquitectura de Rafael Moneo.Postprint (published version

Reprogramming of hepatic fat accumulation and 'browning' of adipose tissue by the short-chain fatty acid acetate

Background/Objectives: Short-chain fatty acids, produced by microbiome fermentation of carbohydrates, have been linked to a reduction in appetite, body weight and adiposity. However, determining the contribution of central and peripheral mechanisms to these effects has not been possible. Subjects/Methods:C57BL/6 mice fed with either normal or high-fat diet were treated with nanoparticle-delivered acetate, and the effects on metabolism were investigated. Results:In the liver, acetate decreased lipid accumulation and improved hepatic function, as well as increasing mitochondrial efficiency. In white adipose tissue, it inhibited lipolysis and induced 'browning', increasing thermogenic capacity that led to a reduction in body adiposity. Conclusions:This study provides novel insights into the peripheral mechanism of action of acetate, independent of central action, including ‘browning’ and enhancement of hepatic mitochondrial function

Rôle de l'oxydation mitochondriale hépatique des acides gras dans la stéatose hépatique, l'insulinorésistance et la lipotoxicité

Une diminution de la ß-oxydation mitochondriale des acides gras (OAG) dans le foie peut entraîner l apparition d une stéatose hépatique et contribuer à l instauration de l insulinorésistance (IR). La carnitine palmitoyltransférase 1 hépatique (CPT1A) est le site majeur du contrôle hépatique de l OAG. L objectif de ma thèse a été de déterminer si une augmentation de l OAG, via l expression d une CPT1 constitutivement active (CPT1mt), représente une cible potentielle pour corriger la stéatose hépatique et l IR. L expression hépatique de la CPT1mt dans deux modèles animaux d obésité (souris ob/ob, régime hyperlipidique et hyperglucidique (HF/HS)) ne modifie pas la stéatose hépatique mais améliore la tolérance au glucose chez les souris HF/HS et ob/ob et diminue l IR chez les souris ob/ob. Ces résultats suggèrent une dissociation entre la stéatose hépatique et l IR. Dans le foie des souris HF/HS, l amélioration de la signalisation de l insuline résulte en partie d une diminution de la lipotoxicité, du stress oxydant et de l inflammation. Ainsi, la CPT1A est une cible de choix pour diminuer les désordres métaboliques associés à l obésité. Au cours de ma thèse, j ai aussi participé à un projet visant à mieux comprendre le métabolisme lipidique dans le foie de patients obèses. Nos résultats préliminaires montrent qu au cours du développement de la stéatohépatite non alcoolique (NASH) l orientation métabolique des acides gras n est pas modifiée ainsi que l expression de la plupart des gènes clés du métabolisme glucido-lipidique. Cependant, l OAG semble être incomplète chez les patients obèses avec NASH, ce qui pourrait participer au développement du stress oxydantA decrease in hepatic mitochondrial fatty acid oxidation (FAO) leads to hepatic steatosis that can participate to the induction of insulin resistance (IR). The liver carnitine palmitoyltransferase 1 (CPT1A) constitutes the key regulatory site in the control of FAO. My PhD objective was to determine if an increase in FAO, through the expression of a constitutively active CPT1A (CPT1mt), could represent a potential target to counteract hepatic steatosis and IR. Liver CPT1mt expression in diet (high-fat/high-sucrose (HF/HS))- or genetic (ob/ob)-induced obese mice does not alter hepatic steatosis but ameliorates glucose tolerance in HF/HS and ob/ob mice and attenuates insulin resistance in ob/ob mice. These results suggest a dissociation between hepatic steatosis and IR. In HF/HS mouse liver, improved insulin signaling was linked to a decreased lipotoxicity, oxidative stress and inflammation. Therefore, CPT1A is a pertinent target to diminish metabolic disorders associated with obesity. I also participated to a project which aim is to better understand hepatic lipid metabolism in obese patients. Our preliminary data suggest that during steatohepatitis (NASH) development, metabolic FA orientation and gene expression pattern of most of the key enzymes involved in glucido-lipidic metabolism are not modified. However, the hepatic capability to fully oxidize oleate into CO2 seems to be decreased in obese patients with NASH, which could participate to oxidative stress developmentPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF