6 research outputs found

    Investigating metabolic dysfunction and arrhythmogenesis in an early-onset atrial fibrillation patient cohort

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    Despite the prevalence of atrial fibrillation (AF) and the burden it places on health care systems, there remains much that is unknown regarding heritable factors influencing its development and progression. In this study, I investigated whole-exome sequencing (WES) data from a cohort of patients presenting with early-onset AF to explore the role that metabolic dysfunction might play in contributing to disease onset. I curated a metabolism-related gene panel and, following in silico prediction of variant pathogenicity, performed gene-level burden testing using reference data from the Genome Aggregation Database (gnomAD) and the human mitochondrial genome database MITOMAP. I further explored genes associating with AF in the UK Biobank data set, and discovered associations with several AF comorbidities including diabetes, hypertension, and stroke

    Role of adipose tissue in the pathogenesis and treatment of metabolic syndrome

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    漏 Springer International Publishing Switzerland 2014. Adipocytes are highly specialized cells that play a major role in energy homeostasis in vertebrate organisms. Excess adipocyte size or number is a hallmark of obesity, which is currently a global epidemic. Obesity is not only the primary disease of fat cells, but also a major risk factor for the development of Type 2 diabetes, cardiovascular disease, hypertension, and metabolic syndrome (MetS). Today, adipocytes and adipose tissue are no longer considered passive participants in metabolic pathways. In addition to storing lipid, adipocytes are highly insulin sensitive cells that have important endocrine functions. Altering any one of these functions of fat cells can result in a metabolic disease state and dysregulation of adipose tissue can profoundly contribute to MetS. For example, adiponectin is a fat specific hormone that has cardio-protective and anti-diabetic properties. Inhibition of adiponectin expression and secretion are associated with several risk factors for MetS. For this purpose, and several other reasons documented in this chapter, we propose that adipose tissue should be considered as a viable target for a variety of treatment approaches to combat MetS

    Nutritional Immunotherapy: targeting immunometabolism with bioactive food compounds

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    La immunoter脿pia nutricional es basa en fomentar la salut mitjan莽ant el consum de compostos bioactius presents de manera natural en els aliments, com les procianidines, un tipus de flavonoid, i/o l鈥櫭燾id docosahexaenoic (DHA), un 脿cid gras omega-3, optimitzant la funcionalitat del propi sistema immune i millorant aix铆 el seu paper com a responsable de la preservaci贸 de l鈥檕rganisme enfront desestabilitzadors de la home貌stasis. La recerca que aquesta tesi abasta es centra en el paper del perfil nutricional en la regulaci贸 de la interacci贸 immunitat-metabolisme (immunometabolisme). Amb aquesta finalitat, en la primera part del treball presentat en aquesta tesi, es va determinar si els macr貌fags, les c猫l鈥ules efectores de la immunitat innata, poden percebre de manera diferencial la composici贸 de la dieta. Hem demostrat que els compostos bioactius dels aliments modulen, a nivell molecular, l鈥檃ctivaci贸 dels macr貌fags. A m茅s, aquest efecte immunomodulador 茅s dependent del compost, on factors intr铆nsecs com les propietats qu铆miques o nutritives s贸n determinants per la seva bioactivitat. La segona part va tenir com a objectiu determinar el paper primordial del patr贸 nutricional en la regulaci贸 de la interacci贸 entre el sistema immune i el metabolisme. Utilitzant un model d鈥檕besitat indu茂da per la dieta es va inferir que, mentre una dieta hipercal貌rica provoca un deteriorament de l鈥檌mmunometabolisme, el consum de bioactius pot enfortir-ne la relaci贸. A la tercera part, es va analitzar el paper de les interaccions gen-dieta en l鈥檈xpressi贸 fenot铆pica dels trets associats amb la obesitat. Per aquest motiu, dos races de rates cong猫nites, fenot铆picament diferents, van ser sotmeses a un desequilibri immunometab貌lic com a conseq眉猫ncia de la ingesta d鈥檜na dieta hipercal貌rica. Es va deduir que les interaccions entre els factors gen猫tics i nutricionals s贸n fonamentals per a la susceptibilitat d鈥檜n genotip a l鈥檕besitat indu茂da per la dieta. Hem establert que el perfil nutricional 茅s una eina poderosa per orientar la funcionalitat de l鈥檈ix immunometab貌lic. A m茅s, arribem a la conclusi贸 que compostos bioactius presents en els aliments poden millorar-ne l鈥檈fici猫ncia d鈥檃quest eix, promovent aix铆 un estat saludable.La immunoterapia nutricional se basa en fomentar la salud mediante el consumo de componentes bioactivos presentes de forma natural en los alimentos, como las procianidinas, un tipo de flavonoides, o el 谩cido docosahexaenoico (DHA), un 谩cido graso omega-3, optimizando la funcionalidad del propio sistema inmune y mejorando as铆 su papel como responsable de la preservaci贸n del organismo frente a desestabilizadores de la homeostasis. La investigaci贸n que engloba esta tesis se centra en el papel del perfil nutricional en la regulaci贸n de la interacci贸n inmunidad-metabolismo (immunometabolismo). Con esta finalidad, en la primera parte del trabajo presentado es esta tesis, se determin贸 si los macr贸fagos, las c茅lulas efectoras de la inmunidad innata, pueden percibir de manera diferencial la composici贸n de la dieta. Hemos demostrado que los compuestos bioactivos de los alimentos modulan, a nivel molecular, la activaci贸n de los macr贸fagos. Adem谩s, este efecto immunomodulador es dependiente del compuesto, donde factores intr铆nsecos tales como sus propiedades qu铆micas o nutritivas son determinantes para su bioactividad. La segunda parte tuvo como objetivo determinar el papel primordial del patr贸n nutricional en la regulaci贸n de la interacci贸n entre el sistema inmune y el metabolismo. Utilizando un modelo de obesidad inducida por la dieta se infiri贸 que, mientras una dieta hipercal贸rica provoca un deterioro del immunometabolismo, el consumo de bioactivos pueden fortalecer su estrecha relaci贸n. En la tercera parte, se analiz贸 el papel de las interacciones gen-dieta en la expresi贸n fenot铆pica de los rasgos asociados con la obesidad. Para ello, dos razas de ratas cong茅nitas, fenot铆picamente diferentes, fueron sometidas a un desequilibrio immunometab贸lico como consecuencia de la ingesta de una dieta hipercal贸rica. Se dedujo que las interacciones entre los factores gen茅ticos y nutricionales son fundamentales para la susceptibilidad de un genotipo a la obesidad inducida por la dieta. Hemos establecido que el perfil nutricional es una herramienta poderosa para orientar la funcionalidad del eje immunometab贸lico. Adem谩s, llegamos a la conclusi贸n que compuestos bioactivos presentes en los alimentos pueden mejorar la eficiencia de este eje, promoviendo as铆 un estado saludable.Nutritional immunotherapy is based on promoting health through the dietary intake of natural bioactive compounds found in food, such as the procyanidins and docosahexaenoic n-3 polyunsaturated fatty acid (DHA), optimising the functionality of the host鈥檚 own immune system and improving its role in the preservation of the body against destabilisers of homeostasis. The research that this thesis encompasses is focused on the role of the nutritional profile in the regulation of immunometabolism. To accomplish this purpose, in the first part of the work presented in this thesis, we determined whether macrophages, the effector cells of innate immunity, could differentially sense dietary composition. We demonstrated that bioactive food compounds modulate, at the molecular level, the functionality of macrophages by hindering macrophage activation. Furthermore, this immunomodulatory effect is compound-dependent, relying on the intrinsic factors of each compound, such as chemical and nutritional properties, to determine its bioactivity. The second part was aimed at determining the role of the dietary pattern within the complex crosstalk of immunity and metabolism using an in vivo model of diet-induced obesity. We determined that immunometabolic regulation depends on the nutritional profile. While a diet based on foods with a high energy content can weaken immunometabolism, the presence of bioactive foods can strengthen the relationship. Within the third part, we evaluated the role of gene-diet interactions in the phenotypic expression of obesity-related complex traits. Using a diet-induced obesity model, two distinct genetic backgrounds (phenotypically different inbred rat strains) were immunometabolically challenged. Our results revealed that interactions between genetic and dietary factors are fundamental for the susceptibility of a genotype to diet-induced obesity. We established that the nutritional profile is a powerful tool to target the functionality of the immunometabolic axis. We further concluded that bioactive compounds present in food improve the efficiency of this axis, thereby promoting a healthy state

    A systems approach to sub-typing of rheumatoid arthritis

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    The current health care system is severely challenged by for instance rising costs, fewer new blockbuster drugs and increasing numbers of hospitalizations due to side effects. Especially in the area of chronic diseases the current disease fighting strategy is failing and a more personalized medicine approach is needed. In this thesis new sub-types of rheumatoid arthritis are characterized with metabolomics analysis and symptoms patterns. The sub-types are based on diagnostic knowledge from Chinese medicine. The two sub-types of RA patients were found to have differences in apoptosis regulation of T-cells and differences in urine acylcarnitine levels. A questionnaire was designed to distinguish the two sub-types and to evaluate symptom patterns of arthritis patients. In the future the response to treatment of these sub-types of patients can be studied and specific treatment can be targeted to these sub-types.LEI Universiteit LeidenArtrose & Reuma StichtingAnalyse en stochastie

    Identification of prognostic and diagnostic biomarkers of glucose intolerance in ApoE3Leiden mice

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    The prevalence of diabetes mellitus Type 2 could be significantly reduced by early identification of subjects at risk, allowing for better prevention and earlier treatment. Glucose intolerance (GI) is a hallmark of the prediabetic stage. This study aims at identifying 1) prognostic biomarkers predicting the risk of developing GI later in life and 2) diagnostic biomarkers reflecting the degree of already manifest GI. To this end, disease development was followed over time in mice, and biomarkers were identified using lipidomics and transcriptomics. Young adult ApoE3Leiden mice were treated a high-fat diet for 12 wk to induce GI. Blood was collected before and during disease development. The individual extent of GI was determined with a glucose tolerance test and the area under the curve (AUC) was calculated for each animal. Subject-specific AUC values were correlated to the plasma lipidome (t = 0) and the white blood cell (WBC) transcriptome (t = 0, 6, and 12 wk) to identify prognostic and diagnostic biomarkers, respectively. The plasma ratio of specific free fatty acids prior to high-fat feeding (C16:1/C16:0, C18:1/C18:0 and C18:2/C22:6) was significantly correlated with the AUC and predictive for future GI. Subsequently, the expression level of specific WBC genes (Acss2, Arfgap1, Tfrc, Cox6b2, Barhl2, Abcb4, Cyp4b1, Sars2, Fgf16, and Tceal8) reflected the individual degree of GI during disease progression. Specific plasma free fatty acids as well as their ratio can be used to predict future GI. The expression levels of specific WBC genes can serve as easy accessible markers to diagnose and monitor already existing GI