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Epigenetic Biomarkers in Obesity, Weight Loss and Inflammation: a Role for Circadian Rhythm and Methyl Donors

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Epigenetic Biomarkers in Obesity, Weight Loss and Inflammation: a Role for Circadian Rhythm and Methyl Donors Facultad de Farmacia y Nutrición Epigenetic biomarkers in obesity, weight loss and inflammation: a role for circadian rhythm and methyl donors Mirian Samblas García Pamplona, 2018 Facultad de Farmacia y Nutrición Memoria presentada por Dña. Mirian Samblas García para aspirar al grado de Doctor por la Universidad de Navarra. Mirian Samblas García El presente trabajo ha sido realizado bajo nuestra dirección en el Departamento de Ciencias de la Alimentación y Fisiología de la Facultad de Farmacia y Nutrición de la Universidad de Navarra y autorizamos su presentación ante el Tribunal que lo ha de juzgar. Pamplona, 26 de Febrero de 2018 VºBº Director VºBº Co-Director Dr. Fermín I. Milagro Yoldi Prof. J. Alfredo Martínez Hernández Este trabajo ha sido posible gracias a la financiación de diversas entidades: Ministerio de Economía y Competitividad (AGL2013-45554-R), Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituo de Salud Carlos III (ISCIII), Centro de Investigación en Nutrición (Universidad de Navarra). La investigación que ha dado lugar a estos resultados ha sido impulsada por la beca predoctoral 2014-2015 del Centro de Investigación en Nutrición y las becas predoctoral 2015-2018 y de movilidad del Ministerio de Educación, Cultura y Deporte. “Necesitamos especialmente de la imaginación en las ciencias. No todo es matemáticas y no todo es simple lógica, también se trata de un poco de belleza y poesía” Maria Montessori Dedicado a las dos personas que me lo han dado todo, Mi aita Ray, Mi ama Ana Con especial cariño a, Mi hermana, Bea Mi sobrina, Aroa Mi abu, Esther Agradecimientos/Acknowledgements En estas líneas quisiera mostrar mi más sincero agradecimiento a todas aquellas personas e instituciones que han hecho posible la actual tesis. No hay palabras ni espacio suficiente para plasmar todo el apoyo, ayuda, fuerza, ánimo y cariño que se me ha dado, y solo me queda daros las gracias, MUCHAS GRACIAS a cada uno de vosotros. Mis primeras palabras de agradecimiento me gustaría dedicarlas a los directores de la presente tesis el Dr. Fermín Milagro y el Prof. Alfredo Martínez. En primer lugar quisiera expresaros mi agradecimiento por la confianza depositada en mí desde el primer momento y haberme dado la oportunidad de realizar este trabajo. Gracias por haber guiado y dirigido esta tesis. Juntos habéis formado el equilibrio perfecto para guiarme y dirigirme a lo largo de esto años de trabajo. Sé que no siempre ha sido fácil, sin embargo siempre he contado con vuestro tiempo, implicación, paciencia y apoyo. Ha sido un placer poder crecer profesionalmente y personalmente junto a dos grandes investigadores y personas. Os agradezco todo el esfuerzo invertido en mí y sinceramente espero haber cumplido, aunque sea mínimamente, vuestras expectativas. Muchísimas gracias. Quisiera agradecer al Centro de Investigación en Nutrición de la Universidad de Navarra (beca predoctoral) y al Ministerio de Educación, Cultura y Deporte (beca predoctoral y de movilidad) por la financiación recibida durante estos años de tesis doctoral, sin la cual todo esto no hubiera sido posible. Muchísimas gracias a la Universidad de Navarra, en especial a la Facultad de Ciencias, en la que comencé mi formación ya hace 11 años, y a la Facultad de Farmacia y Nutrición por haberme acogido y haberme ofrecido la oportunidad de comenzar mi formación como investigadora. No quisiera dejar de agradecer a todo el personal del Departamento de Ciencias de la Alimentación y Fisiología que han hecho más fácil este camino. A las super técnicos Ana, Verónica, Neira y María que son fundamentales en el departamento. A nuestra gran secretaría Alba, gracias por tener siempre una sonrisa y haberme ayudado en todo lo posible. A los grandes profesores e investigadores, que siempre me han ayudado cada vez que lo necesitaba. A Paula por estar siempre dispuesta a ayudarme. A Jose Ignacio por su humor y su buen rollismo que nos alegra cada día. A Marian y Amelia por hacer más divertidos los ratos del café. A Pedro y Silvia por sus consejos. A Jaione por haberme ayudado a desarrollarme como profesora de prácticas. A Eva, Carlos, Santiago y Xavi gracias por vuestras conversaciones tan provechosas. Además, no quisiera olvidarme de todos aquellos doctorandos (ya doctores) que formaron parte del desarrollo de las intervenciones, ya que sin ser conscientes han hecho posible que yo pueda realizar esta tesis. Y como no, gracias a los voluntarios que han participado en cada uno de los estudios aplicados en el presente trabajo, ya que sin ellos esto no hubiera sido posible. Así mismo, me gustaría agradecer de todo corazón a todos los compañeros y amigos que han hecho el camino junto a mí todos estos años de tesis. Gracias a todos los compañeros con los que compartí mis primeros momentos y ya no están, por haber tenido la oportunidad de haber conocido grandes investigadores y mejores personas. Kike, bioinformático y amigo, gracias por toda tu ayuda y por todos los ratos que pasamos juntos. Amaya y Leire, comenzamos juntas esta aventura y me enorgullece decir que juntas la estamos acabando pero como amigas. Amaya, Leire, Irene y Marcos habéis sido un pedazo de apoyo en todos estos años profesionalmente y personalmente. Sé que os esperan grandes cosas y espero vivirlas junto a vosotros. No puedo expresar con palabras todo el agradecimiento que siento, solo os puedo decir que parte de esta tesis os pertenece. Gracias a Elisa y Ana, mis andaluzas favoritas, por todos los buenos momentos que hemos vivido juntas y porque ¡sois increíbles! Gracias a Jorge, Cris, Ana A., Lidia, Lucía, Amanda y Angy por todas las risas y los buenos momentos que hemos tenido. De verdad, muchas gracias a todos, sois una parte importante de este trabajo. No me puedo olvidar de mis amigas de Brasil. Muchas gracias de coraÇão a Carol y Julia por haberme dado la oportunidad de conoceros no solo profesionalmente si no personalmente. Hemos disfrutado de muchos momentos juntas, aquí en Pamplona y allá en Brasil, pero sé que son aún muchos los que nos quedan por vivir. ¡Muchas gracias! Obrigada! I wish to express my sincere gratitude to Dr. Miguel Constanza for giving me the opportunity to stay and work with your team at the Cambridge University. Thank you to all team for the warm welcome. Many thanks for the kind help to Niamh. Gracias a mis bioamigas por todos estos (11) años, porque aunque cada una estemos casi en una punta del mundo, cuando nos juntamos es cómo si no hubiera pasado el tiempo. En especial a Teresa, Bea y Miriam, sé que os esperan grandes éxitos en la vida y estoy muy orgullosa de vosotras. Muchísimas gracias a mis “Neskatxis” por estar siempre conmigo y preguntarme sobre mi trabajo, sé que os parece confuso pero siempre me escucháis con total atención. No sabéis la suerte que tengo de contar con vosotras y vuestra amistad. Muy en especial a mi amiga Irantzu, por compartir tantos momentos juntas, apoyarme en mis “tesis bajones” y saber sacarme siempre una sonrisa. ¡Maite zaituztet! Maitia, has sido mi mejor apoyo en estos años. Eres parte de esta tesis, no solo porque hayas sido el ilustrador de este trabajo, sino también por haber caminado junto a mí en todo este proceso. Gracias por tu cariño, paciencia y sobre todo compresión, gracias por sacarme miles de carcajadas, gracias por hacerme tan feliz. Y por último, gracias a mi familia. A ti abuela porque siempre has sido la luz de mi vida. Gracias Bea por estar siempre ahí y haberme ayudado toda mi vida. ¡Eres la mejor hermana del mundo! Gracias a Oskar y a ti por todos esos ratos, cenas, risas y conversaciones que me ayudan a desconectar. Pero sobre todo gracias por Aroa, la única que consigue que con solo mirarla se me olviden todas las preocupaciones. Mis últimas palabras de agradecimiento pertenecen a mis padres. Muchísimas gracias ama y aita por todo lo que habéis hecho por mí. Sois lo mejor y más importante de mi vida, sin vuestro apoyo, cariño, consejos, ánimo y amor no hubiera llegado a este momento. Ni en mil vidas os podría agradecer y devolver todo lo que me habéis dado. Os quiero con toda mi alma y corazón, gracias. List of abbreviations 5mC 5-methylcytosine AA Arachidonic acid ABCG1 ATP binding cassette subfamily G member 1 AHA American heart association Alu Transposable element characterized by the action of the Arthrobacter luteus restriction endonuclease ATP Adenosine triphosphate BDNF Brain-derived neurotrophic factor BMAL1 Aryl hydrocarbon receptor nuclear translocator-like protein 1 BMI Body mass index BMI z-score Conversion of BMI values into standard deviation scores BP Blood pressure CAMKK2 Calcium/calmodulin-dependent protein kinase kinase 2 CCL C-C motif chemokine ligand CD40 Cluster of differentiation 40 CD44 CD44 molecule (Indian blood group) cDNA Complementary DNA CGI Cpg islands CLOCK Circadian locomoter output cycles kaput CpG Cytosine linked by a phosphate to guanine CPT1A Carnitine palmitoyltransferase 1A CRY1 Cryptochrome 1 CVD Cardiovascular disease DHA Docosahexanoic acid DHF Dihydrofolate DMR Differentially methylated region DNMT DNA methyltransferase EPA Eicosapentaenoic acid ESRA Estrogen receptor 1 EWAS Epigenome-wide association study FA Fatty acid FHL2 Four and a half LIM domains 2 FOXP3 Forkhead box P3 GAPDH Glyceraldehyde-3-phosphate dehydrogenase GENOI Grupo de estudio Navarro de la obesidad infantil hcy Homocysteine HDL-C High-density lipoprotein cholesterol HFD High fat diet HIF3A Hypoxia-inducible factor 3 alpha HOMA Homeostatic model assessment HR High responders
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