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Gut Microbiota and Metabolomic Changes Associated to the Beneficial Effects of Polyphenols on Obesity

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Gut Microbiota and Metabolomic Changes Associated to the Beneficial Effects of Polyphenols on Obesity Faculty of Pharmacy GUT MICROBIOTA AND METABOLOMIC CHANGES ASSOCIATED TO THE BENEFICIAL EFFECTS OF POLYPHENOLS ON OBESITY Usune Etxeberria Aranburu Pamplona, 2015 Faculty of Pharmacy GUT MICROBIOTA AND METABOLOMIC CHANGES ASSOCIATED TO THE BENEFICIAL EFFECTS OF POLYPHENOLS ON OBESITY Memoria presentada por Dña. Usune Etxeberria Aranburu para aspirar al grado de Doctor por la Universidad de Navarra Usune Etxeberria Aranburu El presente trabajo ha sido realizado bajo nuestra dirección en el Departamento de Ciencias de la Alimentación y Fisiología y autorizamos su presentación ante el tribunal que lo ha de juzgar. Pamplona, 26 de Noviembre de 2015. Dr. Fermin I. Milagro Yoldi Prof. J. Alfredo Martínez Hernández If you always do what you always did, you will always get what you always got (Albert Einstein) Acknowledgements/Agradecimientos Acknowledgements/Agradecimientos A lo largo de estas líneas quisiera mostrar mi más sincero agradecimiento a todas aquellas personas que de alguna manera u otra, han contribuido y me han ayudado a llegar al final de esta etapa. Me siento una persona privilegiada, he contado con vuestro apoyo, cariño y me habéis transmitido mucha fuerza y ánimo. Hoy, sólo puedo y me queda daros las gracias, MUCHAS GRACIAS a todos. En primer lugar, mis primeras palabras de agradecimiento están dedicadas a los directores de esta tesis el Prof. Alfredo Martínez y el Dr. Fermín Milagro. Quisiera daros las gracias por haber sabido guiar y dirigir este trabajo. Gracias porque en vosotros he encontrado el rigor y la diligencia necesarias, así como vuestro apoyo, tiempo, paciencia e implicación en todo momento. Os quiero dar las gracias por la confianza que habéis depositado en mí desde el primer momento, por haberme dado la oportunidad de llevar a cabo este trabajo. Junto a vosotros puedo decir que he crecido no sólo profesionalmente, sino también personalmente. Os agradezco todo el tiempo que habéis invertido en mí y sinceramente espero haber cumplido, aunque sea parcialmente, con vuestras expectativas. Muchísimas gracias a los dos. En segundo lugar, quiero agradecer a la Universidad de Navarra estos años de formación. A la Asociación de Amigos de la Universidad de Navarra, así como al Gobierno Vasco la ayuda económica que me han otorgado sin la cual todo esto no hubiese sido posible. En particular, quisiera agradecer al Departamento de Ciencias de la Alimentación y Fisiología por haberme acogido, y haberme ofrecido la oportunidad de realizar esta etapa investigadora junto a los mejores profesionales, a todos y cada uno de vosotros gracias. Gracias, a todos los profesores, técnicos, PAS. En general, a todos los compañeros y amigos de CAF, aquellos con los que compartí mis primeros años de tesis y aquellos con los que finalizo este camino. Así mismo, me gustaría a agradecer también a los compañeros que han estado de paso por el departamento, gracias porque he tenido la oportunidad de conocer a grandes personas. Gracias a mis amigos de máster E-MENU (Lucía, Blanca, Candela, Alfredo, Angels) por todos los momentos disfrutados, nuestras conversaciones de café y comidas que echaré de menos. Gracias a Miguelin por tantos y tantos momentos divertidos que hemos pasado en el laboratorio y fuera de él, has sido un gran apoyo para mí, he ganado un gran amigo y espero poder compartir en el futuro muy buenos momentos contigo. Gracias a mis chicas del “Granada team”, os echaré enormemente de menos, espero que tengamos oportunidad de juntarnos y repetir algún que otro viaje juntas. Este trabajo no hubiera sido posible sin la gran aportación y la colaboración del grupo Nutrición y Obesidad de la Universidad del País Vasco. Muy especialmente, me gustaría trasladar mi más sincero agradecimiento a la Prof. i Acknowledgements/Agradecimientos Mª Puy Portillo, muchísimas gracias por todo, ha sido un gusto y una suerte tener la oportunidad de trabajar con todos vosotros. Así mismo, me gustaría extender este agradecimiento a la Dra. Mª Teresa Macarulla, Dr. Alfredo Fernández, Leixuri, Ana, Saioa, Iñaki y a todo el grupo en general. Por último, me gustaría agradecer a Noemí Arias toda su disposición, ayuda y en definitiva su gran profesionalidad, muchas gracias, ha sido un lujo conocerte y poder trabajar contigo. I would like to express my gratitude to Prof. Nathalie Delzenne and Dr. Audrey Neyrinck for giving me the opportunity to stay and work with your team in the Metabolism and Nutrition Research Group, Louvain Drug Research Institute (Brussels). I would like to thank you for your warm welcome, for your trust on me, for you generosity, hope we will have the chance to keep in touch in the future. It was a great experience working with you. I would also like to thank all the people from the lab. Particularly, I wish to thank Remi for his help. I would like to express also my sincere gratitude to Nuria and Marcelo. Por la suerte que tengo de contar con vuestra amistad, quiero dar las gracias a todos mis amigos. A Anetxu, que aunque no tengamos muchas oportunidades para juntarnos, siempre que nos vemos parece como si el tiempo no hubiera pasado. A mis amigos de la Kuadrilla, quizás no sepáis qué es lo que he estado haciendo exactamente durante todo este tiempo, pero vuestras preguntas especialmente vuestro continuo interés sobre “mis ratitas”, han sido suficientes para arrancarme siempre una sonrisa. Por todos esos viernes de reencuentro, desconexión y buenos momentos que me habéis dado, mila esker Kuadrilla. Quiero agradecer especialmente a Ainara su apoyo. Askotan denbora luzez ikusi gabe egonda ere, asteroko mezutso hori falta izan ez degulako, zure animoengatik, zure laguntasunagatik, mila esker Ainari. A mis pittinas Nai y Elitxu, qué deciros, habéis sido uno de mis mayores apoyos, gracias por animarme, por creer tanto en mí, por alegraros con mis pequeños éxitos y avances profesionales, gracias por estar a mi lado siempre, por vuestra amistad incondicional. Mila esker. Hitz hauek ez dira nahikoak matti eskertu behar dizudan guztia eskertu eta nere pentsamendu guztiak papelean isladatzeko, baina era labur batean bada ere saiatuko naiz. Maitia, esfortzu honen fruitu hau zurea ere delako ESKERRIK ASKO, mila esker. Mila esker bide hau nerekin batera ibiltzeagatik, momento errazenetan bai, baina momentu zailenetan ere, hor izan zaitudalako. Mila esker beti nigan sinistu izanagatik eta nik konfidantza falta izan dudan momentu gogor horietan, indarrak eman eta aurrera eginarazi izanagatik. Eskerrak eman nahi dizkizut, urte hauetako egunerokotasunean, eskeini eta eman dizkidazun maitasun, indar eta goxotasunarekin etapa hau bizitzako epe polit eta ahaztezin bihurtu dituzulako. Asko maite zaitut. Gracias, eskerrik asko, a mis “suegros” Maite y Xabier, y a toda la family, eskerrik asko zuei guztiei. ii Acknowledgements/Agradecimientos Me gustaría dedicar las últimas palabras a mi familia. A mis tíos, tías, primos, primas que siempre han estado ahí, mostrando interés por todo lo que hago y arrancándome una sonrisa cada vez que nos reuníamos. Me gustaría agradecer muy especialmente a mi AMONA todo el cariño que me da, sus palabras de aliento, su fuerza y vitalidad que hace que me sienta orgullosa de mí misma, sin saber que el orgullo es mío por poder tenerle a mi lado. Eres única, una joya. Maite zaitut amona. Eskerrik asko Andertxo beti zugan aurkitu dudan babes eta laguntzagatik, edozein momentutan entzuteko prest egon zarelako, aholkorik hoberenak zugan aurkitu izan ditudalako. Izugarri haundia zarelako eta zorte handia dudalako zu anai bezela izateagatik, asko asko maite zaitut eta faltan botatzen zaitut. Mis últimas palabras de agradecimiento están dirigidas a mis padres. Aita, ama, no puedo agradeceros lo suficiente todo lo que habéis hecho por mí. Sois lo más importante de mi vida. Sois el pilar de mi vida, sin vuestro apoyo no hubiera llegado a estar hoy donde estoy y no me sentiría capaz de luchar por metas que se me hacen inalcanzables. Gracias por todos vuestros consejos, vuestros ánimos y cariño, vuestra confianza y comprensión. Os lo debo todo, absolutamente todo, a vosotros. Por ello, esta tesis os la quiero dedicar especialmente a vosotros con todo mi cariño, os quiero mucho. iii Dedicado a las dos personas que todo me lo han dado, Mis aitas, Javier y Mertxe Con especial cariño a, Mi hermano, Ander Mi amona, Mª Carmen Maitia, beti zuri List of abbreviations/Listado de abreviaturas List of abbreviations/Listado de abreviaturas ‐ WHO World Health Organization ‐ BMI Body Mass Index ‐ LEP Leptin ‐ LEPR Leptin receptor ‐ MC4R Melanocortin 4 receptor ‐ POMC Pro‐opiomelanocortin ‐ PCSK1 Prohormone convertase 1 ‐ BDNF Brain‐derived neurotrophic factor ‐ SIM1 Single‐minded 1 ‐ NTRK2 Neurotrophic tyrosine kinase, receptor, type 2 ‐ BW Body weight ‐ T2DM Type 2 Diabetes Mellitus ‐ CVD Cardiovascular disease ‐ AHA/ACC/TOS American Heart Association/American College of Cardiology/The Obesity Society ‐ GI Gastrointestinal ‐ EPIC European Prospective Investigation into Cancer and Nutrition ‐ UK United Kingdom ‐ GLUT Glucose transporter ‐ PPARγ Peroxisome proliferator‐activated receptor gamma ‐ HFD High‐fat diet ‐ VAS iNOS Visceral adipose tissue inducible nitric oxide ‐ COX2 Cyclooxygenase‐2 ‐ Nrf2 Nuclear factor‐related factor‐2 ‐ HO‐1 Heme oxygenase‐1 ‐ NF‐κβ Nuclear factor Kappa β ‐ ERK1/2 Extracellular signal‐related kinase ‐ AMPK AMP‐activated protein kinase ‐ LPH Lactase phlorizin hydrolase ‐ UGT Uridine 5’‐diphosphate glucuronosyltransferase ‐ COMP Catechol‐O‐methyltransferase ‐ PST Phenol sulfotransferase ‐ BCRP1 Breast cancer resistance
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