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Novel Mechanisms of CNS Fuel Sensing UNIVERSITY OF CINCINNATI Date:___________________ I, _________________________________________________________, hereby submit this work as part of the requirements for the degree of: in: It is entitled: This work and its defense approved by: Chair: _______________________________ _______________________________ _______________________________ _______________________________ _______________________________ Novel fuel sensing mechanisms in the regulation of food intake A dissertation submitted to the Division of Research and Advanced Studies of the University of Cincinnati in partial fulfillment of the requirements for the degree of DOCTORATE OF PHILOSOPHY (Ph.D.) in the Graduate Program in Neuroscience of the College of Medicine May 22, 2006 by Karine Proulx B.S., Université Laval, 2000 M.S., McGill University, 2002 Committee Chair: Randy J. Seeley, Ph.D. ABSTRACT An emerging model is that CNS fuel sensors, such as AMP kinase (AMPK) and the mammalian target of rapamycin (mTOR), integrate signals from stored and immediately available fuels, and in turn regulate food intake. The experiments described in this dissertation focus on novel CNS fuel sensing mechanisms by which fatty acid derivatives and compounds that affect fatty acid metabolism modulate food intake. Oleoylethanolamide (OEA), a derivative of oleic acid synthesized in the intestine following refeeding, reduces food intake. OEA shares similarities with other nutrient- derived hormones that signal energy status to the CNS, but its mechanisms of action remain unclear. We tested whether OEA-induced anorexia occurs through specific interactions with hormones that modulate food intake through CNS pathways involved in energy homeostasis, or is rather due to unspecific behaviors. Our results indicate that OEA suppresses feeding without causing visceral illness, and that neither ghrelin, PYY, GLP-1, apo A-IV nor CCK play a critical role in this effect. OEA is not the only fatty acid metabolism related compound that suppresses food intake. C75 is a fatty acid synthase inhibitor that inhibits food intake via direct actions in the CNS. MTOR, a member of the phosphatidylinositol kinase-related protein kinase family, plays a crucial role in nutrient sensing and the control of protein synthesis. Its inhibition stimulates food intake in rats. We hypothesized that C75-induced anorexia depends on its ability to activate the mTOR pathway in the hypothalamus. Consistent with this hypothesis, C75 increases the phosphorylation of key components of the mTOR pathway and inhibitors of mTOR reverse C75-induced anorexia. Previous work showed that C75 is ineffective when rats are on a ketogenic diet. Consistent with a role for mTOR in mediating the - I - effects of C75, C75-induced anorexia and activation of the mTOR pathway were abolished in rats maintained on a ketogenic diet. Together, these data argue that neuronal nutrient metabolism is monitored by CNS fuel sensors and contribute to the regulation of food intake. - II - - III - ACKNOWLEDGEMENTS Randy: Maybe one of the reasons you always say that you trust my scientific judgment is that you know you are the one who made me build one over the last four years! As challenging as those conversations in your office might have been sometimes, I can honestly say that they are what made me the young scientist I am today. You taught me how to develop a critical sense, stand up for my ideas and, most importantly, build some confidence throughout the whole process. I now leave this lab feeling strong and ready to move to the next step. Thank you also to you and Steve, for showing us what “work hard- play hard” really means, allowing the passion for science to remain even in tougher times! Steve: I remember the very first question Steve asked me during my interview: “Why would someone coming from such a beautiful city as Montreal (as he said it with his classic Woodsilian French accent!) would want to live in Cincinnati?”. While such a broad question could have been intimidating coming from someone like Steve Woods, I exactly knew the answer. My motivation obviously didn’t come from the attractions of the city (no offense, but that has never been a secret to anyone!). After a few mornings that I popped my head in his office for questions, he suggested we schedule a weekly meeting, where we would talk about the philosophy of research. Every time we met from then until now confirmed that I made the right decision in coming to Cincinnati, and that I have found exactly the training environment I was looking for. In addition to be a great mentor, you and Nancy have also been a great second family by making me feel home during celebrations like Thanksgiving and Easter. Thank you! - IV - Committee members: Drs. Herman, Jandacek and Williams, I learned so much from our discussions during and outside of our official committee meetings. I truly felt that you were supportive of my research and cared about my career. Our program is blessed to have faculty members like you, who despite their busy schedules maintain an “open- door” policy. You have always made me feel welcome when I needed help for either technical issues or last minute recommendation letters and I want to thank you for that. Beth: Where should I start, how can I put all those feelings into words? We’ve started together and are finishing it together. We shared so much! You were always there for me, in good as well as bad/ “life threatening” times (I will always remember our infamous New Orleans episode and how you helped me keep my hot temper low after that guy crashed my car!). I knew I could rely on you whether for intellectual, moral or “technical” support. I am sure you’ll be a great and successful scientist. I’ll be there to celebrate your tenure-track position on your thirtieth birthday! I wish you the best of luck for your post-doc and I am looking forward to your visit in the UK! April and Torsten: Thank you for taking me under your wings and getting me started in the lab. You guys were there for my first rat bite, as well as those crazy tail-bleeding sessions at 7h00 AM, after a night of too much celebration at Randall’s house, or at 1h00 AM, because of a light-dark cycle that we chose to accommodate my classes! We can only laugh about it now! Daniela: You have been not only an awesome colleague, but also a great friend. You were there to celebrate every happy moment, and to support me through all the troubles of this thesis (despite what the ratio between those two might have been, I don’t care anymore!). I want to say how much it meant to me to be able to share ideas and have - V - scientific conversations that always remained authentic and free of any competition. I say goodbye for now, but I have the feeling it is only temporary. I will probably be meeting Prof. Cota for a cappuccino in some European café pretty soon! The Tschoep’s lab: Matthias, Tamara, Paul and Diego: You guys made the OEA paper happened. I still think that we shouldn’t have had to spend so much time figuring out how something with a name like “The Clever System” works! Despite how ridiculous it was to play with the red light until we got the proper “Chinese shadows” to detect the rat in its cage, I have to admit we had fun! I’ll keep great memories of the time we spent together in and outside of GRI. Like I said for Daniela, I am sure that our roads will cross again in the near future my dear European friends. My non-official committee members: Probably the result of working in such a collaborative environment as the one within the Obesity Research Center and the GRI: Randall Sakai: Thank you for professional and personal support throughout my time at UC. Among the many things I will remember from my interactions with you are when you were there to get me coffee and calm me down the morning of my first big talk at SFN, your “PR” and networking qualities and, of course, the parties and wine at your house! David D’Alessio: Although not an official member of my committee, you surely behaved like one! You contributed to solving so many issues from the ADX, to OEA to C75 project. I really appreciated you keeping your door opened for my spontaneous questions, I learned a lot from you. Patrick Tso: Your enthusiasm for science is contagious and your approach to scientific questions very unique. I learned a lot from those drawings on the board next to your - VI - office! Thank you for contributing to my OEA project, and also to regularly check on my future post-doc career. Kay Ellis: It was always fun to go drop those plasma samples to you Kay. It was the occasion to get a little girlie chat, and laugh at how many tubes there were in those boxes! Matt and Debbie: Although you guys had already left by the time I’ve started working on C75, you generously offered your help. Sorry for making you go through messy lab books (mine are not any better!) or trying to find on which paper towel you wrote the design of the experiment on that day! Thanks for sharing your knowledge of the FAS system and your insightful discussions. Past and present members of the “team room” ( Beth, Daniela, Claire, Lynda, Dong-Hoon, Jason, Darleen, April, Ryuichi, Debbie D., Brad, Debbie C., Stephen, Matt and Koroh): Despite what Randy says about its lack of light and its small size, this “team-room” has probably been the most enriching environment I have ever been in.
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