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Hormonal Influence on Insulin Transport Through the Blood-Brain Hormonal influence on insulin transport through the blood- brain barrier and hypothalamic inflammation A dissertation submitted to the Graduate School of the University of Cincinnati In partial fulfillment of the requirements for the degree of DOCTORATE OF PHILOSOPHY In the Graduate Program of Pathobiology and Molecular Medicine of the College of Medicine December 2016 By Aaron A. May B.S. Agricultural Biochemistry, Iowa State University, Ames, IA Committee chair: Min Liu, PhD. ABSTRACT Insulin is an important effector of energy balance, and it reduces food intake and body weight via its actions in the hypothalamus. Because little or no insulin is produced by the brain, the majority of insulin’s effects in the central nervous system (CNS) are dependent on the transport of insulin through the blood-brain barrier (BBB). My research tests the hypothesis that some of the hormones involved in maintaining energy homeostasis exert their effects by influencing the transport of insulin into the CNS. Specifically, we examined the intestinal hormone, cholecystokinin (CCK), and the gonadal hormone, estrogen, due to their common catabolic actions and their pronounced interactions with central insulin. After observing that CCK receptors and estrogen receptors are both co-expressed with insulin receptors in endothelial cells of the BBB, we found that CCK, but not estrogen (E2), increased the transport of insulin into the CNS. These findings spawned an additional investigation into how E2 mediates its interaction with insulin signaling in the hypothalamus. Although insulin signaling was not increased by E2, we observed a significant reduction of inflammatory signaling in the hypothalamus of these E2-treated rats. Further, we found that insulin, itself, can influence inflammation. This work identifies novel mechanisms that influence energy balance and offers a potential approach for enhancing drug delivery into the CNS. i COPYRIGHT NOTICE This dissertation is based on the following papers, referred to by their Roman numeral: I. CCK increases the transport of insulin into the brain II. Estrogen and insulin transport through the blood-brain barrier A figure in this dissertation also appears in the manuscript: Using Cerebrospinal Fluid to Understand ingestive Behavior ii ACKNOWLEDGEMENTS Advisors Min Liu (primary advisor): Thank you for all that you’ve taught me and for always being willing to help or discuss, no matter how busy you were. I have learned so much from you, including your unprecedented ability to plan out experiments in detail and execute them with precision. I am also inspired by your work ethic, your organizational skills, and your attention to detail, which have all been immensely formative. I am very grateful for our friendship and daily conversations about science and life; you have been so thoughtful, kind, and generous. And, of course, I will also always be indebted to you for introducing me to Linda! Stephen Woods: Thanks for teaching me so many valuable life lessons and for being such a great friend. I’ve thoroughly enjoyed our discussions about science, life, birding, and all things esoteric during our meetings and lunch outings. You always managed to find ways to build my confidence, while also challenging me to keep improving in every way possible and to become a well-rounded scientist. Most importantly, you lead by example; even during some of the roughest phases of health, you went above and beyond in order to help me in any way you could. Your level of perseverance and commitment is beyond inspirational to me. Committee Patrick Tso: Thanks for everything you’ve done for me and our lab. You have provided so much sage advice during lab meetings and lab outings. Thanks also for enabling me to meet with visiting faculty and postdoctoral candidates; I’ve had many memorable experiences. Yve Ulrich-Lai: I have learned so much from you and your lab. Thanks for your willingness to meet whenever I needed another perspective. Your suggestions have always been spot-on. Your scientific rigor is also very impressive and I have the upmost respect for you. SfN dinner outings with you and the lab have been a highlight and I enjoy your witty humor. Silvana Obici: Thank you for making time to meet despite your demanding schedule and providing keen insights in experimental design. I have also cited your publications in every manuscript I’ve written! It has been a pleasure having you as a member of my committee. PMM Graduate Program Laura Woollett: I am so grateful that Dr. Beitz sent me your way. Go ISU! You have been such a great mentor, friend, and inspiration. Your encouragement to pursue community service and to “bloom wherever you’re planted” has enriched my life in numerous ways. David Askew: Thanks also for all you do with teaching, mentoring, and helping students. It is inspiring. I also appreciate that you let me guest lecture and provided such helpful feedback. Last but not least, thank you for hosting such great parties and inspiring me to cook more. Jason Blackard: Thanks for your all of your effort in running the program during my first 2 years here. Most importantly, thanks for accepting me into the PMM program, despite that I “made a big mistake wearing jeans to the interview.” iii Heather Anderson: Thank you for all of your hard work and dedication to the program. You have been so kind and helpful and it was reassuring to know you were there if I ever needed help. Mentors Deborah Clegg: Thanks for being such a strong mentor during a pivotal time of my research, which helped me push through to the finish line. I learned so many valuable insights from our phone conversations and your unique perspective helped me see things in a new light. Anja Jaeschke: I am so appreciative of your help and assistance during the most challenging time of my research. Your ability to brainstorm and deconstruct my complicated thoughts about molecular biology into concise, testable experiments is unlike anyone I’ve met. Phil Howles: It has been great getting to know you over the years while carpooling to main campus. I’ve enjoyed our conversations about science and life. You helped me regain an appreciation for my roots as a biochemist. Matt Wortman: Thanks for your continual support; chapters 5 and 6 of this thesis most likely wouldn’t exist if it wasn’t for you. You always provided such great insights, as well as hilarity. Diego Perez-Tilve: I greatly admire your thoughtfulness and for being the first person to deeply instill in me what it means to test a hypothesis in the most effective way possible. Amy Packard: Thank you for always being so kind to meet with me even when you were busy. You provided so many invaluable insights and have always been very thoughtful. Fellow lab members & troubleshooters; Ling Shen, Yin Liu, Nick Bedel, Alfor Lewis: Thanks for your unfailing guidance and support. You have all taught me so much. I’ve thoroughly enjoyed the deep life discussions, funny stories, and other antics over the years. Friends Thanks to all of you, especially those in the PMM program, namely Gabe and Logan for being so supportive during the tough times and for always providing a good laugh. Family To my mom, dad, Marita, Tony and Lisa, cousins, aunts, uncles, and grandparents: Thank you for your unconditional love, support and unwavering confidence in me. I am beyond blessed to have you all encouraging me to pursue my dreams and cheering me on the whole way. Linda: Life has stepped up to another dimension since I’ve known you. It has been an incredible journey with you so far and I am beyond fortunate to be able to marry the love of my life in April and share the rest of my life with you. You inspire me every single day and have taught me so many invaluable lessons. You have been there with your energy and enthusiasm on so many days when I needed it the most and have been my #1 supporter. No matter where the road ahead leads us, I know it is going to be awesome! iv TABLE OF CONTENTS Abstract………………….…………………………………………………………………….. i Acknowledgements…………………………………………………………………………...ii Table of Contents…………………………………………………………………….……… 1 List of Tables and Figures.……………………………… ………………….……………….3 1. Introduction……………………………………………………………………................4 1.1 The Obesity Epidemic 1.2 Catabolic Effects of Insulin in the Brain 1.3. The Blood-Brain Barrier 1.4 Aims of Investigation 2. Cholecystokinin Increases the Transport of Insulin into the CNS……………...20 2.1 The Discovery of CCK 2.2 CCK Receptors 2.3 Mechanism of Action for CCK 2.4 CCK Increases the Transport of Insulin into the Central Nervous System (Paper I) 3. Estrogen and Insulin Transport Through the Blood-Brain Barrier…..…….…..30 3.1 Background 3.2 Estrogen and Energy Balance 3.3 Estrogen and Insulin Transport into the CNS (Paper II) 4. Estradiol Prevents Diet-Induced Hypothalamic Inflammation………………… 48 4.1 Sex Differences in the Development of Cardiovascular Disease 1 4.2 Role of Hypothalamic Inflammation in Obesity and Cardiovascular Disease 4.3 Estradiol Inhibits Hypothalamic Inflammation 4.4 Influence of Inflammation on ERα Expression 5. Insulin Attenuates Hypothalamic Inflammation……………………………….…...61 5.1 Inflammatory Effects of Insulin 5.2 Anti-Inflammatory Effects of Insulin 6. Summary and General Discussion…………………………………………..…....….81 6.1 CCK Increases Insulin Transport into the CNS 6.2 Estrogen and Insulin Transport into the CNS 6.3 Interactions of Estradiol With Insulin Signaling in the Hypothalamus 6.4 Insulin and Hypothalamic Inflammation 6.5 Conclusions Appendices…………………………………..………………………………………..…....….92 I. Table 1: Antibodies used in the current studies Table 2: qPCR assays used in the current studies II. CCK Increases the Transport of Insulin into the CNS (Paper I) III.
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