The Role of Central Nervous System Glucagon-Like Peptide-1 in the Regulation of Energy Balance
Year: 2009
Type: article
Abstract: Glucagon-like peptide-1 (GLP-1), a product of the preproglucagon (PPG) gene, is synthesized in the intestine and the nucleus of the solitary tract (NTS) and regulates numerous physiological processes, including glucose homeostasis and food intake.Exendin-4 (Ex4), a highly potent, long-acting GLP-1 receptor (GLP-1r) agonist, is used clinically for the treatment of type 2 diabetes mellitus (T2DM).Interestingly, in patients Ex4 not only improves glycemic control, but it also produces weight loss.This finding raises the possibility that the GLP-1 system may be a viable therapeutic target for obesity.To this end, the purpose of this dissertation was to further characterize the role of the central nervous system (CNS) GLP-1 system in the regulation of energy balance.Central administration of Ex4, like GLP-1, robustly reduces food intake.However, several lines of evidence suggest that Ex4 acts via distinct mechanisms.Therefore, we tested the hypothesis that the central anorectic effects of GLP-1 and Ex4 are different.Specifically, these effects, and their sensitivity to GLP-1r antagonists, were compared.In addition, the GLP-1r-dependence of central Ex4 was assessed in GLP-1r knockout (GLP-1r-/-) mice.Consistent with our hypothesis, central Ex4 reduced food intake at doses significantly lower than those required by GLP-1, and this effect was not blocked by GLP-1r antagonists.In contrast, GLP-1r antagonists completely blocked the anorectic effect of peripheral Ex4.Finally, central Ex4 failed to reduce food intake in GLP-1r-/-mice, indicating that this effect is in fact GLP-1r-dependent.Although these data underscore the fact that central GLP-1r agonism is sufficient to reduce food intake, the role of the endogenous CNS GLP-1 system in the regulation of energy balance remains unclear.Therefore, we tested the hypothesis that endogenous iii CNS GLP-1 system activity is required for normal energy balance.Specifically, RNA interference was used to knock down NTS PPG, and chronic intracerebroventricular (ICV) infusion of the GLP-1r antagonist exendin (9-39) (Ex9) was used to block CNS GLP-1r.Consistent with our hypothesis, both NTS PPG knockdown and chronic ICV Ex9 resulted in hyperphagia.However, whereas NTS PPG knockdown exacerbated highfat diet-induced fat accumulation, chronic ICV Ex9 increased fat accumulation irrespective of diet.Finally, NTS PPG expression was found to correlate positively with fat mass, suggesting that CNS GLP-1 system activity may be altered in obesity.Taken together, the data presented in this dissertation reveal a novel role for the CNS GLP-1 system in the long-term regulation of energy balance.Moreover, they indicate that the GLP-1r agonist Ex4 interacts uniquely with this system to produce a powerful anorectic signal.As such, future studies are warranted to determine optimal strategies to target the CNS GLP-1 system for the treatment of obesity.iv v ACKNOWLEDGEMENTS I would like to express my deepest gratitude for the opportunity to train within both the Physician-Scientist Training Program and the Neuroscience Graduate Program at the University of Cincinnati.I am very fortunate to have been a part of both of these excellent programs, whose members past and present have inspired me to strive to achieve my highest potential.In return, I pledge to work toward a career that integrates both sides of my training and seeks to make significant contributions to both clinical medicine and biomedical science.To my mentor, Randy Seeley, thank you for all the opportunities you have given to me over the years.From giving me my first job out of college as a research assistant to training me as your graduate student, you have shown unwavering support of my education and career goals, and I would not be where I am today if it were not for your guidance.Moreover, I cannot think of a better example of somebody whose career truly embodies the goals of a physician-scientist.Randy, you have taught me many valuable lessons over the years, perhaps the most important of which is to always choose my research questions based on the potential significance of the answers.Your success inspires me to pursue science with as much dedication and passion as you have.To my dissertation committee members, which include Steve Woods, Dave D'Alessio, Silvana Obici and Jim Herman, thank your for helping me to successfully navigate through four years of dissertation research.Steve, thank you for being such a strong advocate for graduate students, helping me through the most difficult of times, challenging me to think about the broader implications of my data, and always vi encouraging me to pursue opportunities as a young scientist.Dave and Silvana, as accomplished M.D. researchers, you have been excellent role models for me, and you inspire me to always keep research at the forefront of my career as a physician-scientist.Jim, thank you for helping me work through the challenges of using viral vectors to achieve in vivo RNA interference and reminding me to be proud of my data.To all my friends in the Neuroscience Graduate Program, thank you for making these past four years so much fun.Your friendship has been an invaluable source of both enjoyment and support throughout what has undoubtedly been a challenging endeavor.A special thanks to Rob, Derrick, Brian, Georgette, Valerie and Susan, with whom I share many fond memories.Your intelligence has never ceased to amaze and inspire me, and I look forward to reading about all of your accomplishments in the future.Rob, a second call goes out to you, as I look forward to many more drinks and chats as we embark on this final phase of our time in the PSTP.To all members of the Woods/Seeley lab past and present, it has been an honor to work with each of you.I am fortunate to have crossed paths with such dedicated, enthusiastic and intelligent scientists, with whom I have had the privilege to work in such an enriching and nurturing environment.Like Randy and Steve, you have taught me so much, and as such, you have made me the scientist I am today.Moreover, I will never forget all the fun times we had, both inside and outside the lab.Thank you to all of you for encouraging, helping and inspiring me.I will miss you, but I look forward to future interactions within the world of science down the road.To all my friends and family, thank you for being a constant source of support and relaxation for me, and for keeping me sane.Thanks to you, I have not forgotten that vii viii there is a world outside of science and that I am more than just a scientist.Moreover, you remind me that it is not only one's career that brings happiness, but perhaps more importantly it is the people in one's life.Although it may be somewhat of a mystery to you what I have been doing for the last several years, trust me when I say that you have all played an important role in making it all happen.Finally, to David Shaffer, thank you for being my biggest fan throughout this entire journey.It has been an amazing ride-one that I am fortunate enough to have shared with you.Moreover, you have stood by me throughout the best and worst of times with unwavering support, patience and love, and for that I can neither express the full extent of my appreciation nor repay all that you have given to me.Thank you for always believing in me.You are the reason this work has been possible, and as such, it is with love that I dedicate it to you.
Author: Jason G. Barrera
Institution: University of Cincinnati
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funder: University of Cincinnati
OpenAlex ID: W2480750804