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Neurological - Molecular Interface in Food Intake and Metabolism in Birds And

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Neurological - Molecular Interface in Food Intake and Metabolism in Birds And Neurological - Molecular Interface in Food Intake and Metabolism in Birds and Mammals Wei Zhang Dissertation submitted to the faculty of the Virginia Polytechnic Institute and State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy In Animal and Poultry Sciences Elizabeth R. Gilbert, Chair Mark A. Cline Paul B. Siegel Honglin Jiang Dongmin Liu Leif Andersson July 1st, 2014 Blacksburg, VA Keywords: NPY, adipogenesis, body weight lines, appetite regulation, energy homeostasis, serotonin, 3T3L1 cell line, ZBED6, cytokines, inflammation, obesity Copyright 2014, Wei Zhang Neurological - Molecular Interface in Food Intake and Metabolism in Birds and Mammals Wei Zhang ABSTRACT Obesity is a physiological consequence of dysregulated energy homeostasis. Energy homeostasis depends on energy intake and energy expenditure. Factors controlling the development of different adipose tissue deposits in the body and their distinct metabolic phenotypes are of considerable interest from both an agricultural and biomedical perspective. Following the literature review, the first chapter was devoted to studies designed to bridge the neural-adipose interface in understanding the relationship between appetite regulation and adipose tissue deposition in chickens, using chickens selected for low or high juvenile body weight as a model. Appetite regulation in the brain, particularly the hypothalamus, is the main factor governing food intake. Neuropeptide Y (NPY), known as a potent orexigenic factor, also promotes energy storage in fat in mammals and thus has a dual role in promoting energy intake via appetite regulation in the brain and energy storage/expenditure via direct effects on adipose tissue function. There have been no reports of the effects of NPY on adipose tissue function in any avian species. By exposing chicken preadipocytes to different concentration of NPY, we found that NPY enhances both proliferation and differentiation and thus appears to play a major role in chicken adipogenesis, an effect that has not yet been reported, to our knowledge. In the body weight selected chicken lines, we found that NPY and receptor sub-type expression was elevated in the abdominal fat of chickens from the high body weight chicken line and expression of these genes displayed heterosis in the reciprocal crosses of the parental lines as compared to both the high and low body weight selected lines. Intriguingly, expression of those same genes was greater in the low weight than high weight chickens in the hypothalamus. Hypothalamic transcriptomic profiling revealed that genes involved in serotonergic and dopaminergic systems may also play an important role in both appetite regulation and insulin-regulated energy homeostasis in the body weight chicken lines. Intracerebroventricular injection of serotonin in broiler chicks was associated with a dose and time dependent reduction in food intake that was coupled with the activation of the ventromedial hypothalamus and arcuate nucleus, as determined by c-fos immunoreactivity. The remainder of this dissertation project describes the effects of knocking down expression of a recently discovered transcription factor, ZBED6, on mouse preadipocyte proliferation and differentiation. The dissertation ends with a study using diet-induced porcine prepubertal obesity as a model to examine differences in adipokine gene expression between different fat depots from pigs that consumed diets that differed in carbohydrate composition. Overall, we conclude that both NPY and monoamines such as serotonin and dopamine are of importance in the regulation of energy balance in chickens. Moreover, we propose that NPY is a factor that mediates hypothalamus and adipose tissue crosstalk in chickens. An understanding of this system may provide a new avenue for the treatment of obesity and associated disease complications by re-orchestrating the neuronal outputs or adiposity inputs. This information may also be of value in developing strategies to improve feed conversion and meat yield in commercial broiler. iii Acknowledgements Dr. Gilbert: I am very lucky to have you as my advisor. All of the words are blank for me to express my appreciation to you. I still remember the first day we met at the airport. From that moment, I knew that we were going to rock. Thank you for your patience in teaching me the lab techniques and always keeping your door open for me. Also, thank you for all your encouragement, professional guidance and endless inspirational discussions. Thank you for providing me opportunities to attend various conferences even during the “economic crisis period”. Your efficiency at editing my papers and lab work always made me want to write more. You are more than a teacher to me in many ways. The time we spent hiking, traveling, and talking about life philosophy will always be the best part of my memories. You have made my Ph.D. study enjoyable and rewarding. I could not have made it this far without you. Dr. Cline: Although only be able to work with you for 2 years, you have had a tremendous influence on me. I admire you as a teacher and a scientist. Thank you for helping me with my experiments at 5 in the morning, for always being straight with me about my weakness and helping me to improve in many aspects. You are one of the best teachers, and I thoroughly enjoy your classes. Also, thank you for giving me the chance to teach the lab. It was a great experience. You have ignited my desire for pursuing neuroscience. Dr. Siegel: It is very hard for me to convey my gratitude for everything that you have done for me. Your enthusiasm for science deeply inspired me 5 years ago when you help revised my manuscript in China. Everything feels like it happened yesterday. You have given me every reason for continuing my study abroad, however, I had never imagined iv that I would be able to work with you again someday. Thank you so much for your constructional suggestions to my dissertation. The questions you asked were always thought-provoking, which help me to envision the whole picture. Your presence on the farm, in the office and our lab always motivated me to work harder. I could not have made it all the way to where I am today without your encouragement, support and help. I have learned a lot from you and am going to carry that over to the next journey of my research. I will miss all of your life stories. They always led up to meaningful afterthoughts. Dr. Jiang: Your insightful suggestions and criticisms at different stages of my research have made a big difference in my dissertation. Your strict requirements have held me to a high research standard. Your warm smiles in the hallway always reminded me that nothing is impossible. Thank you for being such a good role model for me to believe that language and culture is not a hindrance for pursuing science. Dr. Liu: I may not be able to achieve my dream for studying abroad without you. Thank you for taking the chance to bring me here 4 years ago and for always keeping me and my career development in your mind. You always kindly helped me before I even asked and reached your hand out at the most critical times. I appreciate all of your suggestions to my work and the intellectual inputs into my dissertation. Thank you for always being there for me and letting me know that there is someone I can come to when I needed advice. Dr. Andersson: You have proved to me that there is a way to balance research and other parts of life. Thank you for taking advantage of every opportunity you can get to advise me and provide suggestions to my projects. v Dr. Susan Hutson: Thank you for the warm welcoming party, for having me over for the Christmas festival many times and for letting me spend the most wonderful time with your family. You are as dear as my family and as close as a dear friend. I admire you for being an outstanding female role model. I just want to let you know that I appreciate everything that you have done for me. Dr. Sally Johnson: You don’t how much you have helped me during my experiments. Thank you for generously showing Yue and me the primary cell culture, for patiently explaining to us how it works and details that we needed to pay attention to. You are so knowledgeable and kind. I also appreciate your help in many other things. You always helped me to cool down and to feel like there is some one that I can count on when things don’t work. Dr. Sungwon Kim: What can I do without you? You are one of the most wonderful friends to have. I wish that I knew you earlier. Through these past three years, you have taught me so much in many aspects. I enjoy the criticism from you because I know you want the best out of me. Thanks for always challenging me in many things. They help to shape my mind and force me to really think hard. You have seen me grow, and I want you to know that I will always do my best. Best of luck in your research and life at the Roslin Institute. Thanks to all the department faculty members, staff, and colleagues, especially to Dr. Jason and Tracy Scheffler, Dr. Rami Dalloul, Dr. Samer EI-Kadi, Dr. Eric Wong, Dr. Michael Denbow, Dr. Ben Dorshorst, Dr. Hao Shi, Dr. Ed Smith, Dr. Rob and Shelly Rhoads, Dr. Jeffery Escobar, Dr. Mike McGilliard, Ellie Stephens, Lee Johnson, Pat Williams, Barbara Self, David Linker, Jennifer Sottosanti Bradley, Melissa Cromer, vi Mary Jane Thompson, Christa Honaker, Mike Graham, Brad Reinholt, Eric England, Sarah McCoski, Tiffany Potter, Myeongseon Park, Alamanda Calvert, Victoria McCracken, and Jason Smith.
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