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Dietary Sphingomyelin for the Prevention of Diet-Induced Metabolic Dysfunction in Mice" (2018)

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University of Connecticut OpenCommons@UConn Doctoral Dissertations University of Connecticut Graduate School 5-10-2018 Dietary Sphingomyelin for the Prevention of Diet- induced Metabolic Dysfunction in Mice Gregory Harrison Norris University of Connecticut - Storrs, [email protected] Follow this and additional works at: https://opencommons.uconn.edu/dissertations Recommended Citation Norris, Gregory Harrison, "Dietary Sphingomyelin for the Prevention of Diet-induced Metabolic Dysfunction in Mice" (2018). Doctoral Dissertations. 1801. https://opencommons.uconn.edu/dissertations/1801 Dietary Sphingomyelin for the Prevention of Diet-induced Metabolic Dysfunction in Mice Gregory H. Norris University of Connecticut, 2018 Metabolic dysfunction directly links of obesity and metabolic disorders. Although poor diet and lack of exercise are known factors for the development of metabolic disorders, there is a clear need to identify dietary components that may be effective for preventing metabolic dysfunction. Therefore, this dissertation aimed to define the effects of dietary sphingomyelin (SM) on diet-induced metabolic dysfunction. In Aim 1, we explored the short-term effects of dietary milk and egg SM on lipid homeostasis in C57BL/6J mice fed a high-fat diet. Milk SM reduced both hepatic lipid accumulation and serum cholesterol, which correlates well with the existing literature. Conversely, egg SM increased both hepatic and serum lipids. Having demonstrated differences between two sources of SM, the study progressed to Aim 2, where we investigated the effects of both egg and milk SM on preventing metabolic dysfunction in C57BL/6J mice on an obesogenic diet. Egg SM reduced hypercholesterolemia and fasting hyperglycemia. Both SM treatments reduced hepatic steatosis and adipose inflammation, however, egg SM was more effective than milk SM. When designing Aim 3, we focused on defining possible anti- inflammatory effects of milk SM. We observed that feeding milk SM reduced circulating cytokine concentrations in mice fed an obesogenic diet. We also tested the effects of milk SM and its hydrolytic products, ceramide and sphingosine, on LPS-stimulation of RAW264.7 macrophages. We observed all three compounds to be effective inhibitors of the LPS-induced inflammatory response. Additionally, SM hydrolysis was required for SM effectiveness. In a normal diet, the consumption of dietary SM found in foods will be accompanied by other dietary phospholipids. Therefore, we also tested the effects of milk phospholipids supplied by beta-serum, a dairy Gregory H. Norris University of Connecticut, 2018 byproduct, on diet-induced metabolic dysfunction and inflammation in hypercholesterolemic LDL-receptor knockout mice. We found that the highest dose of milk phospholipids markedly reduced cholesterol in both serum and liver, with more modest effects on reducing inflammation markers in liver and adipose tissues. Overall, this work demonstrates a clear potential for dietary SM to be useful for the prevention of obesity-associated metabolic dysfunction. More research is warranted to translate this work into human clinical trials. Dietary Sphingomyelin for the Prevention of Diet-induced Metabolic Dysfunction in Mice Gregory H. Norris B.S., University of Connecticut 2010 A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy at the University of Connecticut 2018 i Copyright by Gregory H. Norris 2018 ii APPROVAL PAGE Doctor of Philosophy Dissertation Dietary Sphingomyelin for the Prevention of Diet-induced Metabolic Dysfunction in Mice Presented by Gregory H. Norris, B.S. Major Advisor __________________________________________ Christopher N. Blesso, Ph.D. Associate Advisor ________________________________________ Cameron Faustman, Ph.D. Associate Advisor ________________________________________ Sung I. Koo, Ph.D. Associate Advisor ________________________________________ Ji-Young Lee, Ph.D. Associate Advisor ________________________________________ Alison Kohan, Ph.D. University of Connecticut 2018 iii This dissertation is dedicated in memory of my sister, Kimberly L. Norris (1989-2013), who consistently presented me with challenges throughout my life and provided me with the motivation to finish this degree. May we all remember to be perfectly imperfect. iv Acknowledgments v First and foremost, I would like to thank my major advisor, Dr. Blesso. You presented me with an opportunity to transform my career, from a lack luster undergraduate to a Ph.D. I will always appreciate the chance you took with me. I hope you feel as though it has paid dividends. Throughout these four years I have always had funding to carry out the research. It was with your guidance that I have been able to navigate these past 4 years and been as successful as I have been. Throughout my time in your lab, you kept a constant work flow coupled with more difficult challenges to facilitate my intellectual growth. This has given me the practice and adversity it takes to feel as though I have become a full-fledged scientist. I truly feel prepared to take the next step in my path to becoming a professor myself. As for the rest of my committee: Dr. Faustman, first I would like to thank you for your precious time. As the interim Dean of CANHR, I know every moment is valuable for you. You have embodied how engaging one can be while still remaining technically sound. Your food chemistry class was easily my favorite elective and I will always refer to your advice to “tell a story” when writing and presenting science. Dr. Koo, I also am appreciative of your time as our department head. Throughout my time in this department you have contributed funds for pilot studies, travel, the annual holiday party, and American Society of Nutrition memberships. It is this work that keeps our department feeling lively and like a second home. Aside from that, I appreciate all of your critiques through my exams and in my writings. You have an expertise in the field of dietary sphingomyelin and it is well- appreciated to learn from someone so knowledgeable in the field of nutrition. Dr. Lee, if it was not for your NUSC 4236 I am not sure I would have applied to nutrition doctoral programs. The class married my interests of biochemistry and health in a way I did not imagine in my undergraduate career. It was no more than a year later that I found myself neck deep in “Inflammation, Diets, and Chronic Disease”, which to this day is the hardest, yet most rewarding class I have ever taken. It is with full confidence that I can say that class prepared me for the rest of my graduate course work and jumpstarted my ability to fully understand research articles. Dr. Kohan, it was your positive attitude that raised my spirits again after feeling like I fumbled my way through my oral defense. You have never been too busy for a random visit to your office for advice on job hunting. Additionally, you were the first one to broaden my vision of what a Ph.D. means. During lunch at my first CANHR forum you told me how foreign languages use to be a requirement for a Ph.D. because it demonstrates your capacity to learn. From that, I have made a conscious effort to learn more than only molecular nutrition. I believe this had made me a more well-rounded person and a better scientist. The rest of the faculty members in our department have also done an exceptional job of nurturing my curiosity about topics outside of molecular nutrition. Numerous professors have either raised questions that gave me new perspective or taught me some of the basics of research, writing, and presenting, all vital skills for my future. vi Special thanks go to Kathryn Parlin and Camilla Crossgrove for managing the financial side of graduate school and lab work for me. In my time in the Blesso lab, I have had the pleasure of working alongside my fellow graduate students Nicholas Farrell, Courtney Millar, Quinn Duclos, and Christina Jiang. I want to thank the four of you for your support and the sense of comradery in the lab. We have also seen a plethora of undergraduate students in our lab. Caitlin Porter, Christina Jiang, Julia Ryan, Julia Reedy, Nicholas Santangelo, Alexander Cruz, Chelsea Garcia, Jessica Seltz, and Julia Colliton, it was a pleasure to watch you develop in your undergraduate efforts within the Blesso lab, I appreciate every single tube you guy have labeled. As for my fellow UConn Nutrition graduate students, past and present, there are far too many of you to name in this section. I have had the honor to be among the ranks of some of the most intelligent, motivated, and generally good-spirited people during my time here. Every single one of you has made this department feel like a home to me and I wish you all nothing but the best. Olivia DeWald, thank you for the love and support throughout the past year and a half. You have been my biggest cheerleader, all the while overachieving as an Au.D. student. I will never cease to be amazed by you. Thank you for pushing me to be my best and to find a near perfect Postdoc in Chicago. To my family, I would like to thank you for your continued love and support over the past 26 years. I owe my resiliency and work ethic to you. At some point in my life, each one of you have embodied these values and shown me exactly what is possible when you simply refuse to concede. vii List of Abbreviations 3-Hydroxy-3-methyl-glutaryl-coenzyme A Reductase HMGCR Acetyl-CoA Carboxylase ACC Acyl-Coenzyme A Dehydrogenase 1 ACAD1 Acyl-Coenzyme A Oxidase 1 ACOX1 Adiponectin
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