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View of the Literature Roles of Adipose Tissue-Derived Factors in Adipose Tissue Development and Lipid Metabolism Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Jinsoo Ahn, M.S. Graduate Program in Ohio State University Nutrition The Ohio State University 2015 Dissertation Committee: Kichoon Lee, Ph.D., Advisor Earl H. Harrison, Ph.D. Ramesh Selvaraj, Ph.D. Ouliana Ziouzenkova, Ph.D. Copyright by Jinsoo Ahn 2015 Abstract Obesity is a global trend and major risk factor for serious diseases including type 2 diabetes, heart disease, and hypertension. Obesity is characterized by excess fat accumulation, especially in the visceral area. The pathogenic effects related to common obesity are largely attributed to dysregulated secretion of adipokines followed by insulin resistance in peripheral tissues when adipose tissue mass is altered. White adipose tissue serves as a dynamic endocrine organ as well as a major energy reservoir for whole-body energy homeostasis. Adipokines influence various metabolic processes in the body including adipocyte differentiation; however, precise physiological roles of adipokines need to be further investigated. In addition, a large proportion of adipokines still needs to be identified. Information from the gene expression omnibus (GEO) profile, a public repository for microarray data, combined with confirmatory studies on mRNA and protein expression were used to identify a novel adipose tissue-specific gene, chordin-like 1 (Chrdl1). Further analysis showed that Chrdl1 encodes a putative secreted protein which is a new adipokine. Chrdl1 expression increases during 3T3-L1 adipocyte development in vitro and mouse adipose tissue development in vivo. This pattern, combined with a dramatically increased lipid accumulation and adipocyte differentiation in Chrdl1- overexpressing 3T3-L1 cells suggests that Chrdl1 is a novel pro-adipogenic adipokine which plays stimulatory roles during adipocyte development. ii Adipose tissue is also of great significance in the production of food animals. Reduction of adipose tissue mass will lead to partitioning dietary nutrients towards muscle instead of storage as fat, which enhances feed efficiency and decreases production costs. The net decrease in adiposity is achieved by down-regulation of fat accumulation and up-regulation of fat breakdown or lipolysis. The regulation of lipolysis is likely to be applied to control fat content and increase meat production. The initial step of lipolysis is catalyzed by adipose triglyceride lipase (ATGL) which is the rate-limiting step in this process. Comparative gene identification-58 (CGI-58) and G0/G1 switch gene 2 (G0S2) are known to be an activator and an inhibitor of ATGL-mediated lipolysis, respectively. In the current study, porcine G0S2 was abundantly expressed in adipose tissue and the liver, and its expression was spatially confined in fat cell fraction and temporally specified in late developmental stages, suggesting that G0S2 expression is related to adipocyte development (pro-adipogenic) as well as inhibition of ATGL (anti-lipolytic). In another study, the expression of bovine G0S2 and CGI-58 in muscle of high-marbled steers of Hanwoo, a Korean cattle, was investigated. The regulation of lipolysis in muscle has a potential to increase marbling (intramuscular fat) in beef carcasses. The expression of G0S2 and CGI-58 was significantly higher in longissimus dorsi muscle of high- marbled steers than in less-marbled bulls, suggesting that both genes are novel candidate biomarkers of marbling in beef cattle. In addition, G0S2 was highly expressed in intramuscular fat portion separated from the longissimus dorsi muscle, whereas the expresson of CGI-58 was significantly higher in the remaining portion consisting of the longissimus dorsi muscle without intramuscular fat. It suggests that G0S2 inhibits ATGL- mediated lipolysis in intramuscular fat while CGI-58 activates ATGL in lipids of iii myocytes (intramyocellular triglycerides) which serves as an immediate source of energy during exercise. In another recent study, RBP7 was identified as a novel adipose-specific gene in avian species through gene expression profiling after performing chicken microarray along with real-time PCR and Western blot analysis. Because the RBP7 promoter region was revealed to contain several potential binding sites for adipogenic transcription factors, transgenic quail containing a green fluorescent protein (GFP) gene under the control of the RBP7 promoter were generated by lentivirus-mediated gene transfer. GFP expression in transgenic quail was specific to adipose tissue and increased after adipocyte differentiation. These findings provide compelling evidence that the RBP7 promoter-gene construct can be used to overexpress target genes in adipose tissue. In conclusion, this study has found a new visceral adipokine (Chrdl1), marbling biomarkers (G0S2 and CGI-58), and an adipose-specific gene (RBP7) and its promoter for overexpression of target genes in vivo. It has been shown that Chrdl1 increases lipid accumulation and adipocyte differentiation of 3T3L1 preadipocytes. Expressions of G0S2 and CGI-58, regulators of ATGL-mediated lipolysis, were significantly higher in longissimus dorsi muscle of high-marbled steers. Avian RBP7 gene showed an exclusive expression adipose tissue, and its promoter was used to generate transgenic quail expressing a target gene (GFP) in adipose tissue. Together, this study advances adipose tissue biology through identification of genes related to adipokine, marbling, and adipose-specific expression. iv Acknowledgements First, I would like to express my sincere gratitude to my advisor, Dr. Kichoon Lee, for offering me the opportunity to conduct this research. His continuous guidance and support helped me the entire time required to accomplish my doctoral research. I am grateful of sharing his experience, knowledge, and enthusiasm. Without his advice, this study would not have been successful. I also would like to sincerely thank members of my dissertation committee, Dr. Earl Harrison, Dr. Ramesh Selvaraj and Dr. Ouliana Ziouzenkova for their insightful comments and all the encouragements. I would like to appreciate to Dr. Jeff Firkins, the director of my Interdisciplinary Ph.D. Program in Nutrition, and Ms. Amanda Hargett, the program manager, for their instructions and advice from start to finish. I would also thank all of previous and current members in the Lee Lab and my colleagues and fellow students: Ms. Yeunsu Suh, Dr. Sangsu Shin, Aishlin Lee, Xiang Li, Dr. Yan Song, Shujin Yang, Dr. Young Min Choi, Jibin Zhang, Paula Chen, Elizabeth Kim, Ju Yeon Park for their suggestions and kind assistance, and Dr. Henry Zerby, Dr. Steven Moeller, Dr. Macdonald Wick, Dr. Joe Ottobre, Ann Ottobre, Ben Wenner, Mike Cressman, Yang Cheng, and all other colleagues in the Dept. Animal Sciences for their support and collaborations. v Finally, I would like to give my gratefulness to my late father (Prof. Jong-Cheol Ahn), mother (Seung-Hae Jung), and brother (Taesoo Ahn) for encouraging me to pursue this degree and supporting me throughout my life. vi Vita 1999 ...............................................................B.S. Biotechnology, Yonsei University, Seoul, Korea 2011 ...............................................................M.S. Foods and Nutrition, Ohio University 2011 to present ..............................................Graduate Research Associate, Ohio State University Nutrition, The Ohio State University Publications 1. Ahn J, Oh SA, Suh Y, Moeller SL, Lee K. (2013) Porcine G0/G1 switch gene 2 (G0S2) expression is regulated during adipogenesis and short-term in-vivo nutritional interventions. Lipids, 48(3):209–18. 2. [Song Y, Ahn J], Suh Y, Davis ME, Lee K. (2013) Identification of novel tissue- specific genes by analysis of microarray databases: a human and mouse model. PLoS One, 8(5):e64483. 3. Ahn J, Li X, Choi YM, Shin S, Oh SA, Suh Y, Nguyen TH, Baik M, Hwang S, Lee K. (2014) Differential expressions of G0/G1 switch gene 2 and comparative gene identification 58 are associated with fat content in bovine muscle. Lipids, 49(1):1–14. 4. [Hassan A, Ahn J], Suh Y, Choi YM, Chen P, Lee K. (2014) Selenium promotes adipogenic determination and differentiation of chicken embryonic fibroblasts with regulation of genes in fatty acid uptake, triacylglycerol synthesis, and lipolysis. Journal of Nutritional Biochemistry, 25(8):858–67. vii 5. Zhang J, Suh Y, Choi YM, Ahn J, Davis ME, Lee K. (2014) Differential expression of cyclin G2, cyclin dependent kinase inhibitor 2C and peripheral myelin protein 22 genes during adipogenesis. Animal, 8(5):800–9. 6. Choi YM, Suh Y, Ahn J, Lee K. (2014) Muscle hypertrophy in heavy weight Japanese quail line: Delayed muscle maturation and continued muscle growth with prolonged upregulation of myogenic regulatory factors. Poult Sci, 93(9):2271–7. 7. Ahn J, Shin S, Suh Y, Park JY, Hwang S, Lee K. (2015) Identification of the avian RBP7 gene as a new adipose-specific gene and RBP7 promoter-driven GFP expression in adipose tissue of transgenic quail. PLoS One, 10(4):e0124768. Fields of study Major Field: Ohio State University Nutrition viii Table of Contents Abstract ............................................................................................................................... ii Acknowledgments..............................................................................................................
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