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Identification and Functional Characterization of Adipogenesis-Related Genes

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Identification and Functional Characterization of Adipogenesis-Related Genes Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Sciences Identification and Functional Characterization of Adipogenesis-related Genes Submitted by: Yu Wu In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences Examination Committee Signature/Date Major Advisor: Cynthia M. Smas, D.Sc. Academic Kam Yeung, Ph.D. Advisory Committee: Ronald L. Mellgren, Ph.D. William T. Gunning, Ph.D. Beata Lecka-Czernik, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: October 14, 2008 Identification and Characterization of Adipogenesis Related Genes Yu Wu University of Toledo Health Science Campus 2008 i DEDICATION This work is dedicated to my father, Zixing Wu, and my mother, Zhiping Yan, for their great love, and to my husband Yang Lu, for his continual support, encouragement and love. ii ACKNOWLEDGEMENTS I want to express my most deep gratitude to my advisor, Dr. Cynthia M. Smas for Her guidance, understanding, patience, and encouragement in the past four years. Her infectious enthusiasm and unlimited zeal have always been the major driving forces during my graduate studies. She encouraged me to develop independent thinking and research skills, which prepared me for future challenges. I would like to extend my thanks to the distinguished faculty members who served on my committee: Dr. Kam C. Yeung, Dr. Ronald L. Mellgren, Dr. William T. Gunning III, Dr. Beata Lecka-Czernik and Dr. Ana Maria Oyarce. I have benefited greatly from their advices. This dissertation would not be realized without the help of my colleagues and friends at the University of Toledo. The thanks will go to Dr. Ji Young Kim, Shengli Zhou, Junho Lee, Kun Liu and Kristin Tillison for their friendship, technical advice and emotional support. They have turned my journey through graduate school into a pleasure. I also want to thank all of my friends at the University of Toledo for their consistent encouragement, support and trust during my graduate studies. I also want to give a hearty thank to the personnel who keeps the Biochemistry and Cancer Biology Department together as a cohesive unit. I wish to thank Dr. William Anthony Maltese for his leadership. And our department iii secretaries Jenifer Zak, Melody Knotts, Anna Chlebowski and Mary Ann Schuster, deserve the sincerest thanks for their hardworking to keep the department operating in an efficient manner. In addition, I would like to thank Dr. Cynthia M. Smas, Dr. Kam C. Yeung and Dr. Ronald L. Mellgren for assisting in pursuing my post-doctoral position. Last, but certainly not least, I would like to thank my family for their support and care. They have always been the source of courage for me to face any difficulties. iv TABLE OF CONTENTS Dedication …………………………………………………………………………….ii Acknowledgments …………………………………………………………………...iii Table of Contents ……………………………………………………………………v Introduction …………………………………………………………………………..1 Literature ……………………………………………………………………………..7 Manuscript #1 ……………………………………………………………………….53 Wdnm1-like, a New Adipokine with a Role in MMP-2 Activation Manuscript #2 ……………………………………………………………………….107 Identification and Characterization of TSC-36 as a Preadipocyte Gene Manuscript #3 ……………………………………………………………………….167 Differential screening identifies transcripts with depot-dependent expression in white adipose tissues Manuscript #4……………………………………………………………………….. 220 Generation and Characterization of mBAP-9, a New Brown Preadipocyte Cell Line, Reveals Differentiation-Dependent Regulation of Cmbl and Atabh, Two Novel α/β Hydrolases Manuscript #5 ………………………………………………………………………..280 Expression and regulation of transcript for the novel transmembrane protein Tmem182 in the adipocyte and muscle lineage Discussion and Summary…………………………………………………………. .307 Conclusions ………………………………………………………………………….315 Bibliography ………………………………………………………………………… 319 Abstract ……………………………………………………………………………….346 v INTRODUCTION Obesity is a major and continuing public health problem in the United States and in many industrialized nations. It is a risk factor for a number of pathological disorders, such as cardiovascular disease, hypertension, non-insulin dependent diabetes, cancer, gallbladder disease and atherosclerosis (Gregoire et al., 1998b; Kahn et al., 2006; Ogden et al., 2006; Van Gaal et al., 2006). Obesity occurs when energy intake exceeds energy expenditure and in humans obesity is defined by body mass index (BMI). BMI is calculated as weight in kilograms divided by the square of body height in meters. A person with a BMI between 25 and 29.9 is defined as overweight, and a BMI equal to or great than 30 is obese. White adipose tissue (WAT) is a unique organ designated to store triglyceride and maintain energy homeostasis. Adipose tissue is also recognized as a dynamic endocrine organ, that synthesizes and secretes a number of soluble factors such as leptin, adiponectin, resistin and a variety of cytokines including TNFα (tumor necrosis factor α) (Maeda et al., 2002; Spiegelman and Flier, 1996; Steppan et al., 2001). Adipocytes are formed from preadipocyte precursors and this process of differentiation is termed adipogenesis. Adipogenesis is important for the understanding and control of obesity (Ntambi and Young-Cheul, 2000). In addition to preadipocytes and adipocytes, adipose tissue also consists of many other cell types including small blood vessels, nerve tissue and fibroblasts (Geloen et al., 1989). Within adipose tissue, it is difficult to 1 distinguish preadipocyte precursors from fibroblasts due to the lack of molecular markers for preadipocytes. Additionally, even though the mesodermal pluripotent fibroblasts have the ability to give rise to cartilage, smooth muscle and preadipocyte cell types, the full developmental linage of the preadipocyte from fertilized egg is to date ill-defined. It is therefore difficult to study adipogenesis in vivo and adipogenesis has been studied primarily by using in vitro models. The 3T3-L1 cell line is one of the most well established cell culture models of adipogenesis. 3T3-L1 preadipocytes resemble fibroblasts morphologically, and have the ability to differentiate to mature adipocytes upon treatment with an adipogenic cocktail composed of dexamethasone (Dex) and methylisobutylxanthine (Mix) (Green and Kehinde, 1974, 1975a; Green and Meuth, 1974). The upregulation of gene expression during adipogenesis has been extensively characterized. The adipogenic transcription factors C/EBPs (CCAAT/enhancer binding proteins) and PPARγ (peroxisome proliferator- activated receptor-gamma) play key roles in the transcriptional cascade during adipogenesis (Gregoire, 2001b; Gregoire et al., 1998b; Rajala and Scherer, 2003). Upon the treatment with the adipogenic cocktail, C/EBPβ and C/EBPδ are the earliest transcription factors induced by Mix and Dex respectively. Then C/EBPβ and C/EBPδ act to transactivate two master transcriptional regulators of adipogenesis, PPARγ and C/EBPα. These are central to induce multiple genes that function to facilitate and maintain adipogenic differentiation and phenotype (Rosen and Spiegelman, 2001; Tontonoz et al., 1994b). In addition, other 2 transcription factors, such as KLFs (krüppel-like zinc finger transcription factors), ADD1/SREBP (adipocyte determination and differentiation factor 1/sterol regulatory element-binding protein), ERRα (estrogen-related receptor α) and STAT (signal transducers and activators of transcription), all participate in the regulation of adipogenesis (Kim et al., 1998b). Here we report a novel adipokine secreted by adipocytes named Wdnm1- like, which is a distant member of the whey acidic protein/four-disulfide core (WAP/4-DSC) family. We identified Wdnm1-like in an Affymetrix DNA microarray study aimed at discovering new gene expression patterns in adipogenesis. Wdnm1-like is a novel 6.8 kDa secreted protein. Its transcript is upregulated over 20,000-fold during white preadipocyte and brown preadipocyte cell differentiation. In 3T3-L1 adipocytes, TNFα treatment leads to increased Wdnm1-like transcription expression. Several members of the WAP/4-DSC family have demonstrated roles as proteinase inhibitors. Given the importance of matrix metalloproteinase (MMP) activity and matrix remodeling in respect to adipogenesis, we investigated Wdnm1-like effects on MMP activity; we demonstrate that Wdnm1-like functions to enhance MMP-2 activity. In contrast to transcriptional upregulation of genes during adipogenesis, decreases in gene expression that occur during adipocyte differentiation are far less studied. The characterization of such genes is important for elucidating the molecular definition and developmental lineage of preadipocytes. Several molecules with highly differential level expression in preadipocytes vs. mature adipocytes have been identified. These include preadipocyte factor-1 (Pref-1), 3 Wnts, GATA-2 and GATA-3. Pref-1 is a transmembrane molecule with EGF-like repeats and is markedly downregulated in 3T3-L1 adipogenesis. However, Pref-1 expression is extremely low in adipose tissue (Smas et al., 1997). Wnt10b and GATA-2, 3 are downregulated during differentiation and act as adipogenesis inhibitors (Ross et al., 2000; Tong et al., 2000). We identified TSC-36 (TGF-β1 stimulated clone 36) as a novel adipocyte differentiation-dependent downregulated gene via differential screening of DNA filter arrays. TSC-36 encodes a secreted protein and its RNA expression is dramatically downregulated from high to nearly undetectable
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