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Pathway Profiling Identifies Mechanisms of Adipose Deposition in Domestic Chickens

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Pathway Profiling Identifies Mechanisms of Adipose Deposition in Domestic Chickens University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 5-2013 PATHWAY PROFILING IDENTIFIES MECHANISMS OF ADIPOSE DEPOSITION IN DOMESTIC CHICKENS Bo Ji [email protected] Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Recommended Citation Ji, Bo, "PATHWAY PROFILING IDENTIFIES MECHANISMS OF ADIPOSE DEPOSITION IN DOMESTIC CHICKENS. " PhD diss., University of Tennessee, 2013. https://trace.tennessee.edu/utk_graddiss/1742 This Dissertation is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a dissertation written by Bo Ji entitled "PATHWAY PROFILING IDENTIFIES MECHANISMS OF ADIPOSE DEPOSITION IN DOMESTIC CHICKENS." I have examined the final electronic copy of this dissertation for form and content and recommend that it be accepted in partial fulfillment of the equirr ements for the degree of Doctor of Philosophy, with a major in Animal Science. Brynn H. Voy, Major Professor We have read this dissertation and recommend its acceptance: Arnold M. Saxton, Michael O. Smith, Russell Zaretzki Accepted for the Council: Carolyn R. Hodges Vice Provost and Dean of the Graduate School (Original signatures are on file with official studentecor r ds.) PATHWAY PROFILING IDENTIFIES MECHANISMS OF ADIPOSE DEPOSITION IN DOMESTIC CHICKENS A Dissertation Presented for the Doctor of Philosophy Degree The University of Tennessee, Knoxville Bo Ji May 2013 DEDICATION This dissertation is dedicated to my family. ii ACKNOWLEDGEMENTS First, I would like to delivery my sincerest gratitude to my advisor, Dr. Brynn Voy, for her consistent support guidance, motivation, patience and encouragement. She always generously provides me with numerous training opportunities for my career growth. I am eternally grateful to Dr. Arnold Saxton for his highly supportive role in my statistical study. He is always willing to offer insightful scientific version on statistics, and encourage me to face the challenges and clean up any hurdle during my graduate study. In addition, I would also like to thank my other committee members: Dr. Michael Smith, Dr. Russell Zaretzki, and Dr. Naima Moustaid-Moussa for their kindest advice, support and guidance on the completion of my PhD study. I would also like to thank members of Dr. Voy’s team, Suchita, Ben, Ann, Manny for the friendly atmosphere they fostered, and also for the exchange of knowledge and sharing their personal life with me. This friendship helps me sail through those tough times. Last but not least, I am deeply indebted to my parents for their love, sacrifices, and encouragement. My special thanks to my husband, Ran for his unconditional love and encouragement and my little beloved son, Kevin Ye who brings endless happiness to me and shine in my life. iii ABSTRACT The domestic chicken is an attractive, but underutilized, animal model for studies of adipose tissue biology, metabolism and obesity: 1.) like humans, chickens rely on liver rather than adipose tissue for the majority of de novo lipogenesis; 2.) quantitative trait loci (QTLs) linked to fatness in chickens contain genes implicated in human susceptibility to obesity and diabetes; 3.) chickens are naturally hyperglycemic and insulin resistant; and 4.) a broad selection of genetic models exhibiting a range of fatness are available. To date, however, little is known about regulation of adipose metabolism in this model organism. Affymetrix arrays were used to profile gene expression in abdominal adipose tissue from broiler chickens fed ad libitum or fasted for five hours. Quantitative real time polymerase chain reaction (QPCR) was used to validate microarray results for select genes. A total of 1780 genes were differentially expressed in fasted vs. ad libitum fed (p<0.05) tissue after correction for multiple testing. Gene Ontology and pathway analyses, combined with Western blot validation, indicated significant effects on a broad selection of pathways related to metabolism, stress signaling and adipogenesis. In particular, fasting upregulated rate-limiting genes in both the mitochondrial and peroxisomal pathways of beta-oxidation. Enhanced fatty acid oxidation in white adipose tissue was further suggested by a significant increase in tissue content of the ketone beta- hydroxybutyrate. Expression profiles suggested that, despite the relatively brief duration of feed withdrawal, fasting suppressed adipogenesis; expression of key genes in multiple steps of adipogenesis, including lineage commitment from mesenchymal stem cells, were iv significantly down-regulated in fasted vs. fed adipose tissue. Interestingly, fasting increased expression of several inflammatory adipokines and components of the toll-like receptor 4 signaling pathway. A second study with Affymetrix microarrays of Fayoumi, Leghorn and broiler adipose tissue revealed that genetic leanness shared molecular signatures with the effects of fasting. In supervised clustering analysis, fasted broiler chickens clustered with lean Fayoumi and Leghorn lines rather than with the fed broiler group, suggesting that fasting manipulated expression profiles to resemble those of the lean phenotype. v Table of Contents Chapter I ..................................................................................................... 1 Literature review ....................................................................................... 1 Introduction and Objectives .........................................................................................1 Domestic Chickens ......................................................................................................2 Adipose Tissue Biology ...............................................................................................7 White adipose tissue & brown adipose tissue ..........................................................7 Adipogenesis ............................................................................................................7 Adipose Tissue Metabolism .........................................................................................9 De novo lipogenesis ...............................................................................................10 Fatty acid uptake, re-esterification and lipolysis ...................................................14 Fatty acid oxidation................................................................................................15 Regulation of Adipose Metabolism .......................................................................18 Mechanisms of Adipose Tissue Expansion ...............................................................23 Endocrine Functions of Adipose Tissue ....................................................................25 Adipokines .............................................................................................................25 Genetic Mapping of Fatness-synteny with Human Genetic Studies of Obesity .......................................................................................................................29 Chapter II ................................................................................................. 31 Transcriptomic and metabolomic profiling of chicken adipose tissue in response to insulin neutralization and fasting ........................................................................................................ 31 Introduction ................................................................................................................32 Materials and Methods ...............................................................................................35 Animals ..................................................................................................................35 Gene expression .....................................................................................................36 LC-MS/MS ............................................................................................................37 Statistical analysis ..................................................................................................38 Results ........................................................................................................................39 Discussion ..................................................................................................................53 Conclusions ................................................................................................................64 Chapter III ................................................................................................ 68 Genetic leanness in domestic chickens is associated with increased fatty acid oxidation in white adipose tissue .......................... 68 Introduction ................................................................................................................68 Methods and Materials ...............................................................................................70 Animals ..................................................................................................................70 Determination of physiological parameters ...........................................................70
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