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White Adipose Tissue Beiging in Mice with Increased Growth Hormone Action

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White Adipose Tissue Beiging in Mice with Increased Growth Hormone Action White Adipose Tissue Beiging in Mice With Increased Growth Hormone Action A thesis presented to the faculty of the College of Health Sciences and Professions of Ohio University In partial fulfillment of the requirements for the degree Master of Science Katie M. Troike August 2017 © 2017 Katie M. Troike. All Rights Reserved. 2 This thesis titled White Adipose Tissue Beiging in Mice With Increased Growth Hormone Action by KATIE M. TROIKE has been approved for the School of Applied Health Sciences and Wellness and the College of Health Sciences and Professions by Darlene E. Berryman Adjunct Research Professor of Food and Nutrition Sciences Randy Leite Dean, College of Health Sciences and Professions 3 Abstract TROIKE, KATIE M., M.S., August 2017, Food and Nutrition Sciences White Adipose Tissue Beiging in Mice With Increased Growth Hormone Action Director of Thesis: Darlene E. Berryman White adipose tissue (WAT) is a complex and dynamic endocrine organ that is most commonly recognized for its energy storage capacity. Brown adipose tissue (BAT) functions to dissipate stored energy in the form of heat through a process known as nonshivering thermogenesis. This process is aided by the mitochondrial matrix protein, uncoupling protein 1 (UCP1), which creates a proton leak across the inner mitochondrial membrane causing chemical energy to be released as heat. More recently, clusters of brown-like or “beige” adipocytes have also been identified in WAT. These adipocytes have the capacity to interconvert between the two phenotypes, in part, through increasing their expression of UCP1. This “beiging” is dependent on environmental and chemical conditions present within the cell. Growth hormone (GH), a protein secreted from the anterior pituitary, has been positively correlated with increased BAT mass. However, this evidence is controversial, and the effects of GH on BAT and WAT beiging are not well defined. Bovine growth hormone transgenic (bGH) mice have increased GH action, are giant and lean, yet develop insulin resistance and have shortened lifespans compared to their wild-type (WT) littermates. The purpose of the current study was to compare the expression of beiging-associated factors at both the RNA and protein levels in bGH mice and WT littermate controls. To accomplish this, several different methods were used to measure expression of beiging-associated gene expression in the WAT and BAT depots 4 of these mice. A previously collected RNA-Seq dataset revealed significant genotype and depot differences, with the greatest number of expression changes detected between genotype in the subcutaneous depot and between depot in the bGH mice. Additionally, qPCR, Western blot analysis, and immunohistochemistry with confocal imaging revealed that UCP1 RNA and protein expression were undetectable in the WAT depots of these mice. No significant differences in UCP1 expression were observed between genotype or age in BAT depots. Basal oxygen consumption rate (OCR) in subcutaneous WAT, but not BAT, exhibited a significant effect of genotype and age. Our results indicate that, at a basal level, GH may affect the expression of certain beiging-associated genes and OCR in a depot-dependent manner, but does not appear to have a direct effect on UCP1 expression. 5 Dedication For my grandpa Harry. 6 Acknowledgments I would first like to thank my advisor, Dr. Darlene Berryman, for her encouragement, support, and guidance over the years. She is truly an outstanding role model and an inspiration to her students. I would also like to thank my committee members Dr. Cheryl Howe and Dr. Ed List, for their insight and help throughout this process. This thesis would not have been possible without the help of everyone in the Kopchick lab “family.” I would like to specifically thank Silvana Duran-Ortiz, who allowed me to use her RNA-Seq data, Brooke Henry for her invaluable contributions to my research, and Jon Young for always being there to answer my questions and help me troubleshoot. Also, a big thank you to Dr. John Kopchick for fostering a uniquely collaborative environment of exceptional scientists and for making Athens feel like home. Finally, thank you to my parents John and Sharon, and my husband Adam, for loving and encouraging me. I couldn’t have done it without you. 7 Table of Contents Page Abstract ............................................................................................................................... 3 Dedication ........................................................................................................................... 5 Acknowledgments............................................................................................................... 6 List of Tables .................................................................................................................... 12 List of Figures ................................................................................................................... 13 Chapter 1: Introduction ..................................................................................................... 15 Statement of Problem .................................................................................................... 18 Research Questions ....................................................................................................... 19 Hypotheses .................................................................................................................... 19 Significance .................................................................................................................. 20 Limitations/Delimitations ............................................................................................. 20 Definition of Terms ...................................................................................................... 21 Chapter 2: Review of the Literature .................................................................................. 23 Adipose Tissue .............................................................................................................. 24 White adipose tissue. ................................................................................................ 24 Function. ............................................................................................................... 25 White adipose tissue depots. ................................................................................. 27 Depot-specific differences. ................................................................................... 28 Obesity and white adipose tissue remodeling. ...................................................... 30 Brown adipose tissue. ............................................................................................... 32 8 Uncoupling protein 1. ........................................................................................... 35 Regulation of thermogenesis................................................................................. 37 Beiging of White Adipose Tissue ................................................................................. 38 Beige adipocytes. ...................................................................................................... 38 Factors affecting beiging. .......................................................................................... 41 Beiging as a potential therapeutic target. .................................................................. 49 Growth Hormone .......................................................................................................... 50 Structure and regulation. ........................................................................................... 50 Growth hormone-induced signaling. ........................................................................ 52 GH function. ............................................................................................................. 54 Acromegaly. .............................................................................................................. 55 Bovine growth hormone transgenic mouse. .............................................................. 56 Laron Syndrome. ....................................................................................................... 59 Growth hormone receptor knockout mouse. ............................................................. 59 Growth Hormone and Adipose Tissue .......................................................................... 63 Growth hormone and adipokines. ............................................................................. 64 Depot-dependent growth hormone action. ................................................................ 65 Growth hormone and brown adipose tissue or beiging. ........................................... 66 Summary ....................................................................................................................... 67 Chapter 3: Materials and Methods .................................................................................... 68 Animals ......................................................................................................................... 68 Body Weight and Body Composition ........................................................................... 69 9 Adipose Tissue Depots ................................................................................................. 69 RNA-Seq Analysis .......................................................................................................
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