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Role of Vascular Endothelial Growth Factor Signaling in Brown Adipocyte Survival, Proliferation and Function

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Role of Vascular Endothelial Growth Factor Signaling in Brown Adipocyte Survival, Proliferation and Function Role of Vascular Endothelial Growth Factor Signaling in Brown Adipocyte Survival, Proliferation and Function The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Bagchi, Mandrita. 2012. Role of Vascular Endothelial Growth Factor Signaling in Brown Adipocyte Survival, Proliferation and Function. Doctoral dissertation, Harvard University. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:10417574 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Copyright © 2012, Mandrita Bagchi, all rights reserved Dissertation Advisor: Dr. Patricia A. D’Amore Mandrita Bagchi Role of Vascular Endothelial Growth Factor Signaling in Brown Adipocyte Survival, Proliferation and Function ABSTRACT Both white and brown adipose tissues exhibit extensive vascularity. Increased angiogenesis in brown adipose tissue (BAT) is crucial for brown fat activation and thermogenesis in animals during cold acclimation. BAT can be similarly activated by food intake to generate heat through cellular respiration, in a process known as diet induced thermogenesis. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that regulates both pathological and physiological angiogenesis and can stimulate cell proliferation, migration, survival and vessel permeability. However, VEGF has also been shown to affect an increasing number of non-vascular cells such as skeletal muscle and kidney podocytes. The expression and function of VEGF in white and brown adipocytes are not fully understood. We have previously shown that the expression of VEGF is concomitantly regulated with skeletal muscle differentiation. Here we show that VEGF is expressed in BAT and all major white adipose depots in mice. VEGF expression was increased during white and brown adipocyte differentiation and was regulated in cultured brown adipocytes by the PPARγ agonist troglitazone and by PGC1α in BAT in vivo. iii Systemic VEGF neutralization led to brown adipocyte apoptosis in vivo, loss of mitochondrial cristae and increased mitophagy and was associated with increased inflammation and fibrosis. VEGFR2 was expressed in both brown preadipocytes and adipocytes. Blockade of VEGF signaling using anti-VEGFR2 antibody DC101 increased brown adipocyte apoptosis in vitro. VEGF also functioned as a mitogen and survival factor for brown preadipocytes. VEGF 164 and VEGF 188, isoforms that can bind heparan sulfate proteoglycans, comprise >98% of total VEGF in BAT, subcutaneous and perigonadal fat depots. Embryos that lacked VEGF 164 and 188 displayed abnormal BAT development with fewer brown adipocytes, lower levels of mitochondrial uncoupling protein 1 and Cox IV. These results indicate a direct role for VEGF signaling in brown adipocytes and preadipocytes and suggest the importance of heparan sulfate binding VEGF isoforms in BAT development. Elucidation of the role of VEGF signaling in adipocytes is vital to understanding adipose tissue expansion and activation and may reveal novel therapeutic targets for the activation of brown fat in humans. iv TABLE OF CONTENTS TABLE OF CONTENTS.................................................................................................................. v ACKNOWLEDGEMENTS ........................................................................................................... viii LIST OF ABBREVIATIONS ........................................................................................................... xi INDEX OF FIGURES .................................................................................................................. xiii INDEX OF TABLES ..................................................................................................................... xv Chapter 1 : INTRODUCTION ...................................................................................................... 1 Adipose Tissue ...................................................................................................................... 2 White Adipose Tissue ....................................................................................................... 2 Brown Adipose Tissue ..................................................................................................... 11 Angiogenesis ....................................................................................................................... 28 Adipose Tissue Angiogenesis .......................................................................................... 29 Vascular Endothelial Growth Factor ................................................................................... 37 Chapter 2:EXPRESSION OF VEGF AND VEGF RECEPTORS IN WHITE AND BROWN ADIPOSE . 46 Introduction ........................................................................................................................ 47 Results ................................................................................................................................. 47 Discussion ........................................................................................................................... 63 Chapter 3: ROLE OF VEGF SIGNALING IN BROWN ADIPOCYTES ............................................. 69 Introduction ........................................................................................................................ 70 Results ................................................................................................................................. 70 Discussion ........................................................................................................................... 95 Chapter 4: ISOFORM-SPECIFIC ROLE OF VEGF IN BAT DEVELOPMENT ................................ 105 Introduction ...................................................................................................................... 106 Results ............................................................................................................................... 106 Discussion ......................................................................................................................... 113 Chapter 5 : REGULATION OF VEGF EXPRESSION IN BROWN ADIPOCYTES ........................... 117 Introduction ...................................................................................................................... 118 Results ............................................................................................................................... 118 v Discussion ......................................................................................................................... 123 Chapter 6 : GENERAL DISCUSSION ........................................................................................ 126 Discussion ......................................................................................................................... 127 Closing Thoughts ............................................................................................................... 133 Chapter 7 : MATERIALS AND METHODS ............................................................................... 135 Materials ....................................................................................................................... 136 Methods ........................................................................................................................ 136 APPENDIX .............................................................................................................................. 150 RhoB Controls Adult Angiogenesis and Lymphangiogenesis through VEZF1 ............... 150 BIBLIOGRAPHY ...................................................................................................................... 193 BIBLIOGRAPHY .................................................................................................................. 194 vi To my parents, Swapan and Nilanjana, my brother, Mainak & my husband, Sutirtha vii Acknowledgements I would like to wholeheartedly thank my mentors, all my colleagues, friends and family, many of whom I have named here. I would not have the privilege of writing this dissertation without your continuous encouragement and love. I express my sincerest gratitude to my dissertation advisor, Dr. Patricia D’Amore. Pat has not only provided excellent guidance for my dissertation but has also trained me to be a good and meticulous scientist and has made sure that we learn how to effectively communicate science through good writing and presentation. Pat maintains a great lab, which reflects her own vivacity and enthusiasm and has been a wonderful place to work. I would like to thank all my colleagues for a fun-filled three years. In particular, I want to extend a very special thank you to Dr. Leo Kim for doing sFlt1 tail vein injections and perfusions for me and being very excited in my project all along and to Dhanesh Amarnani for helping me with the sFlt1 mouse work. I am also thankful to D’Amore lab alums, Dr. Tony Walshe, who so kindly took the leap of faith and did the first set of sFlt1 experiments for me and to Dr. Sunita Hett for being such a wonderful friend and guide in lab! To all my DAC members – Drs Zoltan Arany, Ron Kahn and William Aird: thank you
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