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The Suppressive Effects of 1,25-Dihydroxyvitamin D3 and Vitamin D Receptor on Brown Adipocyte Differentiation and Mitochondrial Respiration

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The Suppressive Effects of 1,25-Dihydroxyvitamin D3 and Vitamin D Receptor on Brown Adipocyte Differentiation and Mitochondrial Respiration University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Masters Theses Graduate School 8-2014 The Suppressive Effects of 1,25-dihydroxyvitamin D3 and Vitamin D Receptor on Brown Adipocyte Differentiation and Mitochondrial Respiration Carolyn Jeanne Ricciardi University of Tennessee - Knoxville, [email protected] Follow this and additional works at: https://trace.tennessee.edu/utk_gradthes Part of the Molecular, Genetic, and Biochemical Nutrition Commons Recommended Citation Ricciardi, Carolyn Jeanne, "The Suppressive Effects of 1,25-dihydroxyvitamin D3 and Vitamin D Receptor on Brown Adipocyte Differentiation and Mitochondrial Respiration. " Master's Thesis, University of Tennessee, 2014. https://trace.tennessee.edu/utk_gradthes/2876 This Thesis 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 Masters Theses 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 thesis written by Carolyn Jeanne Ricciardi entitled "The Suppressive Effects of 1,25-dihydroxyvitamin D3 and Vitamin D Receptor on Brown Adipocyte Differentiation and Mitochondrial Respiration." I have examined the final electronic copy of this thesis for form and content and recommend that it be accepted in partial fulfillment of the equirr ements for the degree of Master of Science, with a major in Nutrition. Ling Zhao, Major Professor We have read this thesis and recommend its acceptance: Jay Whelan, Guoxun Chen 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.) The Suppressive Effects of 1,25-dihydroxyvitamin D3 and Vitamin D Receptor on Brown Adipocyte Differentiation and Mitochondrial Respiration A Thesis Presented for the Master of Science Degree The University of Tennessee, Knoxville Carolyn Jeanne Ricciardi August 2014 Copyright © 2014 by Carolyn J. Ricciardi All rights reserved. ii DEDICATION To my mother, Jennifer Fuller-Ricciardi, and my father, Charles Ricciardi, who have been my motivation, my support system, and my biggest fans. iii ACKNOWLEDGEMENTS I’d like to thank my advisor Dr. Ling Zhao and my committee members Dr. Whelan and Dr. Chen for their guidance and expertise over the past two years. I’d also like to thank my lab partners and classmates Matt Goff, Megan Johnstone, Vaishali Keshani, Jaanki Purohit, Pan Hu, and Jiyoung Bae for their willingness to help me with my studies and research. Finally, many thanks to my Tennessee friends for their unconditional support throughout graduate school. iv ABSTRACT The vitamin D system plays a role in metabolism regulation. It has been reported that 1,25(OH)2D3 [1,25-dihydroxyvitamin D] suppresses 3T3-L1 adipocyte differentiation. Vitamin D receptor (VDR) knockout mice showed increased energy expenditure whereas mice with adipose-specific VDR over expression showed decreased energy expenditure. Brown adipose tissue (BAT), which functions in non-shivering thermogenesis by uncoupling ATP synthesis from oxidation, plays important roles in energy expenditure. However, the effects of 1,25(OH)2D3 on brown adipocyte differentiation and mitochondrial respiration have not been studied. Reported here is the mRNA expression of VDR, UCP1, and CYP27B1 (1α[alpha]- hydroxylase) in two mice models of obesity; and the down regulation of mRNA of VDR, CYP24A1 (24-hyrdoxylase), and CYP27B1 during brown adipocyte differentiation in vitro. 1,25(OH)2D3 dose-dependently suppressed brown adipocyte differentiation, as revealed by oil red O (ORO) stained cell morphology, ORO absorbance, and brown adipocyte marker gene expression. Moreover, cellular bioenergetics measurements showed that 1,25(OH)2D3 suppressed isoproterenol-stimulated oxygen consumption rates (OCR), maximal OCR and OCR from proton leak, but had no effects on ATP-generating OCR and spare respiration capacity in brown adipocytes. Consistently, over-expression of VDR also suppressed brown adipocyte differentiation. Furthermore, both 1,25(OH)2D3 and VDR over expression suppressed PPARγ [gamma] transactivation in brown preadipocytes. Taken together, the results demonstrate the suppressive effects of 1,25(OH)2D3/VDR signaling on brown adipocyte differentiation and mitochondrial respiration and suggest a role of 1,25(OH)2D3/VDR signaling in regulating BAT function for obesity treatment and prevention. v Keywords: Vitamin D receptor, brown adipocyte, UCP1, mitochondrial respiration vi TABLE OF CONTENTS CHAPTER I Introduction ................................................................................................... 1 CHAPTER II Literature Review ........................................................................................ 4 2.1 Overview of Vitamin D ............................................................................................. 4 2.1.1 Vitamin D Structure and Function ..................................................................... 4 2.1.2 Dietary and Non-dietary Sources of Vitamin D ................................................. 6 2.1.3 Vitamin D Metabolism and Transportation……………………………………6 2.1.4 Vitamin D and Energy Metabolism……………………………………………7 2.2 Brown Adipose Tissue: Significance and Nutritional Regulation .......................... 12 2.2.1 Brown Adipose Tissue Function ...................................................................... 12 2.2.2 Brown Adipose Development..……………………………………………….13 2.2.3 Brown Adipose Tissue Activation……………………………………………17 2.2.4 Regulation of Brown Adipose Mass by Nutritional and Non-nutritional Regulators………………………………...…………………………………..18 2.3 The Research Gap………………………………………………………………..21 CHAPTER III Materials and Methods .............................................................................. 22 3.1.1 Reagents ........................................................................................................... 22 3.1.2 Animals ............................................................................................................. 22 3.1.3 Cell Culture and differentiation ....................................................................... 22 3.1.4 Western Blot Analysis ...................................................................................... 23 3.1.5 RNA preparation and quantitative real time PCR analysis .............................. 24 3.1.6 MTT Assay ....................................................................................................... 24 3.1.7 Analysis of mitochondrial content by MitoTracker green staining .................. 25 3.1.8 Reporter Gene Assays………………………………………………………...25 3.1.9 Cell respiration measurements ......................................................................... 26 3.1.10 Statistical Analysis ......................................................................................... 27 CHAPTER IV Results, Discussion, and Future Directions ............................................. 28 4.1 Results ..................................................................................................................... 28 4.1.1 VDR, CYP24A1 and CYP27B1 mRNA expression in the BAT of mice model of obesity and during brown adipocyte differentiation in cultured cells……………28 4.1.2 Effects of 1,25(OH)2D3 on the vitamin D system during brown adipocyte differentiation ………………………………………………………………..28 4.1.3 Effects of 1,25(OH)2D3 on brown adipocyte lipid accumulation, mRNA expression, and mitochondrial content……...………………………………..29 4.1.4 Brown adipocyte time sensitivity to 1,25(OH)2D3 treatment………………...30 4.1.5 Effects of 1,25(OH)2D3 on mitochondrial respiration in brown adipocytes…..31 4.1.6 Effects of over-expression of VDR on brown adipocyte differentiation……...31 4.1.7 1,25(OH)2D3/VDR suppresses PPARγ transactivation in brown preadipocytes…………………………………………………………..32 4.2 Discussion………………………………………………………………………….32 4.3 Future Directions…………………………………………………………………...36 LIST OF REFERENCES…………………………………………………………………39 APPENDIX……………………………………………………………………………….48 Vita………………………………………………………………………………………..60 vii LIST OF FIGURES Figure 1 Endogenous metabolism of Vitamin D3…...…………………………………...…......49 Figure 2 mRNA expression of VDR, CYP27B1, and UCP1 in mice models of obesity.............50 Figure 3 mRNA expression of VDR, CYP24A1 and CYP27B1 during brown adipocyte differentiation…………………………………………………………………………………….51 Figure 41,25(OH)2D3 dose-dependently suppresses brown adipocyte differentiation………….52 Figure 4A-C 1,25(OH)2D3 dose-dependently suppresses brown adipocyte differentiation…….53 Figure 4D 1,25(OH)2D3 dose-dependently suppresses brown adipocyte differentiation……….54 Figure 4E-F 1,25(OH)2D3 dose-dependently suppresses brown adipocyte differentiation..........55 Figure 5 Effects of 1,25(OH)2D3 treatment timing on brown adipocyte differentiation..............56 Figure 6 Effects of 1,25(OH)2D3 on mitochondrial respiration in brown adipocytes..................57 Figure 7 Over-expression of VDR suppresses brown adipocyte differentiation..........................58 Figure 8 1,25(OH)2D3/VDR suppress PPARγ transactivation in brown preadipocytes………...59 viii CHAPTER I INTRODUCTION Obesity, physiologically, is a result of hyperplasia and/or hypertrophy of lipid storing adipose tissue [1]. It is defined clinically as having a body mass index ≥30kg/m2 and is currently a major health concern
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