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Mechanisms of Paracrine and Endocrine Actions of Angiotensin II

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Mechanisms of Paracrine and Endocrine Actions of Angiotensin II University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Doctoral Dissertations Graduate School 8-2004 Mechanisms of paracrine and endocrine actions of Angiotensin II Suyeon Kim University of Tennessee, Knoxville Follow this and additional works at: https://trace.tennessee.edu/utk_graddiss Part of the Life Sciences Commons Recommended Citation Kim, Suyeon, "Mechanisms of paracrine and endocrine actions of Angiotensin II. " PhD diss., University of Tennessee, 2004. https://trace.tennessee.edu/utk_graddiss/4533 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 Suyeon Kim entitled "Mechanisms of paracrine and endocrine actions of Angiotensin II." 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 requirements for the degree of Doctor of Philosophy, with a major in Human Ecology. Naima Moustaid-Moussa, Major Professor We have read this dissertation and recommend its acceptance: Jay Whelan, Jung Han Kim, Brynn H. Jones, John Koontz 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.) To the Graduate Council: I am submitting herewith a dissertationwritten by Suyeon Kim entitled "Mechanisms of paracrine and endocrineactions of Angiotensin II." I have examined the finalpaper copy of this dissertation for formand content and recommend that it be accepted in partial fulfillment of the requirements forthe degreeof Doctor of Philosophy, with a major in Human Ecology. Naima Moustaid-Moussa, Ph.D., Major Professor We have read this dissertation and recommend its acceptance: D. � -O-:�H0vlA- Jung Han Kim, Ph.D. Accepted forthe Council: Vice Chancellor a Graduate Studies MECHANISMS OF PARACRINE AND ENDOCRINE ACTIONS OF ANGIOTENSIN II A Dissertation Presented for the Doctor of Philosophy Degree The University of Tennessee, Knoxville Suyeon Kim August 2004 DEDICATION This dissertation is dedicated to my parents, Mr. Kim, Kun-Tae and Mrs. Kang, Jo-Ja and sister, Ms. Kim, Ji-Yeon For their ongoing support and encouragement throughout my life 11 ACKNOWLEDGEMENTS I am especially gratefulto Dr. Moustaid-Moussa, my major professor who has been both a great mentor and teacher, forher encouragement, scientificguidance, invaluable advice and enormous support throughout my graduate study andfor giving me the opportunity to pursue my research. I am verythankful to my committee members fortheir helpfulsuggestions and tremendous support. My deepest thanks go to Dr. Jay Whelan forhis insight direction and impressive support throughout my graduate study:Special thanksgo also to Dr. Jung Han Kirn, Dr. Brynn Jones-Voy and Dr. John Koontz fortheir scientificadvice and words of encouragement. Special appreciation is extended to my fellowgraduate studentsand staffmembers in Nutrition Department for their great help and support. Finally, my greatestdebt of thanks must be to my parents and sister for their continued and unfailing support, encouragement, patience and love. iii ABSTRACT Adipose tissue expresses high levels of angiotensinogen (agt), the only known precursor of Angiotensin II (Ang IQ and we have previously shown thatthis hormone plays a paracrine role in regulation of adipocyte metabolism by increasing activity and gene expression of two key lipogenic enzymes, fatty acid synthase (FAS) and glycerol-3-phosphate dehydrogenase (GPDH). However, molecular mechanisms by which Ang II regulates an adipocyte lipogenic gene, namely FAS and transcription factors mediating this regulation are largely unknown. Furthermore, signaling mechanisms whereby Ang II induces adiposity need to be further explored. Accordingly, our studies were designed to investigate transcriptional regulation of FAS gene by Ang II and determine signaling mechanisms of Ang II leading to activate FAS gene transcription. We demonstrated that Ang II responsive element is anE box within adipocyte FAS gene and the adipocyte determination and differentiation factorl/sterol-regulatory element binding protein le (ADDl/SERBPlc) functionsas a transcription factormediating these actions. Ang II induced FAS transcription as well as ADDI gene expression in a glucose-dependent manner. Using immunoprecipitation and western blot analyses, we found that Ang II regulates adipocyte metabolism via activation of insulin signaling molecules including IR�, IRS, PI-3K and Akt. This signaling mechanism was mainly mediated by angiotensin receptor type 1 receptors (ATl) and in part by angiotensin receptor type 2 receptors (AT2). Next, with agt knockout (agt-/-, KO) and transgenic (Tg-KO mice expressing agt exclusively in adipose tissue and Tg-WT mice overexpressing agt in adipose tissue) mouse models, we examined changes in adipose tissue metabolism in vivo and renal gene regulation in these mice and furtherdissected endocrine effects of adipocyte agt. We found that compared with those of WT mice, body weight gain and fatpad weight were lower in response to high fatdiet in KO mice exhibiting hypotension and renal iv abnormalities. Targeted expression of the agt gene only in adipose tissue {Tg-KO) partlyrescued thesephenotypes whereas agt overexpression in adipose tissue of transgenicmice (Tg-WT) was associated with increased epididymal fatpad mass and blood pressure. Subsequent westernblot and renal gene expression analyses indicated that adipocyte agt participatesin systemic blood pressure regulation at least partly by increasing renal agt andATl receptor production in Tg-WT mice. Additionally, microarraydata revealed that adipose tissue-specificagt restoration was able to correct altered expression of genes associated with blood pressure homeostasis and renal functionin KO mice. In conclusion, Ang II plays a hypertrophicrole in adipocytes by a paracrine/autocrine mechanism. Furthermore,adipocyte Ang II exerts endocrine effectson renal functionand gene expression, thereby contributing to systemic blood pressure regulation and kidney homeostasis. This studymay provide valuable approaches in treatmentsof obesity and obesity-associated metabolic alternations such as insulin resistance and hypertension. V TABLE OF CONTENTS PART I. INTRODUCTION Literature Cited .................................................................................................................5 PART II. LITERATURE REVIEW 10 A. Obesity................................................................................... ............ 11 B. Genetics of Obesity ................................................................................ 19 C. Role of Adipose Tissue in Obesity ............................................................... 24 D. Role of Angiotensin II in Obesity ............................................................... 35 Literature Cited ........................................................................................ 100 PART III. ANGIOTENSIN II RESPONSIVE ELEMENT IS THE INSULIN RESPONSVIE ELEMENT IN THE ADIPOCYTE FATTY ACID SNYTHASE GENE: ROLE OF ADIPOCYTE DETERMINATION AND DIFFERENTIATION FACTOR 1/STEROL REGULATORY ELEMENT BINDING PROTEIN IC 138 A. Abstract ............................................................................................. 139 B. Introduction................................................................................. ......... 140 C. Materials andMethods ............................................................................ 141 D. Results ............................................................................................... 145 E. Discussion .......................................................................................... 155 Literature Cited ........................................................................................ 159 PART IV. EFFECTS OF HIGH FAT DIET, ANGIOTENSINOGEN GENE INACTIVATION AND TARGETED EXPRESSION TO ADIPOSE TISSUE ON LIPID METABOLISM AND RENAL GENE EXPRESSION 163 A. Abstract .............................................................................................164 B. Introduction......................................................................................... 165 C. Materials andMethods ............................................................................ 166 D. Results ............................................................................................... 168 E. Discussion .......................................................................................... 174 Literature Cited ........................................................................................ 177 PART V. CROSSTALK BETWEEN ANGIOTENSIN II AND INSULIN SIGNALING IN 3T3-Ll ADIPOCYTES 181 A. Abstract ............................................................................................. 182 B. Introduction......................................................................................... 183 C. Materials and Methods .............................................................................184 D. Results ................................................................................................ 188 E. Discussion .. .. .. .. .. .
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