TURNING UP THE HEAT: ROLE OF BROWN ADIPOSE TISSUE IN METABOLIC DISEASE MARIËTTE BOON Proefschrift_MB.indb 1 05-05-14 11:57 Turning up the heat: Role of brown adipose tissue in metabolic disease Cover design & Layout: Mirjam de Bruin Printing: Gildeprint Drukkerijen, Enschede ISBN: 978-94-6108-682-2 © 2014, Mariëtte Boon Proefschrift_MB.indb 2 05-05-14 11:57 Cover Page The handle http://hdl.handle.net/1887/25979 holds various files of this Leiden University dissertation Author: Boon, Mariëtte Title: Turning up the heat : role of brown adipose tissue in metabolic disease Issue Date: 2014-06-12 Turning up the heat: Role of brown adipose tissue in metabolic disease Proefschrift ter verkrijging van de graad van Doctor aan de Universiteit Leiden, op gezag van Rector Magnificus prof. mr. C.J.J.M. Stolker, volgens besluit van het College van Promoties te verdediging op donderdag 12 juni 2014 klokke 12.30 uur door Mariëtte Rebecca Boon geboren te Alkmaar in 1988 Proefschrift_MB.indb 3 05-05-14 11:57 PROMOTIECOMMISSIE Promotor Prof. dr. P.C.N. Rensen Copromotor Dr. I.M. Jazet Overige leden Prof. dr. ir. L.M. Havekes Prof. dr. J.W. Jukema Prof. dr. M. Yazdanbakhsh Prof. dr. W. van Marken Lichtenbelt (MUMC, Maastricht) Prof. dr. J. Heeren (University of Hamburg, Hamburg) The work described in this thesis was performed at the department of Endocrinology and Metabolic Diseases at the Leiden University Medical Center, Leiden, the Netherlands, and at the Einthoven Laboratory for Experimental Vascular Medicine, Leiden, the Netherlands. Mariëtte Boon was supported by the Board of Directors of the LUMC and the Dutch Diabetes Research Foundation (grant 2012.11.1500). The printing of this thesis was kindly supported by Sanofi, Novo Nordisk B.V. and TSE systems. Proefschrift_MB.indb 4 05-05-14 11:57 Proefschrift_MB.indb 5 05-05-14 11:57 Proefschrift_MB.indb 6 05-05-14 11:57 TABLE OF CONTENTS PART 1 General introduction and outline 9 11 23 37 49 PART 2 Animal studies on role of brown adipose tissue in metabolism and obesity 51 CHAPTER 1 Physiological aspects of brown adipose tissue CHAPTER 2 Involvement of brown adipose tissue in metabolic disease CHAPTER 3South Asians: a population with a disadvantageous metabolic phenotype Outline CHAPTER 4Brown adipose tissue internalizes fatty acids by selective delipidationof lipoproteins rather than by uptake of lipoproteins CHAPTER 5BMP7 activates brown adipose tissue and reduces diet-induced obesity only at subthermoneutrality CHAPTER 6Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue CHAPTER 7Cannabinoid receptor 1 blockade diminishes dyslipidemia via peripheral activation of brown adipose tissue CHAPTER 8Inhibition of the central melanocortin system decreases brown adipose tissue activity CHAPTER 9Central role for brown adipose tissue in dyslipidemia and atherosclerosis development PART 3 Human studies on role of brown adipose tissue in metabolism and obesity CHAPTER 10Short-term high-fat diet increases macrophage markers in skeletal muscle accompanied by impaired insulin signaling in healthy male subjects CHAPTER 11E-selectin is elevated in cord blood of South Asian compared to Caucasian neonates CHAPTER 12South Asians exhibit disturbed HDL functionality as compared to white Caucasians CHAPTER 13Brown adipose tissue volume is markedly lower in healthy lean adolescents from South Asian compared to white Caucasian origin CHAPTER 14Supraclavicular skin temperature as a measure of 18F-fluorodeoxyglucose uptake by brown adipose tissue in human subjects PART 4 General discussion, summary and curriculum vitae CHAPTER 15 General discussion and future perspectives CHAPTER 16 Summary en Nederlandse samenvatting Proefschrift_MB.indb 7 List of publications Curriculum vitae 53 69 95 123 149 167 189 191 209 221 239 257 273 275 297 309 313 05-05-14 11:57 Proefschrift_MB.indb 8 05-05-14 11:57
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