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Metabolic Adaptation of White Adipose Tissue to Nutritional and Environmental Challenges

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Metabolic Adaptation of White Adipose Tissue to Nutritional and Environmental Challenges Metabolic adaptation of white adipose tissue to nutritional and environmental challenges Femke P.M. Hoevenaars Thesis committee Promotors Prof. Dr J. Keijer Professor of Human and Animal Physiology Wageningen University Co-promotor Dr E.M. van Schothorst Assistant Professor, Human and Animal Physiology Centre Wageningen University Other members Prof. Dr A.H. Kersten, Wageningen University Dr P. Oliver Vara, Universitat de les Illes Balears, Palma de Mallorca, Spain Prof. Dr E.C.M. Mariman, Maastricht University Dr W.J.J. Gerrits, Wageningen University This research was conducted under the auspices of the Graduate School of Wageningen Institute of Animal Sciences (WIAS) Metabolic adaptation of white adipose tissue to nutritional and environmental challenges Femke P.M. Hoevenaars Thesis submitted in fulfilment of the requirements for the degree of doctor at Wageningen University by the authority of the Rector Magnificus Prof. Dr M.J. Kropff, in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Friday 25 April 2014 at 1.30 p.m. in the Aula. Femke P.M. Hoevenaars Metabolic adaptation of white adipose tissue to nutritional and environmental challenges, 168 pages. PhD thesis, Wageningen University, Wageningen, NL (2014) With references, with summaries in Dutch and English ISBN 978-90-6173-916-2 5 CONTENT Chapter 1 General introduction 7 Chapter 2 Effects of dietary history on energy metabolism and physiological parameters in C57BL/6J mice 23 Chapter 3 Adipose tissue metabolism and inflammation are differently affected by weight loss in obese mice due to either a high fat diet restriction or change to a low fat diet 41 Chapter 4 Thermoneutrality results in prominent diet-induced body weight differences in C57BL/6J mice, not paralleled by diet induced metabolic differences 61 Chapter 5 Mild oxygen restriction reveals serum branched chain amino acids and CCDC3 in white adipose tissue as biomarkers, without an increase in inflammation 87 Chapter 6 BIOCLAIMS standard diet (BIOsd): a reference diet for nutritional physiology 111 Chapter 7 General Discussion 125 Appendices Summary of main findings 151 Samenvatting 155 Dankwoord 159 List of Publications 161 Curriculum Vitae 163 Education statement 165 CHAPTER GENERAL INTRODUCTION 1 GENeral INtroductioN 9 ADIPOSE TISSUE, AN ORGAN 1 White adiposeAdipose tissue is tissue,an organ anwhich organ consists primarily of lipid filled adipocytes (approximatelyWhite 50% ofadipose the cellular tissue content) is an which organ are held which together consists by a networkprimarily of of lipid filled adipocytes collagen fibres.(approximately Other cell types, 50% collectivelyof the cellular called content) the stroma which vascular are heldfraction, together are by a network of collagen found in betweenfibres. adipocytes Other cell and types, within collectively the adipose called tissue the are s tromafibroblasts, vascular stromal fraction, are found in between cells, pre-adipocytes,adipocytes leukocytes and within and macrophages the adipose [1](Figure tissue 1).are fibroblasts, stromal cells, pre-adipocytes, leukocytes and macrophages (Figure 1). Figure 1 StructureFigure of 1 white Structure adipose. of white(adapted adipose. from [1]) (adapted from ) Until 1994 adipose tissue was primarily viewed as a depot for storage of triglycerides during energy consumption and fatty acid release when energy expenditure exceeded energy intake. Until 1994 adipose tissue was primarily viewed as a depot for storage of triglyceridesNext during to that,energy its consumptionsecond function and wasfatty that acid of releasean insulating when layerenergy under the skin which helps to expenditure regulateexceeded body energy temperature intake. Next and to that,to cushion its second and function protect was body that parts. of Since the discovery of the an insulatingobesity layer under gene the leptin skin whichin 1994 helps , it tobecame regulate clear body that temperature white adipose and to tissue also has an important cushion andmetabolic protect body and parts. immune Since function,the discovery which of the involved obesity thegene s ecretionleptin in and perception of peptide 1994 [2], it becamehormones clear and that cytokines. white adipose tissue also has an important metabolic and immune function, which involved the secretion and perception of peptide hormones andEnergy cytokines. storage White adipose tissue is the major site in the body for storage of surplus energy. Energy can be Energy storage stored in the form of triglycerides in various anatomical depots i.e. subcutaneous, and visceral White adiposefat tissuedepots is andthe majora small site portion in the ofbody around for storage 5% will of besurplus stored energy. in the liver or in muscle. Storage Energy can be stored in the form of triglycerides in various anatomical depots capacity is regulated by either growth or shrinkage of the adipose tissue mass. Growth can take i.e. subcutaneous, and visceral fat depots and a small portion of around 5% will be stored inplace the liver via oradipogenesis, in muscle. Storage a tightly capacity regulated is regulated cellular bydifferentiation either growth process from a fibroblast like or shrinkagepre-adipocyte of the adipose to tissue a mature mass. Growthlipid loaded can take adipocyte place via . adipogenesis,So, adipocyte morphology and adipocyte number are able to adapt in response to the demands of the energy balance . The balance is determined by the amount of fat synthesis (lipogenesis) and fat break down (lipolysis). In lipogenesis, fatty acids are synthesized from acetyl-CoA. This process is responsive to nutritional and hormonal regulation . In lipolysis, triacylglycerol molecules are hydrolysed into free fatty acids and glycerol so they can be used as an energy source for β-oxidation in liver, muscle and 10 Chapter 1 a tightly regulated cellular differentiation process from a fibroblast like pre- adipocyte to a mature lipid loaded adipocyte [3]. So, adipocyte morphology and adipocyte number are able to adapt in response to the demands of the energy balance [4]. The balance is determined by the amount of fat synthesis (lipogenesis) and fat break down (lipolysis). In lipogenesis, fatty acids are synthesized from acetyl-CoA. This process is responsive to nutritional and hormonal regulation [5]. In lipolysis, triacylglycerol molecules are hydrolysed into free fatty acids and glycerol so they can be used as an energy source for β-oxidation in liver, muscle and other tissues. Some of the released free fatty acids are re-esterified to triglycerides in adipocytes. This process is important to be able to directly respond to changes in peripheral energy homeostasis and concomitant changes in fatty acid requirements [6]. In obesity, levels of free fatty acids are elevated in plasma of most subjects [7]. High levels of these circulating free fatty acids have been associated with insulin resistance and atherosclerosis [8]. These high circulating levels lead to an increased lipid accumulation into non-adipose tissues such as muscle, liver, pancreas and heart and may lead to cellular dysfunction or even cell death [9, 10]. Endocrine organ Some twenty years ago it has been reported that adipose tissue played a role in the secretion of factors that influence appetite and sex steroid metabolism [11, 12]. In 1994 the ‘obese gene’ leptin was discovered as the first secreted peptide hormone by adipose tissue [2]. This progress stimulated the discovery of more new adipose tissue secreted protein signals and factors also called adipokines or adipocytokines [13, 14]. They function as part of a complex set of physiological control systems that regulate local tissue and systemic physiology. A listing with their functions is shown in table 1. Dysregulation of adipokine secretion plays a fundamental role in the pathogenesis of obesity [15]. Expression of several of these adipokines (Tumor necrosis factor alpha (TNF-α), interleukin-6 (Il-6), adiponectin and C - reactive protein (CRP)) is often dependent on cell size or volume and location [16]. In general, most adipokines are more abundantly expressed and secreted in relation to the amount of fat mass. Two well described adipokines are leptin and adiponectin. Leptin serves as a metabolic signal which regulates energy homeostasis via inhibiting food intake and increasing energy expenditure [17]. Next to that, its levels are proportional to the amount of adipose tissue mass [18]. In obesity, leptin levels are therefore high, however usually there is no reduction in feed intake, which is attributed to leptin resistance. Serum leptin levels are linked to meal times via circadian oscillation and could be a bridge between energy homeostasis and circadian control [19]. Adiponectin levels are negatively correlated to adipose tissue mass, and are decreased upon obesity [20]. However, an increase in adiponectin is also shown in targeted interventions studies which did not induce weight loss [21]. Adiponectin is a modulator of glucose regulation; GENeral INtroductioN 11 it increases rates of fatty acid oxidation, improves insulin sensitivity and reduces inflammation vascular injury [22]. 1 Table 1 Major adipokines secreted by adipose tissue. (Continued) Adipokine Gene symbol Primary source (s) Function Leptin Lep Adipocytes Satiety signal Adiponectin Adipoq Adipocytes Insulin sensitizer; anti-inflammatory Resistin Retn Adipocytes Increases insulin resistance; promotes endothelial dysfunction Adipsin/complement Cfd Adipocytes,
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