On the Neurobiology of Physical Activity in Mice and Human in Search of Eating Disorders Determinants

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On the Neurobiology of Physical Activity in Mice and Human in Search of Eating Disorders Determinants On the Neurobiology of Physical Activity in Mice and Human In Search of Eating Disorders Determinants Elżbieta Kostrzewa ISBN 9789-0393-6090-3 Printed by: CPI Koninklijke Wöhrmann Layout: Elżbieta Kostrzewa and Wouter Wiltenburg Cover design: Elżbieta Kostrzewa and Wouter Wiltenburg More artwork at surrella.wordpress.com . This cover was inspired by The Elephant in the Room , Banksy exhibition, 2006 Barely Legal show, Los Angeles. © Elżbieta Kostrzewa On the Neurobiology of Physical Activity in Mice and Human In Search of Eating Disorders Determinants Over de Neurobiologie van Lichaamsbeweging in Muizen en Mens Op Zoek naar Determinanten van Eetstoornissen (met een samenvatting in het Nederlands) Badania nad neurobiologicznymi podstawami aktywności fizycznej myszy i ludzi W poszukiwaniu determinantów zaburzeń odżywiania (ze streszczeniem w języku polskim) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op donderdag 6 februari 2014 des ochtends te 10.30 uur door Elżbieta Kostrzewa geboren op 10 maart 1983 te Krakau, Polen Promotor: Prof. dr. R.A.H. Adan Co-promotor: Dr. M.J.H. Kas Table of Contents CHAPTER 1 07 General Introduction Physical Activity 08 Eating Disorders 29 Translational Approach in Genetic Studies 43 Scope of the Thesis 49 CHAPTER 2 53 A Candidate Syntenic Genetic Locus is Associated with Physical Activity Levels in Mice and Humans CHAPTER 3 77 A QTL on Chromosome 19 is Associated with Voluntary Running Wheel Activity Levels in Mice CHAPTER 4 91 Nfatc2 Deficient Mice Exhibit a Specific Decrease in Voluntary Running Wheel Activity CHAPTER 5 103 Hippocampal Ptpn1 Expression Affects Food Anticipation CHAPTER 6 127 The Expression of Excessive Exercise Co-Segregates with the Risk of Developing an Eating Disorder in Women CHAPTER 7 141 Longitudinal Changes in the Physical Activity of Adolescents with Anorexia Nervosa and their Influence on Body Composition and Leptin Serum Levels After Recovery CHAPTER 8 163 High Leptin Levels in Recovered AN Patients Reflect Individual Variation in Body Weight Loss During Illness Progression CHAPTER 9 179 Perspective Paper: The Use of Mouse Models to Unravel Genetic Architecture of Physical Activity CHAPTER 10 189 General Discussion Overview and Discussion of the Main Findings 190 Methodological Considerations 198 Clinical Implications 201 Future Directions 203 Concluding Remarks 205 REFERENCES 207 ADDENDUM 245 Nederlandse Samenvatting 246 Streszczenie w języku polskim 251 List of Abbreviations 256 List of Publications 258 Affiliations of the Co-authors 260 Curriculum Vitae 263 Acknowledgements 265 General Introduction Physical Activity 8 Eating Disorders 29 Translational Approach in Genetic Studies 43 Scope of the Thesis 49 Partly based on: Kostrzewa E. and Kas M. J. H. The use of mouse models to unravel genetic architecture of physical activity; a review. Genes Brain Behav. 2013. [Epub ahead of print], which has been published in final form at: http://onlinelibrary.wiley.com/doi/10.1111/gbb.12091/abstract 1 Chapter 1 Physical Activity Definitions Physical activity (PA) may be defined as ‘bodily movement produced by contraction of skeletal muscles’ (Dishman 2008) and be further subdivided into spontaneous physical activity (SPA) and voluntary exercise (VE). The VE is defined as ‘locomotor activity that is not directly required for survival or homeostasis and not directly motivated by any external factor’ (Garland, Jr. et al., 2011b) which could be understood as sports and fitness-related activities. All remaining PA such as activities of daily life, non-specific ambulatory behavior and maintaining posture may be considered SPA (Garland, Jr. et al., 2011b; Levine et al., 1999). It is not always easy to classify a particular type of PA into one of the two categories; however, this division enables some conceptualization and research on effects of PA and voluntary exercise in particular on health. Operationalization of physical activity in humans Voluntary exercise Various methods of assessment may be used to study PA levels in humans e.g. direct observation, questionnaires (diaries and retrospective recall), surveys, calorimetry, heart rate monitors and motion sensors (Garland, Jr. et al., 2011b; Westerterp 2009). Choice between the methods involves a trade-off between feasibility and reliability. As a result of practical difficulties related to the use of objective methods, many studies involve the self-reported PA assessment (Dishman 2008) which may have limited reliability and validity (Shephard 2003). Attempts to validate the self- reported measurement methods show that the correlations between objective and subjective measurement methods are rather low (de Vilhena e Santos DM et al., 2012; Dishman 2008; Garland, Jr. et al., 2011b). Furthermore, various PA assessment methods lead to discrepant results regarding genetic associations and heritability estimates (Butte et al., 2006; Cai et al., 2006; Choh et al., 2009; de Vilhena e Santos DM et al., 2012; Seabra et al., 2008; Simonen et al., 2003a). These observations suggest that various PA assessment methods measure, in fact, partially different phenotypes or theoretical constructs (de Vilhena e Santos DM et al., 2012). A possible solution to this problem would be to involve both objective and subjective PA assessment methods in one study. It would enable comparison of the methods within one 8 General Introduction population and give detailed assessment of different features of PA such as duration, type, context, motivation and energy expenditure (Dishman 2008). Spontaneous physical activity In humans, there is a partial overlap between methods that can be used to assess VE and SPA. Generally, pedometers, accelerometer and observation (direct or video recording) may be used to estimate the levels of SPA (Garland, Jr. et al., 2011b). Animal models of physical activity Animal models are often used to overcome some of the limitations hampering human studies. They enable standardization of the complex conditions influencing the levels of PA and methods of PA measurement. Therefore, it is hypothesized that they may be effectively used to assess biological factors influencing PA levels. The VE and SPA in humans may be best modeled by distinct animal models (Eikelboom 1999; Garland, Jr. et al., 2011b; Kelly et al., 2010; Rezende et al., 2009). In general, (voluntary) running wheel activity (RWA) is proposed as a model of voluntary exercise (Kelly and Pomp 2013; Rezende et al., 2009) while spontaneous locomotor activity, especially in the home cage (HC) environment, may be considered a model of SPA (Garland, Jr. et al., 2011b). The expressions of the two forms of energy expenditure (RWA and HC activity) are not independent. When animals are given access to a running wheel they reduce their HC activity (Koteja et al., 1999) while their total time spent on activity increases (de Visser L. et al., 2005; Kas and Edgar 1998). Furthermore, mice bred for high running wheel activity show also a reduction in the total home cage activity (Careau et al., 2012; Malisch et al., 2009) and the RWA and HC activity weakly correlate in the outbred strain used in these selection experiments (Zombeck et al., 2011). Voluntary exercise If voluntary exercise is defined as locomotor activity ‘that is not directly required for survival or homeostasis and not directly motivated by any external factor’ (Garland, Jr. et al., 2011b), then voluntary RWA may be considered the most suitable rodent behavior to model human voluntary exercise (Eikelboom 1999; Garland, Jr. et al., 2011b; Kelly et al., 2010; Rezende et al., 2009). There are several arguments to support this notion. First, RWA in rodents, similarly to human VE, is performed without any obvious immediate goals (Eikelboom, 1999). It may be considered a classic example of self-rewarding behavior (Brene et al., 2007; Garland, Jr. et al., 2011b; Kagan and Berkum 1954; Novak et al., 2012; Sherwin 1998). Indeed, rodents show conditioned 9 Chapter 1 place preference to the location associated with wheel running (Lett et al., 2000) and are willing to perform an instrumental reaction in order to obtain access to the running wheel (Belke and Garland, Jr. 2007; Kagan and Berkum 1954). Secondly, age- related decline in PA is observed in both, humans and rodents (Ingram 1983; Sallis 2000) (see also further in this chapter). Thirdly, both VE and RWA may in some situations involve changes in brain reward systems that are comparable to the ones present in addictive behavior (Belke and Garland, Jr. 2007; Garland, Jr. et al., 2011b). Finally, voluntary wheel running and VE occur in environments which per se require low energy expenditure (laboratory housing in case of mice or modern industrialized Western culture) (Booth et al., 2002; Eikelboom 1999; Garland, Jr. et al., 2011b). It is of note that there are also some arguments against the validity of RWA as a model of VE. First, gender differences in PA are observed in both humans and mice, however, in an opposite direction suggesting important differences in biological determinants of the behavior (see further in this thesis). Second, some researchers believe that wheel running is merely an artifact resulting from poor laboratory housing conditions (Sherwin 1998). Third, it was estimated that laboratory mice went through selection for more than 400 generations, which resulted in diminished PA levels. In contrast, humans from Western cultures are said to go through similar environmental pressure for no more than 25 generations (Booth et al., 2002; Garland, Jr. et al., 2011b). As a consequence, it is possible that the natural state for the laboratory mouse is to maintain low PA levels while for human it is to continue to exercise (Booth et al., 2002; Garland, Jr. et al., 2011b). This raises questions regarding the validity of using mouse models as a model of normal human behavior and physiology (Garland, Jr. et al., 2011b). Finally, some researchers point to the ‘behavioral common path’ as an argument against possibility to use RWA as a model of VE (Sherwin 1998).
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