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Obesity Predisposing Genes in Drosophila Melanogaster

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Obesity Predisposing Genes in Drosophila Melanogaster OBESITY PREDISPOSING GENES IN DROSOPHILA MELANOGASTER: THE METABOLIC FUNCTIONS OF SPLIT ENDS by KELSEY ELIZABETH HAZEGH B.S., University of Denver, 2012 A thesis submitted to the Faculty of the Graduate School of the University of Colorado in partial fulfillment of the requirements for the degree of Doctor of Philosophy Molecular Biology 2017 This thesis for the Doctor of Philosophy degree by Kelsey Elizabeth Hazegh has been approved for the Molecular Biology Program by Tom Evans, Chair Tânia Reis, Advisor Aaron Johnson Emily Bates Jed Friedman Date: December 15, 2017 ii Hazegh, Kelsey Elizabeth (Ph.D., Molecular Biology) Obesity Predisposing Genes in Drosophila melanogaster: The Metabolic Functions of Split ends Thesis directed by Assistant Professor Tânia Reis ABSTRACT Obesity is a result of excess energy storage in the form of triglycerides (TAGs). Preventing obesity requires a precise balance between deposition into and mobilization from fat stores, which is tightly controlled by metabolic enzymes and their regulators. Genetic background plays a major role in the predisposition to obesity, however it is estimated that <2% of interindividual variation in BMI can be explained by the genes identified so far. A recent unbiased forward genetic screen by Reis et al. identified 66 genes that altered Drosophila larval fat levels. Here we describe the identification of expression pattern for 33 of these genes to identify those that may regulate the storage or utilization of fat in the larval fat body (FB). Nineteen of the genes express in the FB, fourteen of which were individually depleted by RNAi expression in the FB and tested for changes in larval fat levels by means of a buoyancy assay. Depletion of fatty acid binding protein (Fabp) in the FB results in decreased fat levels, matching previous results in the mammalian literature and serving as a proof of principle for our screening methods. Nuclear factor of activated T cells (NFAT) and Alan shepard (Shep) were identified as having novel pro-fat storage roles in the FB. Shep also serves an opposing role in the brain where it promotes the usage of organismal fat and is furthermore regulated by the nutritional intake of the larvae. Split ends (Spen), an RNA-binding protein previously implicated in transcriptional control of conserved signaling pathways, was also identified in this screen. We found that iii Spen function is necessary and sufficient to promote fat depletion in the fat body in a cell autonomous manner. Interestingly, despite being fat, larvae in which Spen is depleted from the FB are sensitive to starvation, suggesting that these animals are incapable of using their excess fat stores. Consistent with this phenotype, metabolomics and RNA sequencing demonstrate metabolic alterations in Spen-depleted FBs indicative of a defect in mobilization of TAGs and utilization of other metabolites (proteins and carbohydrates) as primary sources of energy. We further find that another Spen family member Spenito (Nito) plays an opposing role in fat storage. FB overexpression of an N-terminal Spen fragment containing the RNA Recognition Motifs (RRMs) and undefined middle region of Spen causes a dominant-negative high-fat phenotype, whereas there was no effect of overexpression of a C- terminal fragment containing only the conserved Spen paralog and ortholog (SPOC) domain. Thus, the RRMs or other undefined N-terminal domain are required for the ability of overexpressed full-length Spen to deplete fat stores, and when overexpressed alone may sequester important Spen binding partners into non-functional complexes. We propose that Nito, which contains RRMs and a SPOC domain but is much smaller than Spen, may act as a negative regulator of Spen function. We further find that levels of the mammalian Spen and Nito orthologues correlate with body weight in a diet-induced obese mice, supportive of a model where Spen and Nito act as a counterbalance to finely tune fat storage. No other study has implicated Spen or Nito in the regulation of metabolism or body fat control. Our work provides new directions for understanding metabolic disease as well as a molecular handle to generate novel mechanistic insights into conserved genetic causes of obesity. The format and content of this abstract are approved. I recommend its publication. Approved: Tânia Reis iv To Mom and Dad, for your endless love and encouragement and To Micah, for your constant support and for helping me to find the fun and laughter in all things. v ACKNOWLEDGEMENTS I couldn’t have made it to this point in my career without the help and support from people in all corners of my life. First, I want to acknowledge and thank my mentor Tânia for her guidance. She always pushed me to be my best self and believed in me even when I had doubts. Her passion for science is infectious and I gained new appreciation for genetics through her; like she always says, “genetics is always right!” I’d like also to thank my fellow lab members over the years: Nick Haynes and Jeremy Mosher for introducing me to lab and making me so comfortable upon starting; Lauren Schmitt for Denver Biscuit Co outings and for whipping our lab into shape; Claire Gillette for joining the lab and taking on the Shep project; Darcy Marceau, Shruthi Sivakumar, Johnny Nguyen, Tracey Nguyen, and Taylor Tomita for helping us with our research, even for a little while; and everyone for their help with egg collections every single weekend. I want to especially thank my best friends Vevian Zhang and Brenna Dennison(!) for margaritas, pad thai, and for making me smile, even on bad days. Thanks also to Chris and Michelle Boyd for zillions of dinners and saving the world one Faded at a time. You guys gave me respite when research got tough and I’m so thankful to have you all in my life. A huge reason for who I am today is due to my family. Their love and support over the years has made me realize that I can accomplish anything that I set my mind to. Kim showed me how much you can achieve when you follow your dream. Dad gave me my very first appreciation and passion for science and taught me how to use a microscope for the first time. Mom has been ever supportive, reassuring, and encouraging as I took on all these challenges. My family has always been my biggest fans and I cannot thank them enough for all they’ve ever done for me. vi Finally, I want to thank Micah. He has been my best friend and my rock through the good times and the bad. He has been there for me every step of the way and been supportive even when it was inconvenient. I could not have managed without him and am so excited for all our future adventures together. I love you all, and thank you for being there for me. vii TABLE OF CONTENTS CHAPTER I. INTRODUCTION ...................................................................................................1 The Obesity Pandemic .......................................................................................1 The Genetics of Obesity.....................................................................................6 Lipid Metabolism .............................................................................................12 Drosophila as a Model for Metabolism ...........................................................18 Alan shepard ....................................................................................................24 Split ends ..........................................................................................................29 Summary ..........................................................................................................36 II. MATERIALS AND METHODS ...........................................................................38 Fly Strains and Husbandry ...............................................................................38 Immunohistochemistry ....................................................................................40 Density Assay ..................................................................................................41 Gas Chromatography Mass Spectrometry .......................................................51 Glycogen Quantification ..................................................................................52 Feeding Assay ..................................................................................................52 Activity Assay ..................................................................................................53 Mosaic Analysis ...............................................................................................53 Starvation Assay ..............................................................................................54 viii RNA Library Preparation and Sequencing ......................................................55 Metabolomics ...................................................................................................55 Murine Analysis ...............................................................................................56 III. SCREENING FOR OBESITY PREDISPOSING GENES ...................................58 Abstract ............................................................................................................58 Introduction ......................................................................................................58 Results ..............................................................................................................61 Discussion ........................................................................................................77
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