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Defining the Roles of Kindlin-2 and PAT2 in Adipose Tissue Plasticity and Amino Acid Sensing, Respectively

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Defining the Roles of Kindlin-2 and PAT2 in Adipose Tissue Plasticity and Amino Acid Sensing, Respectively TECHNISCHE UNIVERSITÄT MÜNCHEN Fakultät für Medizin Defining the roles of Kindlin-2 and PAT2 in adipose tissue plasticity and amino acid sensing, respectively Jiefu Wang Vollständiger Abdruck der von der Fakultät für Medizin der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Prof. Dr. Percy A. Knolle Prüfer der Dissertation: 1. TUM Junior Fellow Dr. Siegfried Ussar 2. Prof. Martin Klingenspor Die Dissertation wurde am 24.09.2019 bei der Technischen Universität München eingereicht und durch die Fakultät für Medizin am 10.03.2020 angenommen. Eidesstattliche Erklärung Ich erkläre an Eides statt, dass ich die bei der Fakultät für Medizin zur Promotionsprüfung vorgelegte Arbeit mit dem Titel: “Defining the roles of Kindlin-2 and PAT2 in adipose tissue plasticity and amino acid sensing, respectively” am Institut für Diabetes und Adipositas (Helmholtz Zentrum München) unter der Anleitung und Betreuung durch Dr. Ussar ohne sonstige Hilfsmittel erstellt und bei der Abfassung nur die gemäß § 6 Abs. 6 und 7 Satz 2 angegebenen Hilfsmittel benutzt habe. Ich habe keine Organisation eingeschaltet, die gegen Entgelt Betreuerinnen und Betreuer für die Anfertigung von Dissertationen sucht, oder die mir obliegenden Pflichten hinsichtlich der Prüfungsleistungen für mich ganz oder teilweise erledigt. Ich habe die Dissertation in dieser oder ähnlicher Form in keinem anderen Prüfungsverfahren als Prüfungsleistung vorgelegt. Die vollständige Dissertation wurde noch nicht veröffentlicht. Ich habe den angestrebten Doktorgrad noch nicht erworben und bin nicht in einem früheren Promotionsverfahren für den angestrebten Doktorgrad endgültig gescheitert. Die öffentlich zugängliche Promotionsordnung der TUM ist mir bekannt, insbesondere habe ich die Bedeutung von § 28 (Nichtigkeit der Promotion) und § 29 (Entzug des Doktorgrades) zur Kenntnis genommen. Ich bin mir der Konsequenzen einer falschen Eidesstattlichen Erklärung bewusst. Mit der Aufnahme meiner personenbezogenen Daten in die Alumni-Datei bei der TUM bin ich einverstanden. München, den Jiefu Wang I I. Abbreviations WAT White adipose tissue BAT Brown adipose tissue UCP-1 Uncoupling protein 1 ATP Adenosine triphosphate Peroxisome proliferator-activated PPARγ receptor γ C/EBPs CCAAT/enhancer-binding proteins HFD High fat diet CD Chow diet SCF Subcutaneous fat PGF Perigonadal fat mRNA Message ribonucleic acid ECM Extracellular matrix Complementary deoxyribonucleic cDNA acid ANOVA Analysis of variance H&E Hematoxylin and eosin GTT Glucose tolerance testing ITT Insulin tolerance test SLC Solute carrier WB Western blot Proton coupled amino acid PAT transporter mammalian target of rapamycin mTORC1 complex 1 or mechanistic target of rapamycin complex 1 S6K phosphorylation of S6 Kinase microtubule-associated protein light LC3 chain 3 Co-IP Co-immunoprecipitation DMEM Dulbecco's Modified Eagle Medium V-ATPase Vacuolar adenylpyrophosphatase Blue native polyacrylamide gel BN-PAGE electrophoresis EM Electron microscope Quantitative polymerase chain qPCR reaction Enhanced green fluorescent EGFP protein FITC Fluorescein isothiocyanate Lysosomal-associated membrane LAMP protein MS Mass spectrometry II II. Abstract In modern society, obesity has become a severe worldwide health problem and related diseases like metabolic syndrome and type 2 diabetes are intractable challenges for public health. Adipose tissues are one of the most important metabolic organs and the main energy storage tissues. In my dissertation I studied the functions of two important proteins; Kindlin-2 and PAT2 in adipose tissues. Kindlin-2 is a broadly expressed protein, with essential functions in many tissues and during embryonic development. Kindlin-2, as an integrin activator, plays a crucial role in ECM signal transduction, but its function in adipose tissue is less known. In my study, Kindlin-2 knockout in adipose tissue causes lipodystrophy. Furthermore, angiogenesis in adipose tissue and whole body glucose homeostasis are also affected by Kindlin2 knockout. Moreover, unlike in other tissues, loss of Kindlin-2 in fat, reduces protein levels of some integrin subunits. PAT2 is a proton coupled amino acid transporter and was identified as a surface marker for brown adipocytes. However, its function in adipocytes is unknown. Several functions of PAT2 are revealed in my study. PAT2 regulates amino acid depletion induced autophagy. PAT2 knockdown or overexpression both lead to impaired autophagy. This function is through modulating acidification of the V-ATPase in brown adipocytes. I show that PAT2 is necessary for V-ATPase assembly in brown adipocytes and enhances V-ATPase activity upon amino acid starvation. Loss of PAT2 causes impaired V-ATPase assembly and the proton pumping activity. In addition I show that the translocation of PAT2 from the cell surface to the lysosome is triggered by amino acid depletion or the inhibition of mTORC1. PAT2 also regulates mitochondrial function and cellular amino acid sensitivity in the brown adipocyte. My study demonstrates the importance of Kindlin-2 in adipose tissues and the crucial role of PAT2 in brown adipocyte to nutrient homeostasis and development. These two proteins can be the targets for the therapy of obesity related diseases. Research of Kindlin-2 III and PAT2 function are helpful to understand the physiological functions of adipose tissues in more detail. IV III. Zusammenfassung In der heutigen Gesellschaft sind Adipositas, sowie die damit assoziierten Erkrankungen, wie das metabolische Syndrom und Typ 2 Diabetes zu einem globalen Problem und einer Herausforderung für die öffentliche Gesundheit geworden. Fettgewebe sind eine der wichtigsten metabolische Gewebe und der Hauptspeicherort für überschüssige Energie. In meiner Arbeit habe ich mich mit der Funktion von zwei wichtigen Proteinen, Kindlin-2 und PAT2, im Fettgewebe beschäftigt. Kindlin-2, welches ein breites Expressionsmuster zeigt, hat essentielle Funktionen in einer Vielzahl von Organen und während der Embryonalentwicklung. Kindlin-2, als ein zentrales Element der Integrinaktivierung, spielt eine zentrale Rolle in der Signaltransduktion der Extrazellulären Matrix. Die Funktion von Kindlin-2 im Fettgewebe ist bislang jedoch nur lückenhaft untersucht worden. In meinen Studien konnte ich zeigen, dass der Knockout von Kindlin-2 im Fettgewebe zu einer Lipodystrophie führt. Des Weiteren führt der Verlust von Kindlin-2 im Fettgewebe zu Störungen der Vaskularisierung und der Glukosehomöostase. Außerdem führt der Verlust von Kindlin-2 im Fettgewebe, im Gegensatz zu anderen bereits untersuchten Organen, zu einer Reduktion der Proteinlevels einiger Integrinuntereinheiten. PAT2 ist ein Protonen gekoppelter Aminosäuretransporter, welcher in vorhergehenden Studien als spezifischer Oberflächenmarker für braune Adipozyten identifiziert wurde. Bislang ist jedoch sehr wenig über die Funktion von PAT2 im braunen Fettgewebe bekannt. In meinen Studien konnte ich mehrere Funktionen und Regulationen von PAT2 aufzeigen. PAT2 reguliert die durch Aminosäuredepletion induzierte Autophagie. Dadurch kommt es sowohl bei der Überexpression als auch der Depletion von PAT2 zu einer Störung der Autophagie. Mechanistisch beruht dies auf einer Regulation der vATPase abhängigen Azidifizierung in braunen Adipozyten. Ich zeige, dass PAT2 eine wichtige Rolle in der Assemblierung der vATPase und der Aktivierung der vATPase während eines Amionsäuremangels spielt. Des Weiteren zeige ich, dass die Translokation von PAT2 von V der Zelloberfläche zum Lysosom durch Aiminosäuredepletion oder die Inhibition von mTORC1 ausgelöst wird. PAT2 reguliert auch mitochondriale Funktion und zelluläre Amionsäuresensitivität in braunen Adipozyten. Meine Studien zeigen die Bedeutung von Kindlin-2 im Fettgewebe und die Rolle von PAT2 in braunen Adipozyten in Bezug auf Nährstoffhomäostase und Entwicklung. Diese zwei Proteine stellen zwei potentielle Angriffspunkte für die Therapie von Adipositas bezogenen Erkrankungen dar. Forschung an Kindlin-2 und PAT2 hilft die physiologische Funktion des Fettgewebes besser zu verstehen. VI IV. List of tables Table 2.1 Reagents .............................................................................................................................. 42 Table 2.2 Antibodies ............................................................................................................................. 45 Table 2.3 Instruments ........................................................................................................................... 46 Table 2.4 Consumable materials .......................................................................................................... 47 Table 2.5 Primers for qPCR ................................................................................................................. 61 V. List of figures Figure 1.1 Fat depots in the mouse. ....................................................................................................... 3 Figure 1.2 Differentiation of stem cell into white, brown, beige adipocytes or myocyte. ......................... 5 Figure 1.3 Representative cartoon for ECM layout. ................................................................................ 9 Figure 1.4 Bi-directional signaling of integrins. ..................................................................................... 10 Figure 1.5 Phases of angiogenesis. ....................................................................................................
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