Title Page

Contents

Abstract 9

Ⅰ. Introduction 11

Ⅱ. Material and Methods 15

Ⅲ. Results 25

Ⅳ. Discussion 89

Ⅵ. References 97

논문요약 106

Table 1. List of primer sequences for qRT-PCR. 95

Table 2. List of all antibodies used in this study. 96

Figure 1. Ssu72 phosphatase is highly enriched in BAT. 27

Figure 2. Ssu72 expression is induced by cold exposure in BAT. 30

Figure 3. Generation of adipocyte-specific Ssu72 knockout mouse. 33

Figure 4. Ablation of Ssu72 affects maintenance of BAT. 35

Figure 5. Ssu72 deficiency in adipocytes results in defective thermogenesis during acute cold exposure. 39

Figure 6. Ssu72 deficiency affects energy expenditure during cold stimulation but does not affect locomotor activity or daily food intake. 41

Figure 7. Ssu72 deficiency alters mitochondrial morphology in BAT. 44

Figure 8. Transcriptional profiling of Ssu72-deficient BAT reveals impaired mitochondrial homeostasis and changes in regulation of fatty acid metabolism and ER signaling pathways. 47

Figure 9. Ssu72 deficiency did not affect phosphorylation of previously known Ssu72 substrates in BAT. 50

Figure 10. Ssu72 is predominantly localized in the cytosol of brown adipocytes. 52

Figure 11. UPR signaling is activated in Ssu72-deficient BAT. 57

Figure 12. Ssu72 phosphatase specifically regulates eIF2α signaling among UPR signaling pathways. 59

Figure 13. Ssu72 depletion in BAT induces eIF2α phosphorylation during cold exposure. 61

Figure 14. Other eIF2α phosphatases appear to have less effect on brown adipocytes. 63

Figure 15. Ssu72 directly binds to eIF2α in vitro. 66

Figure 16. Active Ssu72 dephosphorylates eIF2α in vitro. 68

Figure 17. Ectopic Ssu72 expression in adipocytes restores morphological changes in Ssu72-deficient BAT. 71

Figure 18. Ectopic Ssu72 expression in adipocytes reduces eIF2α phosphorylation in Ssu72-deficient BAT. 73

Figure 19. Disruption of translational control by Ssu72 depletion causes thermogenic defects in BAT. 76

Figure 20. Prolonged eIF2α phosphorylation by Ssu72 depletion in BAT induces UPRmt activation and suppresses ClpP expression.[이미지참조] 80

Figure 21. Loss of Ssu72 in BAT causes reduced translation of mitochondrial OXPHOS subunits. 83

Figure 22. Ectopic Ssu72 expression induces translation of OXPHOS subunits. 86

Figure 23. Thermogenic defects of Ssu72 aKO mice are restored by ectopic Ssu72 expression in aKO;cTg mice. 88

Figure 24. Schematic representation of the proposed mechanism of Ssu72 in BAT thermogenesis. 94