Study on the microenvironment of adipose tissue and lymph node지방조직 및 림프절 미세환경에 대한 연구

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Part I. Angiopoietin-2–integrin $\alpha5\beta1$ signaling enhances vascular fatty acid transport and prevents obesity-induced metabolic syndrome Metabolically healthy obese individuals show efficient fat storage in subcutaneous adipose tissue (SAT) than unhealthy counterparts, yet the underlying mechanism is poorly understood. Here, I identify angiopoietin-2 (Angpt2)–integrin $\alpha5\beta1$ signaling as a marker of healthy obesity and inducer of fat uptake specifically in SAT. Adipocyte-specific deletion of Angpt2 markedly reduces fatty acid uptake and storage in SAT, leading to ectopic lipid accumulation in glucose-consuming organs including skeletal muscle and liver and to systemic glucose intolerance. Mechanistically, Angpt2 activates integrin $\alpha5\beta1$ signaling at the endothelium and triggers fatty acid transport via CD36 and FATP3 in SAT. Genetic or pharmacological inhibition of the endothelial integrin $\alpha5\beta1$ recapitulates adipocyte-specific Angpt2 knockout phenotypes. The findings demonstrate critical roles for Angpt2–integrin $\alpha5\beta1$ signaling at SAT endothelium in regulating whole-body fat distribution for metabolic health and highlight adipocyte–endothelial crosstalk as a potential target for prevention of lipotoxicity and glucose intolerance. Part II. YAP/TAZ direct commitment and reprogramming of lymph node fibroblastic reticular cells Fibroblastic Reticular Cells (FRCs) are immunologically specialized myofibroblasts of mesen-chymal origin that forms the basic infrastructure of the lymph node (LN). Although lymphotox-in-$\beta$ receptor ($LT\betaR$) signaling is known to be critical in FRC maturation, $LT\betaR$ expression on mesenchymal FRC precursors was dispensable in LN development, indicating that other major components are critical for the developmental steps of FRC. Here, we present that YAP/TAZ directs mesenchymal cell commitment of FRC lineage through regulation of the non-canonical $NF-\kappa$ endogenous p52 and RelB to direct mesenchymal cells residing in the adipose tissue upon reaching to the lymph node site. Upon engagement to $LT\betaR$ signaling in the lymph node site, YAP/TAZ was inactivated by the increase in LATS1, 2 for proper maturation. Otherwise, YAP/TAZ activation after $LT\betaR$ engagement caused maturation defects during FRC differentiation. Moreover, hyper-activation of YAP/TAZ in mature FRC leads to myofibroblastic reprogramming of FRC. Thus, I propose that spatiotemporal regulation of YAP/TAZ is critical in regulating the lymph node stroma by directing the fate and reprogramming of FRCs.
Advisors
Koh, Gou Youngresearcher고규영researcher
Description
한국과학기술원 :의과학학제전공,
Publisher
한국과학기술원
Issue Date
2019
Identifier
325007
Language
eng
Description

학위논문(박사) - 한국과학기술원 : 의과학학제전공, 2019.8,[ix, 118 p. :]

Keywords

adipose tissue▼asubcutaneous adipose tissue▼aendothelial cell▼ametabolic syndrome▼aAngpt2▼aintegrin signaling pathway▼afibroblastic reticular cells▼alymph nodes▼ahoppi pathway▼aYAP/TAZ▼alymphotoxin-beta receptor▼amyofibrosis; 지방조직▼a피하지방▼a지방산전달▼a혈관내피세포▼a대사질환▼aAngpt2▼aIntegrin 신호 전달 체계▼a섬유아 세망 세포▼a림프절▼a히포 신호 전달 체계▼aYAP/TAZ▼alympho-toxin beta receptor▼a섬유화

URI
http://hdl.handle.net/10203/283267
Link
http://library.kaist.ac.kr/search/detail/view.do?bibCtrlNo=871435&flag=dissertation
Appears in Collection
MSE-Theses_Ph.D.(박사논문)
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