S-Space College of Natural Sciences (자연과학대학) Dept. of Biological Sciences (생명과학부) Theses (Ph.D. / Sc.D._생명과학부)
Characterization of Adipocyte CD1d and Invariant Natural Killer T Cells in the Regulation of Adipose Tissue Inflammation : 지방조직 염증반응 조절에 관여하는 지방세포 CD1d 유전자와 Invariant Natural Killer T 림프구의 역할 규명
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- 자연과학대학 생명과학부
- Issue Date
- 서울대학교 대학원
- 지방세포 ; CD1d ; invariant Natural Killer T 림프구 ; 지방조직 염증반응
- 학위논문 (박사)-- 서울대학교 대학원 : 생명과학부, 2014. 8. 김재범.
- Recent findings, notably on adipokines and adipose tissue inflammation, have revised the concept of adipose tissues being a mere energy storage depot. Instead, adipose tissues are emerging as endocrine and immunologically active organs with various effects on the regulation of systemic energy homeostasis. Compared with other metabolic organs such as liver and muscle, inflammatory response are dynamically regulated in adipose tissues and most of the immune cells in adipose tissues are involved in obesity-linked metabolic complications, including insulin resistance. Recently, most immune cells such as macrophages, granulocytes, helper T cells, cytotoxic T cells and B cells, have been implicated in the pathogenesis of adipose tissue inflammation. However, it has not been thoroughly understood yet how adipose tissue inflammation is initiated in obesity. To find out the causal factors for early response of adipose tissue inflammation, immune cell types and specific molecules have been investigated in high fat diet (HFD) fed obese mice. Notably, I found that there was significant changes of adipose tissue iNKT cells, one of innate-like lymphocytes which recognize lipids as antigens. In this study, the roles of invariant natural killer T (iNKT) cells and the regulatory mechanisms of iNKT cell response in adipose tissue have been focused.
In chapter one, I have demonstrated that iNKT cells quantitatively decrease in adipose tissue of obese animals, and that activation-induced cell death (AICD) of iNKT cells would confer the decrement of iNKT cells in obesity. Moreover, iNKT cell-deficient J18 knockout (KO) mice became more obese and exhibited increased adipose tissue inflammation upon high fat diet (HFD). These findings suggest that iNKT cells would play a crucial role of anti-inflammatory response in adipose tissue inflammation in obesity.
In chapter two, I have examined the regulatory mechanisms of iNKT cell response in adipose tissues. It is of interest to observe that CD1d, a molecule involved in lipid antigen presentation to iNKT cells, was highly expressed in adipocytes and CD1d-expressing adipocytes stimulated iNKT cell activity through physical interaction. iNKT cell population and CD1d expression were reduced in adipose tissue of obese mice and humans compared to those of lean subjects. To investigate the role of adipocyte-expressing CD1d in the regulation of iNKT cell response in adipose tissue in vivo, I generated adipocyte specific CD1d KO mouse. In adipocyte CD1d KO mice, the absolute number of adipose iNKT cells decreased upon NCD and HFD. In addition, HFD-induced proliferation of iNKT cells was diminished in adipose tissue of adipocyte CD1d KO mice. These data suggest that adipocytes would regulate iNKT cell activity via CD1d molecules and the interaction between adipocytes and iNKT cells may modulate adipose tissue inflammation in obesity.
Taken together, I suggest that excess energy intake would stimulate the activation of iNKT cells via adipocyte expressing CD1d molecules, which contributes to anti-inflammatory response in adipose tissue inflammation in obesity. However, reduction of CD1d expression in adipocytes would affect decrement of anti-inflammatory response mediated by iNKT cells, which results in accumulation of pro-inflammatory response in adipose tissues of late stage of obesity. Therefore, crosstalk between adipocytes and iNKT cells would be crucial to regulate adipose tissue inflammation in obesity.
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