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Identifier 000414796
Title Ο ρόλος του ανοσοποιητικού συστήματος στην ανάπτυξη λιπώδους διήθησης του ήπατος εξαιτίας υπερθερμιδικής δίαιτας
Alternative Title The role of the immune system in the development of diet induced non alcoholic fatty liver disease
Author Κοδέλα, Ελισάβετ
Thesis advisor Βενυχάκη, Μαρία
Reviewer Καραλή, Αικατερίνη
Γραβάνης, Αχιλλέας
Καρδάσης, Δημήτριος
Τσατσάνης, Χρήστος
Χαραλαμπόπουλος, Ιωάννης
Νότας, Γεώργιος
Abstract Non alcoholic fatty liver disease (NAFLD) is characterized by lipid deposition in the liver and includes a range of conditions from benign steatosis to steatohepatitis, fibrosis, cirrhosis and eventually hepatocellular carcinoma. NAFLD is due to dysregulated metabolism primarily associated with obesity and the corresponding insulin resistance. Obesity, a major epidemic with prevalence rates rising steadily among adults and children worldwide, is characterized by excessive accumulation of white adipose tissue (WAT). Obesity is normally associated with the development of a low-grade systemic inflammatory response that contributes to the progress of steatosis to steatohepatitis. The resulting increased inflammatory cytokines and adipokines in the systemic circulation, dysbiosis and the associated release of bacterial endotoxins, endoplasmic reticulum stress and mitochondrial dysfunction further support the worsening of the liver disease. Obesity is also hallmarked by increased leukocyte recruitment in the involved tissues, such as the adipose tissue and the liver. Although the role of macrophages in obesity and insulin resistance and their polarization towards a proinflammatory profile have been established, emerging evidence indicates a critical role of lymphocytes in this process. To further understand the particular role of T lymphocytes in diet-induced obesity, hepatic steatosis and insulin resistance, we used Rag1-/- mice that lack lymphocytes. This model allows for reconstitution experiments where the role of selective lymphocyte subpopulations can be assessed following their adoptive transfer from wild type to Rag1-/- mice. Further, to confirm the genetic background-independent effects, we studied this question in mice of both C57BL/6 and BALB/c backgrounds, two widely used genetic backgrounds used in metabolic and immunology centred studies respectively. Thus, we administered high fat diet to Rag1-/- and WT mice of both C57BL/6 and BALB/c backgrounds for 15 weeks and examined the development of NAFLD, obesity and associated metabolic parameters. Further, we assessed the possible modifying role of natural killer T (NKT) cells and CD8+ Τ lymphocytes on the above. We found that Rag1-/- mice were more protected from the development of obesity, insulin resistance and hepatic steatosis in comparison to the WT group, despite their similar food intake. We showed that Rag1-/- mice had increased metabolic rate and utilized lipids more efficiently than WT mice. More specifically, although the liver was protected from lipid deposition, no significant changes in lipid metabolism were observed within the tissue itself. However, the epididymal white adipose tissue (eWAT) showed increased lipid oxidation and the subcutaneous white adipose tissue (scWAT) showed increased abundance of beige adipocytes and induction of the corresponding thermogenic capacity as assessed by the expression of specific genes. This was also observed in the brown adipose tissue (BAT). Moreover, there was decreased expression of proinflammatory cytokines and increased expression of adiponectin in the eWAT of Rag1-/- mice as compared with the WT tissues. Similar results were obtained in mice of the BALB/c strain, despite their decreased susceptibility to the development of obesity as compared to their C57BL/6 counterparts. Next, the effect of NKT cells on the development of obesity and NAFLD was assessed following neutralization by administration of a CD1d antibody. We could not detect any significant changes in body weight, hepatic steatosis or expression of genes involved in the carbohydrate and lipid metabolism in mice that received CD1d treatment or PBS. On the other hand, adoptive transfer of CD8+ Τ lymphocytes in Rag1-/- mice fed a high fat diet resulted in increased adiposity and hepatic steatosis. Our findings unmask a crucial role for lymphocytes in the development of obesity, insulin resistance, NAFLD and metabolism. More importantly, our results show that lymphocytes exert specific effects on the scWAT by inducing the development of beige adipocytes resulting in increased energy dissipation and protection from NAFLD. Interestingly, despite the aforementioned strain differences, Rag1-/- mice of either strains responded in a similar way in the hypercaloric challenge. The differences in the metabolic activity of Rag1-/- mice provide useful insights for experimental disease modeling and drug testing in studies employing lymphocyte deficient mouse models. Last but not least, the findings on the role of T lymphocytes in energy homeostasis may contribute in the design of new, combinatorial, therapeutic approaches, including immunomodulatory interventions, for the spectrum of serious diseases involving liver steatosis, such as obesity or wasting of chronic diseases such as cancer and systemic infections.
Language Greek
Subject Lymphocytes
Obesity
Steatosis
Λεμφοκύτταρα
Λιπώδης ιστός
Παχυσαρκία
Issue date 2018-03-28
Collection   Faculty/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
Permanent Link https://elocus.lib.uoc.gr//dlib/9/0/2/metadata-dlib-1522834051-971715-21610.tkl Bookmark and Share
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