| 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.
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