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Revisiting the roles of hepatic inflammation and adipokines in metabolic disease

PhD ceremony:Ms N. (Nanda) Gruben
When:May 13, 2015
Supervisor:Prof. M.H. Hofker
Co-supervisor:dr. D.P.Y. (Debby) Koonen
Where:Academy building RUG
Faculty:Medical Sciences / UMCG
Revisiting the roles of hepatic inflammation and adipokines in
metabolic disease

Obesity is a major health problem, because it induces type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). Hepatic inflammation and an altered secretion of adipokines (bioactive substances secreted by fat tissue) are believed to be involved in the pathogenesis of these diseases. In this thesis their role is further elucidated. The role of hepatic inflammation in the development of T2D was studied in two mouse models with hepatic inflammation. We investigated time differences in the development of insulin resistance (IR, precedes T2D) in mice with and without hepatic inflammation. In both models, hepatic inflammation did not affect the development of IR. NAFLD is also associated with IR. Based on a literature review we showed that there is little evidence for a causal relationship. In most cases, the relationship was explained by alterations in body weight. In addition, we investigated in patients if the presence of various adipokines in fat and liver tissue is correlated with NAFLD. Especially the adipokine chemerin was correlated with reduced disease severity. We used mice insensitive to chemerin, and mice with increased chemerin levels to study whether chemerin protects against NAFLD. In both models, chemerin did not protect against the development of NAFLD. From these results we conclude that hepatic inflammation, in contrast to the current dogma, does not contribute to the pathogenesis of T2D. In addition, we conclude that chemerin does not protect against NAFLD. Therefore, this thesis raises the question whether medications directed against inflammation or chemerin will be effective against these diseases.