PhD ceremony Ms. A. Funke: The role of hepatic inflammation in the development of hepatic steatosis and insulin resistance

PhD ceremony: Ms. A. Funke, 11.00 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The role of hepatic inflammation in the development of hepatic steatosis and insulin resistance

Promotor(s): prof. M.H. Hofker

Faculty: Medical Sciences

It is generally assumed that hepatic inflammation in obesity is linked to the pathogenesis of insulin resistance. However, several studies have shed doubt on this view, which questions the causality of this association. Therefore in this thesis, we used 3 different mouse models, i.e. the Ldlr-/- mice, Myd88-/- mice and Csf1op/+ mice to investigate the role of hepatic inflammation in the aetiology of NAFLD and insulin resistance. We have demonstrated that short-term HFC-induced hepatic inflammation does not lead to the development of systemic insulin resistance in lean Ldlr-/- mice. In addition, sustained hepatic inflammation induced by long-term HFC feeding did not aggravate the development of insulin resistance in obese Ldlr-/- mice compared to HF control diets. Furthermore, we have shown that reduced hepatic inflammation in the Myd88-/- mice does not lead to the protection from obesity-induced insulin resistance. In addition, lower inflammatory levels in the liver, adipose tissue and plasma in Csf1op/+ mice are not associated with protection against the development of systemic insulin resistance. Therefore we conclude that hepatic inflammation is not causally linked to the pathogenesis of insulin resistance. Our data clearly show that the current knowledge about the role of inflammation in the development of insulin resistance is far from understood. In addition, we have also shown that cross-talk between Kupffer cells and hepatocytes is important for protecting hepatocytes from the development of hepatic steatosis. These data suggest that a fine balance of inflammatory mediators is necessary for the optimal metabolic control in the liver.