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Research Article

Kupffer cell activation is a causal factor for hepatic insulin resistance

¹Université catholique de Louvain ²Free University ³Universit? catholique de Louvain ⁴Universite catholique de Louvain

Submitted 23 September 2009 ; revision received 14 October 2009 ; accepted in final form 22 October 2009

ABSTRACT

Background/aim: Recruited adipose tissue macrophages contribute to chronic and low grade inflammation causing insulin resistance in obesity. Similarly, we hypothesized here that Kupffer cells, the hepatic resident macrophages, play a pathogenic role in hepatic insulin resistance induced by a high fat diet. Methods: Mice were fed a normal diet or high fat diet for three days. Kupffer cell activation was evaluated by immunohistochemistry and RT-qPCR. Insulin sensitivity was assessed in vivo by hyperinsulinemic-euglycemic clamp and insulin-activated signaling was investigated by western blot. Liposome-encapsulated clodronate was injected intravenously to deplete macrophages prior to a short-term exposure to high fat diet. Results: We characterized a short term high fat diet model in mice and demonstrated early hepatic insulin resistance and steatosis concurrent with Kupffer cell activation. We demonstrated that selective Kupffer cell depletion obtained by intravenous clodronate, without affecting adipose tissue macrophages, was sufficient to enhance insulin-dependent insulin signaling and significantly improve hepatic insulin sensitivity in vivo in this short term high fat diet model. Conclusion: Our study clearly shows that hepatic macrophage response participates to the onset of high fat diet-induced hepatic insulin resistance and may therefore represent an attractive target for prevention and treatment of diet- and obesity-induced insulin resistance.

macrophage; liver; steatosis; clodronate