1. Am J Physiol Gastrointest Liver Physiol. 2009 Oct 29. [Epub ahead of print]

Kupffer cell activation is a causal factor for hepatic insulin resistance.

Lanthier N, Molendi-Coste O, Horsmans Y, van Rooijen N, Cani PD, Leclercq IA.

1Université catholique de Louvain.

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.

PMID: 19875703 [PubMed - as supplied by publisher]