Kupffer cell activation is a causal factor for hepatic insulin resistance.
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. Mice were fed a normal diet or high-fat diet for 3 days. Kupffer cell activation was evaluated by immunohistochemistry and quantitative RT-PCR. 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. Here, 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. 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.
Lanthier
Nicolas
N
Laboratoire de Gastro-entérologie, Université Catholique de Louvain, GAEN 53/79, Ave. Mounier 53, B-1200 Brussels, Belgium.
Molendi-Coste
Olivier
O
Horsmans
Yves
Y
van Rooijen
Nico
N
Cani
Patrice D
PD
Leclercq
Isabelle A
IA
D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D004002:Clodronic Acid / Q000494:pharmacology; D004041:Dietary Fats / Q000494:pharmacology; D016503:Drug Delivery Systems; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D015309:Glucose Clamp Technique; D006505:Hepatitis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D006946:Hyperinsulinism / Q000378:metabolism; D007275:Injections, Intravenous; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008081:Liposomes / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D004041:Dietary Fats; D007328:Insulin; D008081:Liposomes; D004002:Clodronic Acid