The aim of this study was to investigate the role of Kupffer cell in glucose metabolism and hepatic insulin sensitivity in mice. Both phagocytic activity and secretory capacity of Kupffer cells were blunted 24 h after GdCl3 administration. Glucose tolerance - evaluated following an oral glucose tolerance test (OGTT) was higher in GdCl3-treated mice whereas fasting insulinemia and HOMA-IR index decreased. The improvement of glucose tolerance and hepatic insulin signalling pathway after inhibition of kupffer cells was supported by a lower hepatic gluconeogenic enzyme expression and a higher phosphorylation of Akt upon insulin challenge. Moreover, fasting hyperglycemia, insulin resistance and impaired glucose tolerance -induced by high fat (HF) diet - were improved through chronic administration of GdCl3. Interestingly, the inhibition of Kupffer cell exerted antiobesity effects in HF-fed mice, and lowered hepatic steatosis. Therefore, strategies targeting Kupffer cell functions could be a promising approach to counteract obesity and related metabolic disorders. (C) 2009 Elsevier Inc. All rights reserved.