Abstract

Objective: Increased activity of the innate immune system has been implicated in the pathogenesis of the dyslipidemia and insulin resistance associated with obesity and Type 2 diabetes mellitus (T2DM). In this study we addressed the potential role of Kupffer cells (liver-specific macrophages, KC) in these metabolic abnormalities.

Research Design and Methods: Rats were depleted of KC by administration of gadolinium chloride after which all animals were exposed to a 2-week high fat or high sucrose diet. Subsequently, the effects of these interventions on the development of hepatic insulin resistance and steatosis were assessed. In further studies, the effects of M1 polarized KC on hepatocyte lipid metabolism and insulin sensitivity were addressed.

Results: As expected, a high fat or high sucrose diet induced steatosis and hepatic insulin resistance. However, these metabolic abnormalities were prevented when liver was depleted of KC. In vitro, KC recapitulated the in vivo effects of diet by increasing hepatocyte triglyceride accumulation and fatty acid esterification, and decreasing fatty acid oxidation and insulin responsiveness. To address the mechanisms(s) of KC action we inhibited a panel of cytokines using neutralizing antibodies. Only neutralizing antibodies against TNFα attenuated KC-induced alterations in hepatocyte fatty acid oxidation, triglyceride accumulation, and insulin responsiveness. Importantly, KC TNFα levels were increased by diet in vivo and in isolated M1-polarized KC in vitro.

Conclusions: These data demonstrate a role for liver macrophages in diet-induced alterations in hepatic lipid metabolism and insulin sensitivity, and suggest a role for these cells in the etiology of the metabolic abnormalities of obesity/T2DM.