Depletion of Liver Kupffer Cells Prevents the Development of Diet-Induced Hepatic Steatosis and Insulin Resistance

  1. Wan Huang1,
  2. Anantha Metlakunta1,
  3. Nikolaos Dedousis1,
  4. Pili Zhang1,
  5. Ian Sipula1,
  6. John J. Dube1,
  7. Donald K. Scott1 and
  8. Robert M. O'Doherty1,2
  1. 1Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania;
  2. 2Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania.
  1. Corresponding author: Robert M. O'Doherty, rmo1{at}pitt.edu.
  1. W.H. and A.M. contributed equally to this work.

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. In this study, we addressed the potential role of Kupffer cells (liver-specific macrophages, KCs) in these metabolic abnormalities.

RESEARCH DESIGN AND METHODS Rats were depleted of KCs 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 KCs 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 KCs. In vitro, KCs 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 tumor necrosis factor-α (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 KCs 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/type 2 diabetes.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received January 8, 2009.
    • Accepted November 11, 2009.
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  1. Diabetes vol. 59 no. 2 347-357
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