RAGE Regulates the Metabolic and Inflammatory Response to High-Fat Feeding in Mice

  1. Ann Marie Schmidt1
  1. 1Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY
  2. 2Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY
  3. 3Program in Molecular Medicine and Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Massachusetts Medical School, Worcester, MA
  4. 4Departments of Population Health (Biostatistics) and Environmental Medicine, New York University School of Medicine, New York, NY
  5. 5Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center and Department of Biomedical Informatics, College of Physicians and Surgeons, Columbia University, New York, NY
  1. Corresponding authors: Anthony W. Ferrante Jr., awf7{at}, and Ann Marie Schmidt,{at}
  1. F.S. and C.H.d.P. contributed equally to this work.

    A.W.F. and A.M.S. contributed equally to this work.


In mammals, changes in the metabolic state, including obesity, fasting, cold challenge, and high-fat diets (HFDs), activate complex immune responses. In many strains of rodents, HFDs induce a rapid systemic inflammatory response and lead to obesity. Little is known about the molecular signals required for HFD-induced phenotypes. We studied the function of the receptor for advanced glycation end products (RAGE) in the development of phenotypes associated with high-fat feeding in mice. RAGE is highly expressed on immune cells, including macrophages. We found that high-fat feeding induced expression of RAGE ligand HMGB1 and carboxymethyllysine-advanced glycation end product epitopes in liver and adipose tissue. Genetic deficiency of RAGE prevented the effects of HFD on energy expenditure, weight gain, adipose tissue inflammation, and insulin resistance. RAGE deficiency had no effect on genetic forms of obesity caused by impaired melanocortin signaling. Hematopoietic deficiency of RAGE or treatment with soluble RAGE partially protected against peripheral HFD-induced inflammation and weight gain. These findings demonstrate that high-fat feeding induces peripheral inflammation and weight gain in a RAGE-dependent manner, providing a foothold in the pathways that regulate diet-induced obesity and offering the potential for therapeutic intervention.


  • Received October 22, 2013.
  • Accepted February 3, 2014.

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