In mammals, changes in the metabolic state, including obesity, fasting, cold challenge and high fat diets activate complex immune responses. In many strains of rodents, high fat diets induce a rapid systemic inflammatory response and lead to obesity. Little is known about the molecular signals required for high fat diet (HFD)-induced phenotypes. Here we studied the function of the receptor for advanced glycation products (RAGE) in the development of phenotypes associated with high fat feeding in mice. RAGE is highly expressed on immune cells, including macrophages. High fat feeding induced expression of RAGE ligand HMGB1 and carboxy methyl lysine (CML)-advanced glycation endproducts (AGE) 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 data argue 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.
^ These co-first authors contributed equally to this work.
* These co-senior authors contributed equally to this work.
- Received October 22, 2013.
- Accepted February 1, 2014.
- © 2014 by the American Diabetes Association.
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