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

Abstract

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.

RAGE-Mediated Suppression of Interleukin-10 Results in Enhanced Mortality in a Murine Model of Acinetobacter baumannii Sepsis

“…4). RAGE deficiency leads to increased IL-10 production by T cells in vitro (37) as well as to increased IL-10 levels in murine models of hemorrhagic shock (38) and traumatic brain injury-induced pulmonary dysfunction (39) and in mice fed a high fat diet (40). Therefore, our finding of RAGE-dependent suppression of IL-10 production is consistent with the findings of others.…”

Isolevuglandin-Type Lipid Aldehydes Induce the Inflammatory Response of Macrophages by Modifying Phosphatidylethanolamines and Activating the Receptor for Advanced Glycation Endproducts

“…For instance, genetic deletion of Ager decreases atherosclerosis in both nondiabetic and diabetic Apoe null mice (31,62). Ager null mice also show decreased obesity, adipose tissue inflammation, and insulin resistance in wildtype C57BL6 mice fed a high-fat diet (61). RAGE expressed on bone marrow-derived cells (e.g., monocyte/macrophages) specifically contributes to atherosclerosis, as transplantation of Ager null/Apoe null bone marrow into Apoe null mice results in markedly reduced atherosclerosis compared with those receiving bone marrow from Ager-positive Apoe null mice (47).…”

Soluble RAGEs — Prospects for treating & tracking metabolic and inflammatory disease

“…Although originally coupled mechanistically largely to hyperglycemia and diabetes, it is established that AGEs accumulate in oxidative and lipid stresses as well [1–4]. Studies in human subjects and animal models suggest the accelerated formation and accumulation of AGEs, especially carboxy methyl lysine (CML) AGE, in obese adipose tissue, even in the absence of diabetes [5, 6]. One of the principal AGE precursors, methylglyoxal (MG), is regulated by the enzyme glyoxalase1 (Glo1).…”