TLR4 Expression in Bone Marrow-Derived Cells Is Both Necessary and Sufficient to Produce the Insulin Resistance Phenotype in Diet-Induced Obesity

• Published in: Endocrinology (Philadelphia) 2015-01, Vol.156 (1), p.103-113
• Main Authors: Razolli, Daniela S, Moraes, Juliana C, Morari, Joseane, Moura, Rodrigo F, Vinolo, Marco A, Velloso, Licio A
• Format: Article
• Language: English
• Subjects: Adipose tissue; Adipose Tissue - metabolism; Animals; Body fat; Bone marrow; Bone Marrow Transplantation; Cell activation; Chimeras; Diet; Dietary Fats - administration & dosage; Dietary Fats - adverse effects; Enzymes; Fatty liver; Gene Expression Regulation - physiology; Glucose; Glucose tolerance; Hepatocytes; High fat diet; Histology; Homeostasis; Immune system; Immunological tolerance; Inflammation; Inflammation - genetics; Inflammation - metabolism; Insulin; Insulin resistance; Insulin Resistance - genetics; Insulin Resistance - physiology; Liver; Liver - metabolism; Liver transplantation; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred C3H; Mice, Knockout; Obesity; Obesity - etiology; Obesity - metabolism; Phenotypes; Proteins; Proto-Oncogene Proteins c-akt; Resistance factors; Signal transduction; Steatosis; TLR4 protein; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Toll-like receptors
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2014-1552

The anomalous activation of toll-like receptor 4 (TLR4) by dietary fats is one of the most important mechanisms linking obesity to insulin resistance. TLR4 is expressed in most tissues of the body, but its activity in the cells of the immune system is expected to underlie its most important roles of inducing inflammation and insulin resistance. Here we explore the hypothesis that TLR4 expression in bone marrow-derived cells mediates most of the actions of this receptor as an inducer of insulin resistance. Wild type and TLR4-mutant mice were used in bone marrow transplant experiments producing chimeras that harbored the functional receptor in all cells of the body except bone marrow-derived cells or only in bone marrow-derived cells. Transplanted mice were fed chow or a high-fat diet, and glucose homeostasis was evaluated by glucose and insulin tolerance tests. Insulin signal transduction and the expression of markers of inflammation were evaluated in the liver and white adipose tissue. In addition, we performed liver histology and evaluated the expression of gluconeogenic enzymes. The expression of TLR4 in bone marrow-derived cells only, but not in non-bone marrow-derived tissues only, was a determining factor in the induction of diet-induced insulin resistance, which was accompanied by an increased expression of inflammatory markers in both white adipose tissue and liver as well as increased liver steatosis and increased expression of gluconeogenic enzymes. TLR4 expressed in bone marrow-derived cells is an important mediator of obesity-associated insulin resistance in mice.