The Radioprotective 105/MD-1 Complex Contributes to Diet-Induced Obesity and Adipose Tissue Inflammation

• Published in: Diabetes (New York, N.Y.) Vol. 61; no. 5; pp. 1199 - 1209
• Main Authors: Watanabe, Yasuharu, Nakamura, Tomoya, Ishikawa, Sho, Fujisaka, Shiho, Usui, Isao, Tsuneyama, Koichi, Ichihara, Yoshinori, Wada, Tsutomu, Hirata, Yoichiro, Suganami, Takayoshi, Izaki, Hirofumi, Akira, Shizuo, Miyake, Kensuke, Kanayama, Hiro-omi, Shimabukuro, Michio, Sata, Masataka, Sasaoka, Toshiyasu, Ogawa, Yoshihiro, Tobe, Kazuyuki, Takatsu, Kiyoshi, Nagai, Yoshinori
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.05.2012
• Subjects: Adipocytes; Adipocytes - cytology; Adipocytes - metabolism; Adipose Tissue - metabolism; Adipose Tissue - pathology; Animals; Antibodies; Antigens, CD - genetics; Antigens, CD - metabolism; Antigens, Surface - genetics; Antigens, Surface - metabolism; Biological and medical sciences; Body fat; Cell receptors; Coculture Techniques; Complications and side effects; Development and progression; Diabetes. Impaired glucose tolerance; Diet; Dietary Fats - administration & dosage; Dietary Fats - adverse effects; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Epididymis; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty acids; Fatty Liver - etiology; Flow cytometry; Gene Expression Regulation - physiology; Genetic aspects; Glucose; Humans; Immunology and Transplantation; Inflammation; Inflammation - etiology; Inflammation - metabolism; Insulin Resistance; Kinases; Ligands; Macrophages - cytology; Macrophages - metabolism; Male; Medical sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Metabolic diseases; Metabolic disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Obesity - etiology; Palmitic Acid; Pathogens; Physiological aspects; Proteins; Risk factors; Stearic Acids; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Japan; Endocrinopathy; Obesity; Adipose tissue; Diet; Diabetes mellitus; Nutrition disorder; Inflammation; Nutritional status; Feeding
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db11-1182

Recent accumulating evidence suggests that innate immunity is associated with obesity-induced chronic inflammation and metabolic disorders. Here, we show that a Toll-like receptor (TLR) protein, radioprotective 105 (RP105)/myeloid differentiation protein (MD)-1 complex, contributes to high-fat diet (HFD)-induced obesity, adipose tissue inflammation, and insulin resistance. An HFD dramatically increased RP105 mRNA and protein expression in stromal vascular fraction of epididymal white adipose tissue (eWAT) in wild-type (WT) mice. RP105 mRNA expression also was significantly increased in the visceral adipose tissue of obese human subjects relative to nonobese subjects. The RP105/MD-1 complex was expressed by most adipose tissue macrophages (ATMs). An HFD increased RP105/MD-1 expression on the M1 subset of ATMs that accumulate in eWAT. Macrophages also acquired this characteristic in coculture with 3T3-L1 adipocytes. RP105 knockout (KO) and MD-1 KO mice had less HFD-induced adipose tissue inflammation, hepatic steatosis, and insulin resistance compared with wild-type (WT) and TLR4 KO mice. Finally, the saturated fatty acids, palmitic and stearic acids, are endogenous ligands for TLR4, but they did not activate RP105/MD-1. Thus, the RP105/MD-1 complex is a major mediator of adipose tissue inflammation independent of TLR4 signaling and may represent a novel therapeutic target for obesity-associated metabolic disorders.