The radioprotective 105/MD-1 complex contributes to diet-induced obesity and adipose tissue inflammation.

Abstract

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.

• Authors: Yasuharu Watanabe, Tomoya Nakamura, Sho Ishikawa, Shiho Fujisaka, Isao Usui, Koichi Tsuneyama, Yoshinori Ichihara, Tsutomu Wada, Yoichiro Hirata, Takayoshi Suganami, Hirofumi Izaki, Shizuo Akira, Kensuke Miyake, Hiro-omi Kanayama, Michio Shimabukuro, Masataka Sata, Toshiyasu Sasaoka, Yoshihiro Ogawa, Kazuyuki Tobe, Kiyoshi Takatsu, Yoshinori Nagai
• Journal: Diabetes (Diabetes) Vol. 61 Issue 5 Pg. 1199-209 (May 2012) ISSN: 1939-327X [Electronic] United States
• PMID: 22396206 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Antigens, Surface
• Dietary Fats
• Ly78 protein, mouse
• Ly86 protein, mouse
• Membrane Glycoproteins
• Stearic Acids
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Palmitic Acid
• stearic acid

Topics

• Adipocytes (cytology, metabolism)
• Adipose Tissue (metabolism, pathology)
• Animals
• Antigens, CD (genetics, metabolism)
• Antigens, Surface (genetics, metabolism)
• Coculture Techniques
• Dietary Fats (administration & dosage, adverse effects)
• Epididymis
• Fatty Liver (etiology)
• Gene Expression Regulation (physiology)
• Humans
• Inflammation (etiology, metabolism)
• Insulin Resistance
• Macrophages (cytology, metabolism)
• Male
• Membrane Glycoproteins (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Obesity (etiology)
• Palmitic Acid
• Stearic Acids
• Toll-Like Receptor 4 (genetics, metabolism)