[1852] Specific Hemosiderin Deposition in the Spleen of TSOD Mice – A Unique Spontaneous Model Showing Obesity, Diabetes, Hyperlipidemia, and Steatohepatitis

Takeshi Nishida, Koichi Tsuneyama, Kazuhiro Nomoto, Shinichi Hayashi, Shigeharu Miwa, Takahiko Nakajima, Yuko Nakanishi, Johji Imura. University of Toyama, Toyama, Japan

Background: Disturbance of iron metabolism was noted in patients with metabolic syndrome (MS). It is proposed that various proinflammatory and oxidant stress are associated with progress of the MS; however, the mechanism is still controversial. We recently reported a unique MS mice model, Tsumura-Suzuki-Obese-Diabetes (TSOD) mice, which develop obesity, type 2 diabetes, hyperlipidemia, and non-alcoholic steatohepatitis without any treatment. Interestingly, TSOD mice had significant hemosiderin deposition specifically in the spleen. It is thought that the state of iron metabolism, which is mainly regulated by the hepcidin-ferroportin system, was destroyed in the living body of TSOD mice. In this study, we investigated the mechanism of abnormal hemosiderin deposition in the spleen and the relationship to symptoms of MS.
Design: TSOD and Tsumura-Suzuki-Non-Obesity (TSNO) male mice, which were controls, were sacrificed at 8, 16, 24, and 32 weeks of age for histological and serum analysis. Spleen, liver, and visceral fat were removed and fixed in 10% formalin. The specimens were evaluated by hematoxylin-eosin staining, iron staining, and immunostaining such as IL-6 and 4-hydroxy-2-nonenal as a marker of oxidative stress. The serum levels of hepcidin and ferritin were measured by ELISA. Additional 4-, and 48-week-old TSOD and TSNO mice were sacrificed for gene expression analysis. The mRNA expression of ferroportin was investigated by real-time PCR analysis.
Results: In TSOD mice, excessive hemosiderin deposition was already observed at 8 weeks of age. The degree of hemosiderin deposition was worse until 32 weeks of age. The serum levels of hepcidin and ferritin of TSOD mice were higher than those of TSNO mice. Hemosiderin was located mainly inside macrophages of the spleen of the TSOD mice, and hemosiderin-laden macrophages expressed IL-6 intensely by immunostaining. In 48-week-old TSOD mice, expression of ferroportin, which has a role in exhausting iron from the cell, was lower than that of TSNO mice of the same age.
Conclusions: It was suggested that abnormal hemosiderin deposition in the spleen of TSOD mice was caused by underexpression of genes related to discharge iron from the macrophages such as ferroportin. On the other hand, hemosiderin-laden macrophages in the spleen showed overexpression of inflammatory cytokines such as IL-6. In this way, the macrophages that accumulated excessive iron may have the function of modifying various symptoms of MS. As a result, abnormal iron deposition may be indirectly related to pathologic progress in patients of MS.
Category: Pathobiology

Monday, March 4, 2013 1:00 PM

Poster Session II # 260, Monday Afternoon

 

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