Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto, Japan;
Am J Physiol Endocrinol Metab. 2014 Feb;306(3):E247-55. doi: 10.1152/ajpendo.00056.2013. Epub 2013 Dec 10.
Recently, fibrosis is observed in obese adipose tissue; however, the pathogenesis remains to be clarified. Obese adipose tissue is characterized by chronic inflammation with massive accumulation of immune cells including mast cells. The objective of the present study was to clarify the relationship between fibrosis and mast cells in obese adipose tissue, as well as to determine the origin of infiltrating mast cells. We observed the enhancement of mast cell accumulation and fibrosis in adipose tissue of severely obese diabetic db/db mice. Furthermore, adipose tissue-conditioned medium (ATCM) from severely obese diabetic db/db mice significantly enhanced collagen 5 mRNA expression in NIH-3T3 fibroblasts, and this enhancement was suppressed by the addition of an anti-mast cell protease 6 (MCP-6) antibody. An in vitro study showed that only collagen V among various types of collagen inhibited preadipocyte differentiation. Moreover, we found that ATCM from the nonobese but not obese stages of db/db mice significantly enhanced the migration of bone marrow-derived mast cells (BMMCs). These findings suggest that immature mast cells that infiltrate into adipose tissue at the nonobese stage gradually mature with the progression of obesity and diabetes and that MCP-6 secreted from mature mast cells induces collagen V expression in obese adipose tissue, which may contribute to the process of adipose tissue fibrosis. Induction of collagen V by MCP-6 might accelerate insulin resistance via the suppression of preadipocyte differentiation.
最近，肥胖脂肪组织中观察到纤维化；然而，其发病机制仍有待阐明。肥胖脂肪组织的特征是慢性炎症，大量免疫细胞包括肥大细胞积聚。本研究的目的是阐明肥胖脂肪组织中纤维化与肥大细胞之间的关系，并确定浸润肥大细胞的来源。我们观察到严重肥胖的糖尿病 db/db 小鼠脂肪组织中肥大细胞积累和纤维化增强。此外，来自严重肥胖的糖尿病 db/db 小鼠的脂肪组织条件培养基（ATCM）显著增强 NIH-3T3 成纤维细胞中胶原 5 mRNA 的表达，并且这种增强可被添加抗肥大细胞蛋白酶 6（MCP-6）抗体抑制。体外研究表明，只有胶原 V 可以抑制前脂肪细胞分化。此外，我们发现 db/db 小鼠非肥胖但肥胖阶段的 ATCM 可显著增强骨髓来源的肥大细胞（BMMC）的迁移。这些发现表明，在肥胖和糖尿病进展过程中，浸润到非肥胖脂肪组织中的幼稚肥大细胞逐渐成熟，并且从成熟肥大细胞分泌的 MCP-6 诱导肥胖脂肪组织中胶原 V 的表达，这可能有助于脂肪组织纤维化过程。MCP-6 诱导的胶原 V 可能通过抑制前脂肪细胞分化加速胰岛素抵抗。
