Laboratory of Veterinary Molecular Pathology and Therapeutics, Division of Animal Life Science, Graduate School, Institute of Agriculture, 3-5-8 Saiwai-cho, Fuchu, Tokyo, Japan.
Am J Physiol Cell Physiol. 2011 Dec;301(6):C1360-7. doi: 10.1152/ajpcell.00514.2010. Epub 2011 Aug 24.
Mast cells are one of the major producers of prostaglandins (PGs). The final metabolite of PGs 15-deoxy-delta-12,14-PGJ(2) (15-deoxy-delta PGJ(2)) is the endogenous ligand of the peroxisome proliferator-activated receptor (PPAR) γ. PPARγ modulates adipocyte differentiation; therefore, we attempted to investigate whether PGs derived from mast cells influenced on adipogenesis. We found the increase of mast cell numbers in fat tissue of obese mice fed with a high-fat diet allowed us to speculate contributions of mast cells to adipogenesis. Mast cell-mediated induction of adipogenesis was evaluated by using 3T3 L1 cells. Supernatants obtained from mast cells stimulated with calcium ionophore or the high-glucose condition contained 15-deoxy-delta PGJ(2) and induced adipogenesis of 3T3 L1 cells. Agonistic activity of PGJ(2) from the supernatants on PPARγ was confirmed by a reporter gene assay. Culture medium collected from calcium ionophore-stimulated bone marrow-derived cultured mast cells (BMCMC) activated PPAR-responsive element in NIH3T3 fibroblasts, and the specific inhibitor of PPARγ canceled the activation. Contribution of mast cells to obesity was evaluated by using mast cell-deficient mice fed with a Western diet. Weight gain of mast cell-deficient mice during high-fat feeding was impaired compared with their littermate wild-type mice; on the other hand, transplantation of bone marrow-derived cultured mast cells to mast cell-deficient mice restored the weight gain by intake of a high-fat diet. In this study, we clearly demonstrated that mast cells produced PGs in response to the high-glucose condition and induced adipocyte differentiation and possibly obesity. This is the first study that provides evidence for a novel role of mast cells in adipogenesis via PPARγ activation.
肥大细胞是前列腺素（PGs）的主要产生者之一。PGs 的最终代谢产物 15-脱氧-delta-12,14-PGJ(2)（15-脱氧-delta PGJ(2)）是过氧化物酶体增殖物激活受体（PPAR）γ的内源性配体。PPARγ 调节脂肪细胞分化；因此，我们试图研究肥大细胞产生的 PG 是否影响脂肪生成。我们发现，高脂饮食喂养的肥胖小鼠脂肪组织中肥大细胞数量增加，这使我们推测肥大细胞对脂肪生成有贡献。通过使用 3T3 L1 细胞来评估肥大细胞介导的脂肪生成诱导。用钙离子载体或高葡萄糖条件刺激肥大细胞获得的上清液含有 15-脱氧-delta PGJ(2)，并诱导 3T3 L1 细胞的脂肪生成。通过报告基因测定证实了上清液中 PGJ(2)对 PPARγ 的激动活性。从钙离子载体刺激的骨髓来源培养的肥大细胞（BMCMC）收集的培养基激活了 NIH3T3 成纤维细胞中的 PPAR 反应元件，而 PPARγ 的特异性抑制剂取消了激活。通过给喂食西方饮食的肥大细胞缺陷型小鼠评估肥大细胞对肥胖的贡献。与同窝野生型小鼠相比，肥大细胞缺陷型小鼠在高脂喂养期间的体重增加受损；另一方面，向肥大细胞缺陷型小鼠移植骨髓来源的培养肥大细胞恢复了通过摄入高脂肪饮食的体重增加。在这项研究中，我们清楚地表明，肥大细胞对高葡萄糖条件产生 PGs，并诱导脂肪细胞分化并可能导致肥胖。这是第一项提供证据表明肥大细胞通过激活 PPARγ 在脂肪生成中发挥新作用的研究。
