Pioglitazone Treatment Reduces Adipose Tissue Inflammation through Reduction of Mast Cell and Macrophage Number and by Improving Vascularity

Context and ObjectiveAdipose tissue in insulin resistant subjects contains inflammatory cells and extracellular matrix components. This study examined adipose pathology of insulin resistant subjects who were treated with pioglitazone or fish oil.Design, Setting and ParticipantsAdipose biopsies were examined from nine insulin resistant subjects before/after treatment with pioglitazone 45 mg/day for 12 weeks and also from 19 subjects who were treated with fish oil (1,860 mg EPA, 1,500 mg DHA daily). These studies were performed in a clinical research center setting.ResultsPioglitazone treatment increased the cross-sectional area of adipocytes by 18% (p = 0.01), and also increased capillary density without affecting larger vessels. Pioglitazone treatment decreased total adipose macrophage number by 26%, with a 56% decrease in M1 macrophages and an increase in M2 macrophages. Mast cells were more abundant in obese versus lean subjects, and were decreased from 24 to 13 cells/mm2 (p = 0.02) in patients treated with pioglitazone, but not in subjects treated with FO. Although there were no changes in total collagen protein, pioglitazone increased the amount of elastin protein in adipose by 6-fold.ConclusionThe PPARγ agonist pioglitazone increased adipocyte size yet improved other features of adipose, increasing capillary number and reducing mast cells and inflammatory macrophages. The increase in elastin may better permit adipocyte expansion without triggering cell necrosis and an inflammatory reaction.背景与研究目的 胰岛素抵抗受试者的脂肪组织（adipose tissue）中存在炎症细胞与细胞外基质成分。本研究旨在探究接受吡格列酮（pioglitazone）或鱼油（fish oil）治疗的胰岛素抵抗受试者的脂肪组织病理学特征。 研究设计、研究场景与研究对象 本研究对9名胰岛素抵抗受试者在接受每日45mg吡格列酮治疗12周前后的脂肪活检（adipose biopsies）样本进行了分析，同时纳入19名接受鱼油治疗的受试者，其给药方案为每日摄入1860mg二十碳五烯酸（EPA）、1500mg二十二碳六烯酸（DHA）。所有研究均在临床研究中心开展。 研究结果 吡格列酮治疗可使脂肪细胞横截面积增加18%（p = 0.01），同时提升毛细血管密度，但对大血管无显著影响。吡格列酮治疗可使脂肪组织总巨噬细胞数量减少26%，其中M1巨噬细胞减少56%，而M2巨噬细胞数量升高。肥胖受试者体内的肥大细胞数量多于瘦体型受试者；吡格列酮治疗组受试者的肥大细胞数量从24个/mm²降至13个/mm²（p = 0.02），但鱼油治疗组未观察到该变化。尽管总胶原蛋白含量未发生显著改变，但吡格列酮可使脂肪组织中的弹性蛋白（elastin）含量提升6倍。 研究结论 过氧化物酶体增殖物激活受体γ（PPARγ）激动剂吡格列酮虽可增大脂肪细胞体积，但可改善脂肪组织的其他病理特征，包括增加毛细血管数量、减少肥大细胞与促炎型巨噬细胞。弹性蛋白含量的提升或可更好地支持脂肪细胞扩张，同时避免触发细胞坏死与炎症反应。