Hevener Andrea L, Olefsky Jerrold M, Reichart Donna, Nguyen M T Audrey, Bandyopadyhay Gautam, Leung Ho-Yin, Watt Matthew J, Benner Chris, Febbraio Mark A, Nguyen Anh-Khoi, Folian Brian, Subramaniam Shankar, Gonzalez Frank J, Glass Christopher K, Ricote Mercedes
Department of Medicine, Division of Endocrinology and Metabolism, UCSD, La Jolla, California, USA.
J Clin Invest. 2007 Jun;117(6):1658-69. doi: 10.1172/JCI31561. Epub 2007 May 24.
PPAR gamma is required for fat cell development and is the molecular target of antidiabetic thiazolidinediones (TZDs), which exert insulin-sensitizing effects in adipose tissue, skeletal muscle, and liver. Unexpectedly, we found that inactivation of PPAR gamma in macrophages results in the development of significant glucose intolerance plus skeletal muscle and hepatic insulin resistance in lean mice fed a normal diet. This phenotype was associated with increased expression of inflammatory markers and impaired insulin signaling in adipose tissue, muscle, and liver. PPAR gamma-deficient macrophages secreted elevated levels of factors that impair insulin responsiveness in muscle cells in a manner that was enhanced by exposure to FFAs. Consistent with this, the relative degree of insulin resistance became more severe in mice lacking macrophage PPAR gamma following high-fat feeding, and these mice were only partially responsive to TZD treatment. These findings reveal an essential role of PPAR gamma in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs.
过氧化物酶体增殖物激活受体γ（PPARγ）是脂肪细胞发育所必需的，并且是抗糖尿病噻唑烷二酮类药物（TZDs）的分子靶点，这类药物在脂肪组织、骨骼肌和肝脏中发挥胰岛素增敏作用。出乎意料的是，我们发现，在喂食正常饮食的瘦小鼠中，巨噬细胞中PPARγ的失活会导致显著的葡萄糖不耐受以及骨骼肌和肝脏胰岛素抵抗的发生。这种表型与脂肪组织、肌肉和肝脏中炎症标志物表达增加以及胰岛素信号受损有关。PPARγ缺陷型巨噬细胞分泌的因子水平升高，这些因子会以一种因暴露于游离脂肪酸（FFAs）而增强的方式损害肌肉细胞中的胰岛素反应性。与此一致的是，高脂喂养后，缺乏巨噬细胞PPARγ的小鼠的胰岛素抵抗相对程度变得更加严重，并且这些小鼠对TZDs治疗仅部分有反应。这些发现揭示了PPARγ在巨噬细胞中对于维持全身胰岛素作用以及介导TZDs的抗糖尿病作用的重要作用。
