Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity
Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity
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DOI：
10.1038/nm.3829
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发表时间：
2015-06-01
期刊：
影响因子：
82.9
通讯作者：
Venteclef, Nicolas
中科院分区：
文献类型：
--
作者：
Dalmas, Elise;Toubal, Amine;Venteclef, Nicolas
内脏脂肪组织的积累与炎症升高和代谢疾病风险增加相关。然而，人们对控制其病理性扩张的分子机制知之甚少。转录因子干扰素调节因子5（IRF5）已涉及使巨噬细胞向炎性表型极化。在这里，我们证明了缺乏Irf 5的小鼠，当置于高脂肪饮食中时，与相同饮食的野生型（WT）小鼠相比，它们的附睾白色脂肪组织（epiWAT）的生长没有差异，但它们的皮下白色脂肪组织显示出扩张。与来自WT小鼠的epiWAT相比，来自Irf5缺陷小鼠的EpiWAT的特征在于交替活化的巨噬细胞的积累、限制脂肪细胞大小的较高胶原沉积以及增强的胰岛素敏感性。在肥胖个体中，IRF5表达与胰岛素敏感性和内脏脂肪组织中的胶原沉积呈负相关。脂肪组织巨噬细胞基因表达的全基因组分析突出了转化生长因子β 1（TGFB1）基因本身作为IRF5介导的抑制的直接靶点。这项研究揭示了IRF5在控制不同脂肪组织库的相对质量以及肥胖症中的胰岛素敏感性方面的新功能，并且它表明IRF5的抑制可以在这种情况下促进健康的代谢状态。
Accumulation of visceral adipose tissue correlates with elevated inflammation and increased risk of metabolic diseases. However, little is known about the molecular mechanisms that control its pathological expansion. Transcription factor interferon regulatory factor 5 (IRF5) has been implicated in polarizing macrophages towards an inflammatory phenotype. Here we demonstrate that mice lacking Irf5, when placed on a high-fat diet, show no difference in the growth of their epididymal white adipose tissue (epiWAT) but they show expansion of their subcutaneous white adipose tissue, as compared to wild-type (WT) mice on the same diet. EpiWAT from Irf5-deficient mice is marked by accumulation of alternatively activated macrophages, higher collagen deposition that restricts adipocyte size, and enhanced insulin sensitivity compared to epiWAT from WT mice. In obese individuals, IRF5 expression is negatively associated with insulin sensitivity and collagen deposition in visceral adipose tissue. Genome-wide analysis of gene expression in adipose tissue macrophages highlights the transforming growth factor beta 1 (TGFB1) gene itself as a direct target of IRF5-mediated inhibition. This study uncovers a new function for IRF5 in controlling the relative mass of different adipose tissue depots and thus insulin sensitivity in obesity, and it suggests that inhibition of IRF5 may promote a healthy metabolic state during this condition.