Acetylation of PPARγ in macrophages promotes visceral fat degeneration in obesity.
Acetylation of PPARγ in macrophages promotes visceral fat degeneration in obesity.
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DOI：
10.1093/lifemeta/loac032
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发表时间：
2022-12
期刊：
影响因子：
--
通讯作者：
Qiang, Li
中科院分区：
文献类型：
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作者：
Aaron, Nicole;Zahr, Tarik;He, Ying;Yu, Lexiang;Mayfield, Brent;Pajvani, Utpal B;Qiang, Li
肥胖的特征是由脂肪组织中的巨噬细胞渗透引起的慢性低度炎症。PPARγ在巨噬细胞中具有抗炎作用已被证实，但其在巨噬细胞中的作用机制仍未完全阐明。PPARγ经历翻译后修饰(PTM)，包括乙酰化，以介导包括代谢功能在内的配体反应。在这里，我们报告了巨噬细胞中PPARγ的乙酰化促进了它们向脂肪组织的渗透，加剧了代谢失调。我们建立了一个表达巨噬细胞特异的、结构性乙酰化模拟形式的PPARγ的小鼠系(K293QFLOX/FLOX：LysM-cRE，mK293Q)，以剖析PPARγ乙酰化在巨噬细胞中的作用。在高脂饮食喂养刺激巨噬细胞向脂肪组织渗透的情况下，我们评估了突变小鼠的整体代谢特征和组织特异性表型，包括对PPARγ激动剂罗格列酮的反应。巨噬细胞特异性PPARγK293Q的表达促进了附睾炎性巨噬细胞在附睾白色脂肪组织中的浸润和纤维化，但在皮下或棕色脂肪组织中却没有，导致能量消耗、胰岛素敏感性、糖耐量和脂肪组织功能的降低。此外，mK293Q小鼠对罗格列酮诱导的脂肪组织重塑的改善具有抵抗力。我们的研究表明，乙酰化是巨噬细胞激活过程中PPARγ调节的新层次，并强调了此类PTM在调节代谢方面的重要性和潜在的治疗意义。
Obesity is characterized by chronic, low-grade inflammation, which is driven by macrophage infiltration of adipose tissue. PPARγ is well established to have an anti-inflammatory function in macrophages, but the mechanism that regulates its function in these cells remains to be fully elucidated. PPARγ undergoes post-translational modifications (PTMs), including acetylation, to mediate ligand responses, including on metabolic functions. Here, we report that PPARγ acetylation in macrophages promotes their infiltration into adipose tissue, exacerbating metabolic dysregulation. We generated a mouse line that expresses a macrophage-specific, constitutive acetylation-mimetic form of PPARγ (K293Qflox/flox:LysM-cre, mK293Q) to dissect the role of PPARγ acetylation in macrophages. Upon high-fat diet feeding to stimulate macrophage infiltration into adipose tissue, we assessed the overall metabolic profile and tissue-specific phenotype of the mutant mice, including responses to the PPARγ agonist Rosiglitazone. Macrophage-specific PPARγ K293Q expression promotes proinflammatory macrophage infiltration and fibrosis in epididymal white adipose tissue, but not in subcutaneous or brown adipose tissue, leading to decreased energy expenditure, insulin sensitivity, glucose tolerance, and adipose tissue function. Furthermore, mK293Q mice are resistant to Rosiglitazone-induced improvements in adipose tissue remodeling. Our study reveals that acetylation is a new layer of PPARγ regulation in macrophage activation, and highlights the importance and potential therapeutic implications of such PTMs in regulating metabolism.