DGAT1-dependent triacylglycerol storage by macrophages protects mice from diet-induced insulin resistance and inflammation
DGAT1-dependent triacylglycerol storage by macrophages protects mice from diet-induced insulin resistance and inflammation
复制标题
DOI：
10.1172/jci36066
复制
发表时间：
2010-03-01
影响因子：
15.9
通讯作者：
Farese, Robert V., Jr.
中科院分区：
文献类型：
--
作者：
Koliwad, Suneil K.;Streeper, Ryan S.;Farese, Robert V., Jr.
饮食诱导的肥胖症（DIO）导致白色脂肪组织（WAT）中巨噬细胞的炎性活化，并随后导致胰岛素抵抗。PPAR γ激动剂;是已知抑制炎性巨噬细胞活化并诱导WAT和脂肪细胞中三酰甘油（TG）合成酶酰基CoA：二酰甘油酰基转移酶1（DGAT 1）表达的抗糖尿病剂。在这里，我们研究了小鼠巨噬细胞脂质储存能力和DIO相关的炎症巨噬细胞活化之间的关系。在巨噬细胞和脂肪细胞中过表达DGAT 1的小鼠（本文中称为aP 2-Dgat 1小鼠）更倾向于DIO，但被保护免于炎性巨噬细胞活化、WAT中的巨噬细胞积累、全身性炎症和胰岛素抗性。为了评估巨噬细胞DGAT 1表达对此表型的贡献，我们将aP 2-Dgat 1 BM移植到野生型小鼠。这些小鼠发生了与对照小鼠相似的DIO，但保留了在aP 2-Dgat 1小鼠中观察到的对WAT炎症和胰岛素抵抗的保护。在分离的巨噬细胞中，Dgat 1 mRNA水平与TG储存能力直接相关，与饱和脂肪酸（FA）引起的炎症激活呈负相关。此外，过氧化物酶体增殖物激活受体γ激动剂增加巨噬细胞Dgat 1的mRNA水平，这些激动剂的保护作用，对FA诱导的炎症巨噬细胞活化是不存在的巨噬细胞从Dgat 1-null小鼠分离。因此，增加DGAT 1。在鼠巨噬细胞中的表达增加了它们的TG储存能力，保护免于FA诱导的炎性活化，并且足以减少DIO的炎性和代谢后果。
Diet-induced obesity (DIO) leads to inflammatory activation of macrophages in white adipose tissue (WAT) and subsequently to insulin resistance. PPAR gamma agonists; are antictiabetic agents known to suppress inflammatory macrophage activation and to induce expression of the triacylglycerol (TG) synthesis enzyme acyl CoA: diacylglycerol acyltransferase 1 (DGAT1) in WAT and in adipocytes. Here, we investigated in mice the relationship between macrophage lipid storage capacity and DIO-associated inflammatory macrophage activation. Mice overexpressing DGAT1 in both macrophages and adipocytes (referred to herein as aP2-Dgat1 mice) were more prone to DIO but were protected against inflammatory macrophage activation, macrophage accumulation in WAT, systemic inflammation, and insulin resistance. To assess the contribution of macrophage DGAT1 expression to this phenotype, we transplanted wild-type mice with aP2-Dgat1 BM. These mice developed DIO similar to that of control mice but retained the protection from WAT inflammation and insulin resistance seen in aP2-Dgat1 mice. In isolated macrophages, Dgat1 mRNA levels correlated directly with TG storage capacity and inversely with inflammatory activation by saturated fatty acids (FAs). Moreover, PPAR gamma agonists increased macrophage Dgat1 mRNA levels, and the protective effects of these agonists; against FA-induced inflammatory macrophage activation were absent in macrophages isolated from Dgat1-null mice. Thus, increasing DGAT1. expression in murine macrophages increases their capacity for TG storage, protects against FA-induced inflammatory activation, and is sufficient to reduce the inflammatory and metabolic consequences of DIO.