Attenuated Pik3r1 expression prevents insulin resistance and adipose tissue macrophage accumulation in diet-induced obese mice.
Attenuated Pik3r1 expression prevents insulin resistance and adipose tissue macrophage accumulation in diet-induced obese mice.
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Pik3r1 表达减弱可防止饮食诱导的肥胖小鼠的胰岛素抵抗和脂肪组织巨噬细胞积累。
DOI：
10.2337/db11-1433
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发表时间：
2012-10
期刊：
影响因子：
7.7
通讯作者：
Friedman JE
中科院分区：
文献类型：
--
作者：
McCurdy CE;Schenk S;Holliday MJ;Philp A;Houck JA;Patsouris D;MacLean PS;Majka SM;Klemm DJ;Friedman JE
肥胖白色脂肪组织（AT）的特点是促炎巨噬细胞大规模浸润，同时伴有全身胰岛素抵抗；然而，启动这种信号级联和趋化因子释放的细胞刺激仍然未知。本研究的目的是确定磷酸肌醇 3 激酶 (PI3K) 调节亚基对肥胖 AT 巨噬细胞 (ATM) 浸润的作用。在这里，我们发现 Pik3r1 调节亚基（即 p85α/p55α/p50α）在高脂肪饮食喂养的肥胖小鼠的 AT 中被高度诱导，同时伴有胰岛素抵抗。尽管严重肥胖，但 Pik3r1 调节亚基 (αHZ) 的整体杂合缺失，而非 Pik3r2 (p85β) 的敲除，仍保留了全身、AT 和骨骼肌的胰岛素敏感性。此外，尽管内质网（ER）应激、缺氧、脂肪细胞肥大和 Jun NH2 末端激酶激活，肥胖 αHZ 小鼠中的 ATM 积累、促炎基因表达和离体趋化因子分泌均显着减少。此外，骨髓移植研究表明，肥胖 αHZ 小鼠的这些改善与造血室中 Pik3r1 表达的减少无关。总而言之，这些研究表明 Pik3r1 表达在介导 AT 胰岛素敏感性中发挥着关键作用，更重要的是，表明 PI3K 活性降低是肥胖 AT 炎症反应启动和传播的关键步骤。
Obese white adipose tissue (AT) is characterized by large-scale infiltration of proinflammatory macrophages, in parallel with systemic insulin resistance; however, the cellular stimulus that initiates this signaling cascade and chemokine release is still unknown. The objective of this study was to determine the role of the phosphoinositide 3-kinase (PI3K) regulatory subunits on AT macrophage (ATM) infiltration in obesity. Here, we find that the Pik3r1 regulatory subunits (i.e., p85α/p55α/p50α) are highly induced in AT from high-fat diet–fed obese mice, concurrent with insulin resistance. Global heterozygous deletion of the Pik3r1 regulatory subunits (αHZ), but not knockout of Pik3r2 (p85β), preserves whole-body, AT, and skeletal muscle insulin sensitivity, despite severe obesity. Moreover, ATM accumulation, proinflammatory gene expression, and ex vivo chemokine secretion in obese αHZ mice are markedly reduced despite endoplasmic reticulum (ER) stress, hypoxia, adipocyte hypertrophy, and Jun NH2-terminal kinase activation. Furthermore, bone marrow transplant studies reveal that these improvements in obese αHZ mice are independent of reduced Pik3r1 expression in the hematopoietic compartment. Taken together, these studies demonstrate that Pik3r1 expression plays a critical role in mediating AT insulin sensitivity and, more so, suggest that reduced PI3K activity is a key step in the initiation and propagation of the inflammatory response in obese AT.
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影响因子：
82.9
作者：
Arkan, MC;Hevener, AL;Karin, M
通讯作者：
Karin, M
影响因子：
15.9
作者：
Crossno, Joseph T., Jr.;Majka, Susan M.;Klemm, Dwight J.
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Klemm, Dwight J.
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7.7
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Kim JB
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10.8
作者：
Kuckleburg, Christopher J.;Yates, Clara M.;Rainger, George Ed
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Rainger, George Ed
影响因子：
15.9
作者：
Mauvais-Jarvis, F;Ueki, K;Kahn, CR
通讯作者：
Kahn, CR