Pro-inflammatory macrophages coupled with glycolysis remodel adipose vasculature by producing platelet-derived growth factor-B in obesity
Pro-inflammatory macrophages coupled with glycolysis remodel adipose vasculature by producing platelet-derived growth factor-B in obesity
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DOI：
10.1038/s41598-019-57368-w
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发表时间：
2020-01-20
影响因子：
4.6
通讯作者：
Sasaoka, Toshiyasu
中科院分区：
文献类型：
--
作者：
Onogi, Yasuhiro;Wada, Tsutomu;Sasaoka, Toshiyasu
脂肪组织巨噬细胞（ATMs）在组织重塑和体内平衡中起着核心作用。然而，atm是否促进肥胖患者的脂肪血管生成仍不清楚。通过脂质体包封氯膦酸盐，研究了ATMs缺失对高脂饮食（HFD）喂养小鼠附睾白色脂肪组织（eWAT）脂肪血管生成和组织扩张的影响。我们进一步阐明了血小板衍生生长因子(PDGF)-B在巨噬细胞中对肥胖相关代谢应激的诱导机制，因为它在组织扩张过程中对周细胞行为的调控中起着重要作用，从而引发新生血管生成。在hfd喂养的小鼠中，ATM消耗通过抑制周细胞脱离血管来阻止脂肪组织扩张，导致eWAT血管减少。脂多糖（LPS）刺激和高葡萄糖浓度通过诱导Pdgfb mRNA增强葡萄糖掺入和糖酵解能力。这种作用是通过细胞外信号调节激酶（ERK）介导的，在RAW264.7巨噬细胞中，有丝分裂原激活的蛋白激酶与糖酵解相结合。Pdgfb诱导系统不同于由雷帕霉素复合物1 （mTORC1）和NF κ B信号传导介导的炎症细胞因子诱导系统。因此，肥胖相关的高血糖和慢性炎症刺激了促炎巨噬细胞中的ERK信号，并伴随着糖酵解，通过pdgf - b依赖性血管重塑促进eWAT的扩张。
Adipose tissue macrophages (ATMs) play a central role in tissue remodeling and homeostasis. However, whether ATMs promote adipose angiogenesis in obesity remains unclear. We examined the impact of ATMs deletion on adipose angiogenesis and tissue expansion in the epididymal white adipose tissue (eWAT) of high-fat diet (HFD)-fed mice by using liposome-encapsulated clodronate. We further elucidated the induction mechanisms of platelet-derived growth factor (PDGF)-B in macrophages in response to obesity-associated metabolic stresses, since it plays a significant role in the regulation of pericyte behavior for the initiation of neoangiogenesis during tissue expansion. ATM depletion prevented adipose tissue expansion in HFD-fed mice by inhibiting pericyte detachment from vessels, resulting in less vasculature in eWAT. The lipopolysaccharide (LPS) stimulation and high glucose concentration augmented glucose incorporation and glycolytic capacity with the induction of Pdgfb mRNA. This effect was mediated through extracellular signal-regulated kinase (ERK) among mitogen-activated protein kinases coupled with glycolysis in RAW264.7 macrophages. The Pdgfb induction system was distinct from that of inflammatory cytokines mediated by mechanistic target of rapamycin complex 1 (mTORC1) and NF kappa B signaling. Thus, obesity-associated hyperglycemia and chronic inflammation fuels ERK signaling coupled with glycolysis in pro-inflammatory macrophages, which contribute to the expansion of eWAT through PDGF-B-dependent vascular remodeling.