Unique metabolic activation of adipose tissue macrophages in obesity promotes inflammatory responses.
Unique metabolic activation of adipose tissue macrophages in obesity promotes inflammatory responses.
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DOI：
10.1007/s00125-017-4526-6
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发表时间：
2018-04
期刊：
影响因子：
8.2
通讯作者：
Stienstra R
中科院分区：
文献类型：
--
作者：
Boutens L;Hooiveld GJ;Dhingra S;Cramer RA;Netea MG;Stienstra R
最近的研究已经确定细胞内代谢是巨噬细胞功能的基本决定因素。在肥胖症中，促炎性巨噬细胞在脂肪组织中积累并触发慢性低度炎症，这促进了全身性胰岛素抵抗的发展，但其细胞内能量代谢的变化目前尚不清楚。因此，我们着手研究瘦和肥胖条件下脂肪组织巨噬细胞（ATM）的代谢特征。F4/80阳性ATM分离自肥胖小鼠与瘦小鼠。高脂喂养野生型小鼠和骨髓特异性Hif 1 α−/−小鼠，以检测缺氧诱导因子-1 α（HIF-1α）在肥胖脂肪组织ATM部分中的作用。在体外，骨髓来源的巨噬细胞与脂肪组织外植体共培养，以检查脂肪组织诱导的巨噬细胞表型的变化。转录组分析，实时流量测量，ELISA和其他几种方法用于确定巨噬细胞的代谢特征和炎症状态。此外，抑制各种代谢途径，以确定其与细胞因子产生的相关性。小鼠ATM的转录组分析和细胞外通量测量揭示了肥胖症中独特的代谢重新布线，其特征在于糖酵解和氧化磷酸化增加。肥胖个体中类似的CD 14+细胞代谢活化与糖尿病结局相关。在肥胖小鼠与瘦小鼠的腹腔巨噬细胞中未观察到这些变化，并且与M1引发的巨噬细胞中的代谢重新布线不相似。相反，巨噬细胞的代谢活化是由一组脂肪组织来源的因子诱导的，这些因子不能被还原为瘦素或乳酸。使用代谢抑制剂，我们确定了各种代谢途径，包括脂肪酸氧化，糖酵解和γ-氨基丁酸解，这有助于细胞因子释放的ATM在瘦肉脂肪组织。糖酵解似乎是肥胖脂肪组织中巨噬细胞促炎特性的主要贡献者。然而，糖酵解的关键调节因子HIF-1α似乎在肥胖早期ATM的促炎激活中没有发挥关键作用。我们的研究结果揭示了肥胖症中ATM的独特代谢活化，促进炎症细胞因子的释放。对ATM中代谢程序的进一步理解将很可能导致新的治疗靶点，以减少肥胖症的炎症反应。从肥胖或瘦小鼠中分离的ATM的微阵列数据已提交给基因表达综合库（登录号GSE 84000）。本文的在线版本（10.1007/s 00125 -017-4526-6）包含同行评审但未经编辑的补充材料，可供授权用户使用。
Recent studies have identified intracellular metabolism as a fundamental determinant of macrophage function. In obesity, proinflammatory macrophages accumulate in adipose tissue and trigger chronic low-grade inflammation, that promotes the development of systemic insulin resistance, yet changes in their intracellular energy metabolism are currently unknown. We therefore set out to study metabolic signatures of adipose tissue macrophages (ATMs) in lean and obese conditions. F4/80-positive ATMs were isolated from obese vs lean mice. High-fat feeding of wild-type mice and myeloid-specific Hif1α−/− mice was used to examine the role of hypoxia-inducible factor-1α (HIF-1α) in ATMs part of obese adipose tissue. In vitro, bone marrow-derived macrophages were co-cultured with adipose tissue explants to examine adipose tissue-induced changes in macrophage phenotypes. Transcriptome analysis, real-time flux measurements, ELISA and several other approaches were used to determine the metabolic signatures and inflammatory status of macrophages. In addition, various metabolic routes were inhibited to determine their relevance for cytokine production. Transcriptome analysis and extracellular flux measurements of mouse ATMs revealed unique metabolic rewiring in obesity characterised by both increased glycolysis and oxidative phosphorylation. Similar metabolic activation of CD14+ cells in obese individuals was associated with diabetes outcome. These changes were not observed in peritoneal macrophages from obese vs lean mice and did not resemble metabolic rewiring in M1-primed macrophages. Instead, metabolic activation of macrophages was dose-dependently induced by a set of adipose tissue-derived factors that could not be reduced to leptin or lactate. Using metabolic inhibitors, we identified various metabolic routes, including fatty acid oxidation, glycolysis and glutaminolysis, that contributed to cytokine release by ATMs in lean adipose tissue. Glycolysis appeared to be the main contributor to the proinflammatory trait of macrophages in obese adipose tissue. HIF-1α, a key regulator of glycolysis, nonetheless appeared to play no critical role in proinflammatory activation of ATMs during early stages of obesity. Our results reveal unique metabolic activation of ATMs in obesity that promotes inflammatory cytokine release. Further understanding of metabolic programming in ATMs will most likely lead to novel therapeutic targets to curtail inflammatory responses in obesity. Microarray data of ATMs isolated from obese or lean mice have been submitted to the Gene Expression Omnibus (accession no. GSE84000). The online version of this article (10.1007/s00125-017-4526-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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