Institute of Metabolic Science, MDU MRC, University of Cambridge Metabolic Research Laboratories, Cambridge, United Kingdom.
Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Wageningen, the Netherlands.
FASEB J. 2021 Feb;35(2):e21266. doi: 10.1096/fj.202001101R.
Tissue-resident macrophages are required for homeostasis, but also contribute to tissue dysfunction in pathophysiological states. The sympathetic neurotransmitter norepinephrine (NE) induces an anti-inflammatory and tissue-reparative phenotype in macrophages. As NE has a well-established role in promoting triglyceride lipolysis in adipocytes, and macrophages accumulate triglyceride droplets in various physiological and disease states, we investigated the effect of NE on primary mouse bone marrow-derived macrophage triglyceride metabolism. Surprisingly, our data show that in contrast to the canonical role of NE in stimulating lipolysis, NE acting via beta2-adrenergic receptors (B2ARs) in macrophages promotes extracellular fatty acid uptake and their storage as triglycerides and reduces free fatty acid release from triglyceride-laden macrophages. We demonstrate that these responses are mediated by a B2AR activation-dependent increase in Hilpda and Dgat1 gene expression and activity. We further show that B2AR activation favors the storage of extracellular polyunsaturated fatty acids. Finally, we present evidence that macrophages isolated from hearts after myocardial injury, for which survival critically depends on leukocyte B2ARs, have a transcriptional signature indicative of a transient triglyceride accumulation. Overall, we describe a novel and unexpected role of NE in promoting triglyceride storage in macrophages that could have potential implications in multiple diseases.
组织驻留巨噬细胞对于维持内环境稳定是必需的，但在病理生理状态下也会导致组织功能障碍。交感神经递质去甲肾上腺素（NE）可诱导巨噬细胞表现出抗炎和组织修复表型。由于 NE 在促进脂肪细胞中甘油三酯分解方面具有明确的作用，并且巨噬细胞在各种生理和疾病状态下会积累甘油三酯滴，因此我们研究了 NE 对原代小鼠骨髓来源巨噬细胞甘油三酯代谢的影响。令人惊讶的是，我们的数据表明，与 NE 刺激脂肪分解的典型作用相反，NE 通过巨噬细胞中的β2 肾上腺素能受体（B2AR）发挥作用，可促进细胞外脂肪酸摄取，并将其储存为甘油三酯，同时减少富含甘油三酯的巨噬细胞中游离脂肪酸的释放。我们证明这些反应是由 B2AR 激活依赖性增加 Hilpda 和 Dgat1 基因表达和活性介导的。我们进一步表明，B2AR 激活有利于细胞外多不饱和脂肪酸的储存。最后，我们提供的证据表明，心肌损伤后分离的心肌中的巨噬细胞具有一种转录特征，表明其甘油三酯会短暂积累，而白细胞 B2AR 的存活对其至关重要。总体而言，我们描述了 NE 在促进巨噬细胞中甘油三酯储存方面的新的、意想不到的作用，这可能对多种疾病具有潜在意义。
