Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing.
Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing.
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DOI：
10.1038/nature24022
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发表时间：
2017-10-05
期刊：
影响因子：
64.8
通讯作者：
Dixit VD
中科院分区：
文献类型：
--
作者：
Camell CD;Sander J;Spadaro O;Lee A;Nguyen KY;Wing A;Goldberg EL;Youm YH;Brown CW;Elsworth J;Rodeheffer MS;Schultze JL;Dixit VD
儿茶酚胺诱导的脂解是通过甘油三酯（TG）水解产生能量底物的第一步，随着年龄的增长而下降。老年人游离脂肪酸（FFA）动员的缺陷伴随着内脏肥胖增加、运动能力降低、冷应激时不能维持核心体温以及饥饿生存能力降低。虽然老年人脂肪细胞中的儿茶酚胺信号是正常的，但脂肪分解在衰老中如何受损仍不清楚。在这里，我们发现，脂肪组织巨噬细胞（ATM）通过降低去甲肾上腺素（NE）的生物利用度来调节与年龄相关的脂肪细胞脂解减少。出乎意料的是，脂肪巨噬细胞的无偏全转录组分析显示，衰老以NLRP 3炎性小体依赖性方式上调控制儿茶酚胺降解的基因。衰老过程中NLRP 3的缺失通过下调生长分化因子3（GDF 3）和已知降解NE的单胺氧化酶-a（MAOA）恢复了儿茶酚胺诱导的脂解作用。与此一致，在炎性小体激活的巨噬细胞中GDF 3的缺失通过减少MAOA和半胱天冬酶-1来改善脂解。此外，MAOA的抑制逆转了脂肪组织NE浓度的年龄相关性降低，并恢复了脂解，增加了关键脂解酶，脂肪甘油三酯脂肪酶（ATGL）和激素敏感脂肪酶（HSL）的水平。我们的研究表明，靶向交感神经系统和巨噬细胞之间的神经先天信号可能提供新的途径，以减轻慢性炎症引起的代谢障碍和功能下降。
Catecholamine-induced lipolysis, the first step in generation of energy substrates through hydrolysis of triglycerides (TGs) , declines with age . The defect in mobilization of free fatty acids (FFA) in elderly is accompanied with increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. While catecholamine signaling in adipocytes is normal in elderly, how lipolysis is impaired in aging remains unknown . Here we uncover that the adipose tissue macrophages (ATMs) regulate age-related reduction in adipocyte lipolysis by lowering the bioavailability of norepinephrine (NE). Unexpectedly, unbiased whole transcriptome analyses of adipose macrophages revealed that aging upregulates genes controlling catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in aging restored catecholamine-induced lipolysis through downregulation of growth differentiation factor-3 (GDF3) and monoamine oxidase-a (MAOA) that is known to degrade NE. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing MAOA and caspase-1. Furthermore, inhibition of MAOA reversed age-related reduction in adipose tissue NE concentration and restored lipolysis with increased levels of key lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-innate signaling between sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.
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影响因子：
3.3
作者：
ELSWORTH, JD;DEUTCH, AY;ROTH, RH
通讯作者：
ROTH, RH
巨噬细胞的局部扩散有助于与肥胖相关的脂肪组织炎症。
影响因子：
29
作者：
Amano SU;Cohen JL;Vangala P;Tencerova M;Nicoloro SM;Yawe JC;Shen Y;Czech MP;Aouadi M
通讯作者：
Aouadi M
影响因子：
64.5
作者：
Rodeheffer, Matthew S.;Birsoy, Kivanc;Friedman, Jeffrey M.
通讯作者：
Friedman, Jeffrey M.
影响因子：
7.7
作者：
Mowers J;Uhm M;Reilly SM;Simon J;Leto D;Chiang SH;Chang L;Saltiel AR
通讯作者：
Saltiel AR
影响因子：
64.5
作者：
Lavin Y;Winter D;Blecher-Gonen R;David E;Keren-Shaul H;Merad M;Jung S;Amit I
通讯作者：
Amit I