Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

被引:394
作者
Camell, Christina D. [1 ,2 ]
Sander, Jil [3 ]
Spadaro, Olga [1 ,2 ]
Lee, Aileen [1 ,2 ]
Nguyen, Kim Y. [1 ,2 ]
Wing, Allison [4 ]
Goldberg, Emily L. [1 ,2 ]
Youm, Yun-Hee [1 ,2 ]
Brown, Chester W. [5 ]
Elsworth, John [6 ]
Rodeheffer, Matthew S. [1 ]
Schultze, Joachim L. [3 ,7 ,8 ]
Dixit, Vishwa Deep [1 ,2 ,9 ]
机构
[1] Yale Sch Med, Dept Comparat Med, New Haven, CT 06520 USA
[2] Yale Sch Med, Dept Immunobiol, New Haven, CT 06520 USA
[3] Univ Bonn, LIMES Inst, Genom & Immunoregulat, D-53115 Bonn, Germany
[4] Yale Sch Med, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA
[5] Univ Tennessee, Ctr Hlth Sci, Dept Pediat, Div Genet, Memphis, TN 38163 USA
[6] Yale Sch Med, Dept Psychiat, New Haven, CT 06520 USA
[7] Univ Bonn, Single Cell Genom & Epigen Unit, Bonn, Germany
[8] German Ctr Neurodegenerat Dis, Bonn, Germany
[9] Yale Sch Med, Yale Ctr Res Aging, New Haven, CT USA
关键词
ADIPOSE-TISSUE; MONOAMINE-OXIDASE; OBESITY; CELLS; AGE; IDENTIFICATION; ACCUMULATION; DEFICIENCY; ACTIVATION; PROTECTS;
D O I
10.1038/nature24022
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];
摘要
Catecholamine-induced lipolysis, the first step in the generation of energy substrates by the hydrolysis of triglycerides(1), declines with age(2,3). The defect in the mobilization of free fatty acids in the elderly is accompanied by increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. Although catecholamine signalling in adipocytes is normal in the elderly, how lipolysis is impaired in ageing remains unknown(2,4). Here we show that adipose tissue macrophages regulate the age-related reduction in adipocyte lipolysis in mice by lowering the bioavailability of noradrenaline. Unexpectedly, unbiased whole-transcriptome analyses of adipose macrophages revealed that ageing upregulates genes that control catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in ageing restored catecholamine-induced lipolysis by downregulating growth differentiation factor-3 (GDF3) and monoamine oxidase A (MAOA) that is known to degrade noradrenaline. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing levels of MAOA and caspase-1. Furthermore, inhibition of MAOA reversed the age-related reduction in noradrenaline concentration in adipose tissue, and restored lipolysis with increased levels of the key lipolytic enzymes adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-immunometabolic signalling between the sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.
引用
收藏
页码:119 / +
页数:20
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