Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

Christina Camell, Jil Sander, Olga Spadaro, Aileen Lee, Kim Y. Nguyen, Allison Wing, Emily L. Goldberg, Yun Hee Youm, Chester W. Brown, John Elsworth, Matthew S. Rodeheffer, Joachim L. Schultze, Vishwa Deep Dixit

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Catecholamine-induced lipolysis, the first step in the generation of energy substrates by the hydrolysis of triglycerides1, declines with age2,3. 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 unknown2,4. Here we show that adipose tissue macrophages regulate the agerelated reduction in adipocyte lipolysis in mice by lowering the bioavailability of noradrenaline. Unexpectedly, unbiased wholetranscriptome 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.

Original languageEnglish (US)
Pages (from-to)119-123
Number of pages5
JournalNature
Volume550
Issue number7674
DOIs
StatePublished - Oct 5 2017
Externally publishedYes

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Inflammasomes
Lipolysis
Catecholamines
Macrophages
Growth Differentiation Factor 3
Monoamine Oxidase
Norepinephrine
Adipocytes
Adipose Tissue
Sterol Esterase
Caspase 1
Sympathetic Nervous System
Adiposity
Starvation
Body Temperature
Lipase
Nonesterified Fatty Acids
Biological Availability
Hydrolysis
Up-Regulation

Cite this

Camell, C., Sander, J., Spadaro, O., Lee, A., Nguyen, K. Y., Wing, A., ... Dixit, V. D. (2017). Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature, 550(7674), 119-123. https://doi.org/10.1038/nature24022

Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. / Camell, Christina; Sander, Jil; Spadaro, Olga; Lee, Aileen; Nguyen, Kim Y.; Wing, Allison; Goldberg, Emily L.; Youm, Yun Hee; Brown, Chester W.; Elsworth, John; Rodeheffer, Matthew S.; Schultze, Joachim L.; Dixit, Vishwa Deep.

In: Nature, Vol. 550, No. 7674, 05.10.2017, p. 119-123.

Research output: Contribution to journalArticle

Camell, C, Sander, J, Spadaro, O, Lee, A, Nguyen, KY, Wing, A, Goldberg, EL, Youm, YH, Brown, CW, Elsworth, J, Rodeheffer, MS, Schultze, JL & Dixit, VD 2017, 'Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing', Nature, vol. 550, no. 7674, pp. 119-123. https://doi.org/10.1038/nature24022
Camell, Christina ; Sander, Jil ; Spadaro, Olga ; Lee, Aileen ; Nguyen, Kim Y. ; Wing, Allison ; Goldberg, Emily L. ; Youm, Yun Hee ; Brown, Chester W. ; Elsworth, John ; Rodeheffer, Matthew S. ; Schultze, Joachim L. ; Dixit, Vishwa Deep. / Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. In: Nature. 2017 ; Vol. 550, No. 7674. pp. 119-123.
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AU - Wing, Allison

AU - Goldberg, Emily L.

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