Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

Nature. 2017 Oct 5;550(7674):119-123. doi: 10.1038/nature24022. Epub 2017 Sep 27.


Catecholamine-induced lipolysis, the first step in the generation of energy substrates by the hydrolysis of triglycerides, declines with age. 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. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism*
  • Adipose Tissue / cytology
  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism*
  • Aging / drug effects
  • Aging / genetics
  • Aging / metabolism*
  • Animals
  • Caspase 1 / metabolism
  • Catecholamines / metabolism*
  • Catecholamines / pharmacology
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Growth Differentiation Factor 3 / deficiency
  • Growth Differentiation Factor 3 / genetics
  • Growth Differentiation Factor 3 / metabolism
  • Inflammasomes / metabolism*
  • Lipase / metabolism
  • Lipolysis* / drug effects
  • Lipolysis* / genetics
  • Macrophages / metabolism*
  • Mice
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors / pharmacology
  • NLR Family, Pyrin Domain-Containing 3 Protein / deficiency
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Norepinephrine / metabolism
  • Sterol Esterase / metabolism


  • Catecholamines
  • Gdf3 protein, mouse
  • Growth Differentiation Factor 3
  • Inflammasomes
  • Monoamine Oxidase Inhibitors
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Monoamine Oxidase
  • Sterol Esterase
  • Lipase
  • PNPLA2 protein, mouse
  • Caspase 1
  • Norepinephrine