Letter | Published:

Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

Nature volume 550, pages 119123 (05 October 2017) | Download Citation


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 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.

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We thank R. Medzhitov and T. Horvath for presubmission review of the manuscript, and V. M. Dixit at Genentech Inc for providing the anti-caspase-1 antibody and the Nlrp3-deficient mice. We also thank S. Baindur for graphics, S. Sidorov, S. Valle Torres, P. Günther, K. Klee and T. Ulas for support in bioinformatics analyses, The Yale Center on Genomic Analysis (YCGA) for RNA-seq studies and the P. Cresswell laboratory for confocal microscopy support. J.L.S. was funded by the German Research Foundation (SFB704, SFB645) and by the ImmunoSensation Cluster of Excellence Bonn. C.C. was supported by NIA postdoctoral training fellowship under AG043608. E.L.G was supported by AFAR (American Federation of Aging Research). The Dixit laboratory is supported in part by NIH grants P01AG051459, AI105097, AG051459, AR070811, the Glenn Foundation on Aging Research and Cure Alzheimer’s Fund.

Author information


  1. Department of Comparative Medicine, Yale School of Medicine, New Haven, Connecticut 06520, USA

    • Christina D. Camell
    • , Olga Spadaro
    • , Aileen Lee
    • , Kim Y. Nguyen
    • , Emily L. Goldberg
    • , Yun-Hee Youm
    • , Matthew S. Rodeheffer
    •  & Vishwa Deep Dixit
  2. Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut 06520, USA

    • Christina D. Camell
    • , Olga Spadaro
    • , Aileen Lee
    • , Kim Y. Nguyen
    • , Emily L. Goldberg
    • , Yun-Hee Youm
    •  & Vishwa Deep Dixit
  3. Genomics and Immunoregulation, LIMES-Institute, University of Bonn, 53115, Bonn, Germany

    • Jil Sander
    •  & Joachim L. Schultze
  4. Department of Molecular, Cellular and Developmental Biology, Yale School of Medicine, New Haven, Connecticut 06520, USA

    • Allison Wing
  5. Genetics Division, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA

    • Chester W. Brown
  6. Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut 06520, USA

    • John Elsworth
  7. Single Cell Genomics and Epigenomics Unit at the University of Bonn and the German Center for Neurodegenerative Diseases, Bonn, Germany

    • Joachim L. Schultze
  8. Yale Center for Research on Aging, Yale School of Medicine, New Haven, Connecticut 06520, USA

    • Vishwa Deep Dixit


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C.D.C. carried out most experiments. O.S., E.L.G., K.Y.N. and Y.-H.Y. helped with experiments. A.W. and M.S.R. generated adipocytes from sorted progenitors and helped with co-culture experiments. C.W.B. generated the Gdf3 mouse model. A.L. and O.S. performed whole-mount confocal microscopy. J.E. measured noradrenaline using HPLC. J.S. and J.L.S. performed the bioinformatics analysis and interpretation. C.D.C. and V.D.D. conceived the project, analysed data and wrote the manuscript with input from all co-authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Vishwa Deep Dixit.

Reviewer Information Nature thanks M. Montminy, L. O’Neill, R. Zechner and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    This file contains full scans for all western blots (figures 4b, h, i and extended data figures 1i, j, 2e, 8e.

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