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Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

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 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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Figure 1: Adipose tissue macrophages drive lipolysis resistance during ageing.
Figure 2: NLRP3 inflammasome activation is required for lipolysis resistance.
Figure 3: NLRP3 inflammasome regulates catecholamine degradation genes in aged ATMs.
Figure 4: GDF3 dependent increased MAOA expression impairs lipolysis in ageing.

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Acknowledgements

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

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Vishwa Deep Dixit.

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The authors declare no competing financial interests.

Additional information

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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Extended data figures and tables

Extended Data Figure 1 Age-related adipose tissue defects in response to fasting.

Data are related to Fig. 1. a, Body weight after 24 h feeding or fasting. n = 13 4-month fed; n = 10 21-month fed; n = 16 21-month fasted; n = 11 21-month fasted pooled from 2 independent experiments. b, Percentage body weight change after 24 h fasting. n = 13 4-month fed; n = 10 21-month fed; n = 16 21-month fasted; n = 11 21-month fasted pooled from 2 independent experiments. c, Blood glucose. n = 6 4-month fed; n = 6 21-month fed; n = 8 21-month fasted; n = 7 21-month fasted. d, Percentage change in blood glucose after feeding or fasting. n = 6 4-month fed; n = 6 21-month fed; n = 8 21-month fasted; n = 7 21-month fasted. e, VAT weight, displayed as a percentage of fed. n = 13 4-month fed; n = 10 21-month fed; n = 16 21-month fast; n = 11 21-month fasted pooled from 2 independent experiments. f, Serum FFA levels in fed and fasted mice. Data are pooled from 4 independent experiments. n = 23 4-month fed; n = 13 21-month fed; n = 26 4-month fasted; n = 13 21-month fasted. Each symbol represents an individual mouse. g, Body-weight, VAT weight, serum FFA levels, glycerol and FFA release from VAT explants in 4-month-old fed, 12-h fasted or 24-h fasted animals. Data are pooled from 2 independent experiments. n = 10 fed; n = 10 12-h fasted; n = 5 24-h fasted. h, Hsl and Atgl gene expression in floating adipocytes isolated from VAT of 4- (black) or 21- (red) month-old mice that were fed or fasted for 24 h. n = 5 4-month fed; n = 6 21-month fed; n = 6 4-month fasted; n = 9 21-month fasted pooled from 2 independent experiments. i, Western blot of lipolytic signalling pathway (pHSL, HSL, ATGL) in VAT from 4- or 21-month-old mice fed or fasted for 12 h. Each lane is an individual animal that received indicated treatment. Actin was probed for as a loading control. Representative of one experiment. j, Western blot of lipolytic signalling pathway (pHSL, HSL, ATGL) in VAT explants from 4- or 21-month-old fed mice that were left unstimulated or stimulated with 1 μM noradrenaline. Each lane represents a biological replicate. Representative of two individual experiments. Actin was probed for as a loading control. In all graphs (ah), each symbol represents an individual mouse and data are mean ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, Tukey’s test (ah).

Extended Data Figure 2 Age-related changes in ATMs in response to fasting.

Data are related to Fig. 1. a, Representative gating strategy for ATM analyses. b, Representative contour plots of CD206 and CD11c expression within F4/80+CD11b+ ATMs from VAT of fed or fasted mice. Values denote mean for each condition from 2 individual experiments. Exact n values are shown in the Methods. c, Quantification of CD11c+CD206 (top) and CD11c+CD206+ (bottom) populations from b, expressed as a percentage of total F4/80+ CD11b+ cells. Data are mean ± s.e.m. and pooled from two independent experiments. Each symbol represents an independent biological sample pooled from 1–4 mice; exact n values are shown in parentheses and in the Methods. ***P < 0.001, ****P < 0.0001, Tukey’s test, d, FFA release from 3- or 21-month-old fasted VAT explants that were co-cultured with sorted ATMs from 3-month-old adipose. Data are mean ± s.e.m. Exact n values (biological replicates) are shown in parentheses and are combined from three individual experiments. *P < 0.05, Student’s t-test. e, Western blot of MAOA in VAT from 4- or 21-month-old mice that were fasted for 24 h. Each lane represents an individual animal. A short (5 min; top) and long (30 min; middle) exposure are shown for clarity. Actin was probed for as a loading control. Representative of one independent experiment.

Extended Data Figure 3 ATMs are unique tissue-resident macrophage cell type.

a, Workflow, related to Fig. 2. b, PCA based on 13,954 present genes revealing the distribution of samples according to tissue origin and age. c, Heat map of differentially expressed genes between 24- and 3-month-old macrophages in VAT or spleen using a fold change < −1.5 or > 1.5 and an FDR-adjusted P < 0.05. Expression values were z-transformed and scaled to a minimum of −2 and a maximum of 2. Rows and columns were ordered based on hierarchical clustering. d, Heat map of the 1,000 most variable genes. Expression values were z-transformed and scaled to a minimum of −2 and a maximum of 2. Rows and columns were ordered based on hierarchical clustering. e, PCA based on 13,846 present genes of a combined dataset containing the four mouse macrophage populations defined by origin and age and a compendium of mouse tissue-resident macrophages of seven different organs (GEO accession GSE63340).

Extended Data Figure 4 Aged ATMs express distinct transcriptome.

a, Workflow, related to Fig. 2. b, Co-expression networks based on 1,887 variable genes having a correlation of at least 0.98 to at least one other gene. For each condition, the fold change compared to the overall mean was mapped onto the networks, ranging from blue (negative fold change) to red (positive fold change). Circles indicate the subclusters, which were identified for each condition. c, Heat map of lipid metabolism-related genes in VAT and splenic macrophages. Expression values were z-transformed and scaled to a minimum of −1.41 and a maximum of 1.41. Genes were ordered by hierarchical clustering.

Extended Data Figure 5 Myeloid cell changes in aged Nlrp3−/− mice.

Data relate to Fig. 3. a, Representative contour plots showing CD206 and CD11c expression, gated through F4/80+CD11b+ cells, from VAT of fasted wild-type and Nlrp3−/− mice. Values represent mean percentage in that quadrant. n values are shown in the Methods. b, Quantification of CD11c+CD206 (top) and CD11c+CD206+ (bottom) cells gated through F4/80+CD11b+ cells from VAT of fasted wild-type (filled) and Nlrp3−/− (open) mice. Data are mean ± s.e.m. c, B220MHCII+CD11c+ frequency as percentages of the stromal vascular fraction of wild-type (filled) and Nlrp3−/− (open) mice at 3 or 24 months of age. Data are mean ± s.e.m. n values are shown in parentheses and in the Methods. d, Percentages of F4/80+CD11b+ cells in the spleen of wild-type and Nlrp3−/− mice at 5 or 24 months of age, which were fed (filled) or fasted (fasted) for 24 h. Data are mean ± s.e.m. n values are shown in parentheses and represent individual mice. e, Quantification of CD206 and CD11c expression, based on percentages of F4/80+CD11b+ cells, from spleen of fasted wild-type (filled) or Nlrp3−/− (open) mice. Data are mean ± s.e.m. Exact n values are shown in parentheses the figure. *P < 0.05, **P < 0.01, ****P < 0.0001, Tukey’s test.

Extended Data Figure 6 Nlrp3 regulation of age-induced genes in ATMs.

Data relate to Fig. 3. a, Workflow for RNA-seq data analysis. b, Left, PCA based on 13,129 present genes revealing the distribution of VAT macrophage populations from three different age/genotype groups. Right, heat map of the 1,000 most variable genes in VAT macrophage populations compared between all three groups. Expression values were z-transformed and scaled to a minimum of −2 and a maximum of 2. Rows and columns were ordered based on hierarchical clustering. c, Left, PCA based on 13,169 present genes reveals the distribution of splenic macrophage populations from three different age/genotype groups. Right, heat map of the 1,000 most variable genes in splenic macrophage populations compared between all three groups. Expression values were z-transformed and scaled to a minimum of −2 and a maximum of 2. Rows and columns were ordered based on hierarchical clustering. d, e, Venn diagrams comparing genes being up- (fold change > 2, left) or downregulated (fold change < −2, right) in 24- compared to 3-month wild-type macrophages with genes being down- (fold change < −2, left) or upregulated (fold change > 2, right) in 24-month Nlrp3−/− compared to 24-month wild-type macrophages in VAT (d) or spleen (e). f, Heat maps showing the expression patterns of the top 20 upregulated (left) or downregulated (right) genes (from e) to be rescued by Nlrp3-deficiency in splenic macrophages. Expression values were z-transformed and scaled to a minimum of −1.15 and a maximum of 1.15. Genes were ranked according to expression in 24-month wild-type splenic macrophages.

Extended Data Figure 7 NLRP3 regulation of senescence and lipid-associated genes in ATMs and splenic macrophages.

a, Workflow, related to Fig. 3. b, Bar chart displaying the fold change between 24- and 3-month wild-type VAT macrophages (pink) and 24-month Nlrp3−/− and wild-type VAT macrophages (turquoise) for senescence-associated genes. Horizontal dashed lines indicate fold changes of 1.5 and −1.5, respectively. c, Heat map of lipid metabolism-related genes in VAT macrophages. Expression values were z-transformed and scaled to a minimum of −1.15 and a maximum of 1.15. Genes were ranked according to hierarchical clustering. d, Heat map of present genes of the spleen macrophage dataset linked to Maoa, Comt, Aldh or Akr families in splenic macrophages. Expression values were z-transformed and scaled to a minimum of −1.15 and a maximum of 1.15. Rows are in the same order as in Fig. 3c, and genes that are not present in the spleen dataset are left blank.

Extended Data Figure 8 Mechanism for GDF3 inhibition of NLRP3 inflammasome activation.

Data relate to Fig. 4. a, Left, Pcsk6 mean expression, from RNA-seq analysis, from sorted ATMs in 3-month wild-type, and 24-month wild-type or Nlrp3−/− VAT. Data are mean ± s.e.m. n values are in the Methods. Right, schematic depicting the interaction between macrophage–PCSK6 and GDF3 and action on adipocyte lipolysis. b, Densitometric quantification of pro-caspase-1 (left) and active p20 caspase-1 (right) immunoblots depicted in Fig. 4b, normalized to actin, in wild-type (filled) or Gdf3−/− (open) BMDMs treated with LPS or LPS plus ATP. Data are mean ± s.e.m. and show n = 3 (WT) and n = 4 (Gdf3−/−) biological replicates. c, Casp1 gene expression in LPS-treated BMDMs generated from wild-type (black) or Gdf3−/− (grey) mice. Data are pooled from 2 independent experiments, each with n = 3 and n = 2 biological replicates, and expressed as mean ± s.e.m. d, Il1b gene expression in LPS-treated BMDMs generated from wild-type (black) or Gdf3−/− (grey) mice and displayed as fold change to untreated BMDMs. Data are pooled from 3 independent experiments, each with n = 3, n = 4 and n = 3 biological replicates, and expressed as mean ± s.e.m. e, Immunoblot showing phopho-p65, total p65, and IκB-α expression in LPS-treated wild-type or Gdf3−/− BMDMs. Representative of one independent experiment. f, Maoa gene expression in wild-type or Gdf3−/− BMDMs that have left untreated. Data are mean ± s.e.m. and pooled from 2 individual experiments. Each symbol represents a biological replicate. *P < 0.05, **P < 0.01, ***P < 0.0001, Tukey’s test (a, b) or Student’s t-test (c, d, f).

Extended Data Figure 9 Schematic to show nerve-associated macrophages and role in aged adipose.

Data relate to Fig. 4. a, Schematic of the mT/mG construct before (top) and after (bottom) Cre-mediated recombination in the LysM-cre+ myeloid cells. LysM-cre+ mT/mG+ traces the myeloid cells with membrane green fluorescence protein (mG, green), whereas LysM-cre mT/mG+ cells that lack Cre recombination indelibly express tomato (mT, red). b, Single-colour images of merged image from Fig. 4e. Use of LysM-cre mT/mG reporter mouse plus antibody staining enabled visualization of all cells (mTomato, red), myeloid cells (mGFP, green), tyrosine hydroxylase (TH)-expressing (blue) and TUBB3-expressing (white) nerves. Representative of 6 independent experiments. c, Schematic representing the model. In young adipose, fasting initiates catecholamine release from sympathetic nerves. Binding of catecholamines on β-adrenergic receptors (β-ARs) causes intracellular cAMP increases, activation of PKA and downstream signalling lipases (ATGL, HSL and MGL), and results in the hydrolysis of triglyceride and release of fatty acid (FA) and glycerol. Lipolysis and FFA release are necessary fuel elements for survival during starvation, and promote cold and exercise tolerance. During ageing, there is an increase in inflammatory danger-associated-molecular patters (DAMPs), leading to the activation of the NLRP3 inflammasome in adipose tissue macrophages. NLRP3-dependent increases in GDF3 and MAOA result in degradation of noradrenaline, prevent noradrenaline activation of lipolytic signalling in adipocytes and cause reduced fatty acid and glycerol release. Inset, the pathway for MAOA-driven degradation of noradrenaline into dihydroxyphenylglycolaldehyde (DOPEGAL), and subsequent breakdown into dihydroxymandelic acid (DHMA) and dihydroxyphenyl glycol (DHPG) by aldehyde dehydrogenases (ALDs) and aldo-keto reductases (AKRs). DG, diglyceride; MG, monoglyceride; TG, triglyceride.

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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. (PDF 6442 kb)

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Camell, C., Sander, J., Spadaro, O. et al. Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature 550, 119–123 (2017). https://doi.org/10.1038/nature24022

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