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Neutrophils preserve energy storage in sympathetically activated adipocytes

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Abstract

Adipose tissue maintains energy homeostasis by storing lipids during nutrient surplus and releasing them through lipolysis in times of energy demand1,2. While lipolysis is essential for short-term metabolic adaptation, prolonged metabolic stress requires adaptive changes that preserve energy reserves2,3. Here we report that β3-adrenergic activation of adipocytes induces a transient and depot-specific infiltration of neutrophils into white adipose tissue (WAT), particularly in lipid-rich visceral WAT. Neutrophil recruitment requires the stimulation of both lipolysis and p38 MAPK in adipocytes, and is mediated by the secretion of leukotriene B4. Recruited neutrophils undergo activation in situ, and locally secrete IL-1β, which suppresses lipolysis and limits excessive energy loss. Neutrophil depletion or blockade of IL-1β production increases lipolysis, leading to reduced WAT mass after repeated β3-adrenergic stimulation. Together, these findings reveal a role of neutrophil-derived IL-1β in preserving lipid stores during metabolic stress, highlighting a physiological function of innate immune cells in limiting lipid loss and maintaining energy homeostasis.

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Fig. 1: Sympathetic activation induces neutrophil infiltration and inflammatory cytokine expression in WAT.
Fig. 2: Adipocyte lipolysis–p38–LTB4 axis mediates neutrophil recruitment into visceral fat after β3-adrenergic stimulation.
Fig. 3: Infiltrated neutrophils produce IL-1β and limit excessive energy loss after β3-adrenergic activation.
Fig. 4: Neutrophil-derived IL-1β restrains lipolysis through catecholamine resistance in adipocytes.

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Data availability

All data supporting the findings of this study are available within the Article and its Supplementary Information. The Supplementary Information includes uncropped western blot scans, qPCR primer sequences and flow cytometry gating strategies. RNA-seq data generated in this paper have been deposited at the NCBI SRA (BioProject: PRJNA1345413). Mouse genome reference sequences used for read alignment were based on the mm10 (GRCm38) build. Publicly available human adipose tissue transcriptomic datasets were obtained from the Adipose Tissue Gene Expression Database (https://adiposetissue.org). Source data are provided with this paper.

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No custom code was used in this study.

References

  1. Sakers, A., De Siqueira, M. K., Seale, P. & Villanueva, C. J. Adipose-tissue plasticity in health and disease. Cell 185, 419–446 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Reilly, S. M. & Saltiel, A. R. Adapting to obesity with adipose tissue inflammation. Nat. Rev. Endocrinol. 13, 633–643 (2017).

    Article  CAS  PubMed  Google Scholar 

  3. Saltiel, A. R. & Olefsky, J. M. Inflammatory mechanisms linking obesity and metabolic disease. J. Clin. Invest. 127, 1–4 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Rohm, T. V., Meier, D. T., Olefsky, J. M. & Donath, M. Y. Inflammation in obesity, diabetes, and related disorders. Immunity 55, 31–55 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Man, K., Kallies, A. & Vasanthakumar, A. Resident and migratory adipose immune cells control systemic metabolism and thermogenesis. Cell. Mol. Immunol. 19, 421–431 (2022).

    Article  CAS  PubMed  Google Scholar 

  6. Wernstedt Asterholm, I. et al. Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab. 20, 103–118 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Burn, G. L., Foti, A., Marsman, G., Patel, D. F. & Zychlinsky, A. The neutrophil. Immunity 54, 1377–1391 (2021).

    Article  CAS  PubMed  Google Scholar 

  8. Nemeth, T., Sperandio, M. & Mocsai, A. Neutrophils as emerging therapeutic targets. Nat. Rev. Drug Discov. 19, 253–275 (2020).

    Article  CAS  PubMed  Google Scholar 

  9. Herro, R. & Grimes, H. L. The diverse roles of neutrophils from protection to pathogenesis. Nat. Immunol. 25, 2209–2219 (2024).

    Article  CAS  PubMed  Google Scholar 

  10. Kaplan, M. J. Of larks and owls. Nat. Immunol. 21, 104–105 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Janssen, H. et al. Monocytes re-enter the bone marrow during fasting and alter the host response to infection. Immunity 56, 783–796 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Brenner, I. K. et al. Immune changes in humans during cold exposure: effects of prior heating and exercise. J. Appl. Physiol. 87, 699–710 (1999).

    Article  CAS  PubMed  ADS  Google Scholar 

  13. Cho, J. S. et al. Neutrophil-derived IL-1β is sufficient for abscess formation in immunity against Staphylococcus aureus in mice. PLoS Pathog. 8, e1003047 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Swanson, K. V., Deng, M. & Ting, J. P. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat. Rev. Immunol. 19, 477–489 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dror, E. et al. Postprandial macrophage-derived IL-1β stimulates insulin, and both synergistically promote glucose disposal and inflammation. Nat. Immunol. 18, 283–292 (2017).

    Article  CAS  PubMed  Google Scholar 

  17. Zhou, H. et al. IL-1 induces mitochondrial translocation of IRAK2 to suppress oxidative metabolism in adipocytes. Nat. Immunol. 21, 1219–1231 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hofwimmer, K. et al. IL-1β promotes adipogenesis by directly targeting adipocyte precursors. Nat. Commun. 15, 7957 (2024).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  19. Roth Flach, R. J. et al. β3-adrenergic receptor stimulation induces E-selectin-mediated adipose tissue inflammation. J. Biol. Chem. 288, 2882–2892 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Silva, H. M. et al. Vasculature-associated fat macrophages readily adapt to inflammatory and metabolic challenges. J. Exp. Med. 216, 786–806 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Watanabe, Y. et al. Bidirectional crosstalk between neutrophils and adipocytes promotes adipose tissue inflammation. FASEB J. 33, 11821–11835 (2019).

    Article  CAS  PubMed  Google Scholar 

  22. Young, J. B., Saville, E., Rothwell, N. J., Stock, M. J. & Landsberg, L. Effect of diet and cold exposure on norepinephrine turnover in brown adipose tissue of the rat. J. Clin. Invest. 69, 1061–1071 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. King, V. L., Dwoskin, L. P. & Cassis, L. A. Cold exposure regulates the norepinephrine uptake transporter in rat brown adipose tissue. Am. J. Physiol. 276, R143–R151 (1999).

    CAS  PubMed  Google Scholar 

  24. Liu, X., Perusse, F. & Bukowiecki, L. J. Mechanisms of the antidiabetic effects of the β3-adrenergic agonist CL-316243 in obese Zucker-ZDF rats. Am. J. Physiol. 274, R1212–R1219 (1998).

    CAS  PubMed  Google Scholar 

  25. Weyer, C., Gautier, J. F. & Danforth, E. Jr. Development of β3-adrenoceptor agonists for the treatment of obesity and diabetes-an update. Diabetes Metab. 25, 11–21 (1999).

    CAS  PubMed  Google Scholar 

  26. Valentine, J. M. et al. β3-Adrenergic receptor downregulation leads to adipocyte catecholamine resistance in obesity. J. Clin. Invest. https://doi.org/10.1172/JCI153357 (2022).

  27. Muzzin, P. et al. An adipose tissue-specific beta-adrenergic receptor. Molecular cloning and down-regulation in obesity. J. Biol. Chem. 266, 24053–24058 (1991).

    Article  CAS  PubMed  Google Scholar 

  28. Nahmias, C. et al. Molecular characterization of the mouse beta 3-adrenergic receptor: relationship with the atypical receptor of adipocytes. EMBO J. 10, 3721–3727 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Carmen, G. Y. & Victor, S. M. Signalling mechanisms regulating lipolysis. Cell Signal. 18, 401–408 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Mottillo, E. P., Shen, X. J. & Granneman, J. G. β3-adrenergic receptor induction of adipocyte inflammation requires lipolytic activation of stress kinases p38 and JNK. Biochim. Biophys. Acta 1801, 1048–1055 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cao, W. et al. p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene. Mol. Cell. Biol. 24, 3057–3067 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Reilly, S. M. et al. Catecholamines suppress fatty acid re-esterification and increase oxidation in white adipocytes via STAT3. Nat. Metab. 2, 620–634 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Metzemaekers, M., Gouwy, M. & Proost, P. Neutrophil chemoattractant receptors in health and disease: double-edged swords. Cell. Mol. Immunol. 17, 433–450 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Reber, L. L. et al. Neutrophil myeloperoxidase diminishes the toxic effects and mortality induced by lipopolysaccharide. J. Exp. Med. 214, 1249–1258 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Flores, J., Noel, A., Foveau, B., Beauchet, O. & LeBlanc, A. C. Pre-symptomatic caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging. Nat. Commun. 11, 4571 (2020).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  36. Yang, X. et al. The G0/G1 switch gene 2 regulates adipose lipolysis through association with adipose triglyceride lipase. Cell Metab. 11, 194–205 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mowers, J. et al. Inflammation produces catecholamine resistance in obesity via activation of PDE3B by the protein kinases IKKepsilon and TBK1. eLife 2, e01119 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Reilly, S. M. et al. An inhibitor of the protein kinases TBK1 and IKK-varepsilon improves obesity-related metabolic dysfunctions in mice. Nat. Med. 19, 313–321 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Koprulu, M. et al. Identification of rare loss-of-function genetic variation regulating body fat distribution. J. Clin. Endocrinol. Metab. 107, 1065–1077 (2022).

    Article  PubMed  Google Scholar 

  40. Ortega-Gomez, A., Perretti, M. & Soehnlein, O. Resolution of inflammation: an integrated view. EMBO Mol. Med. 5, 661–674 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Soehnlein, O., Steffens, S., Hidalgo, A. & Weber, C. Neutrophils as protagonists and targets in chronic inflammation. Nat. Rev. Immunol. 17, 248–261 (2017).

    Article  CAS  PubMed  Google Scholar 

  42. Herrero-Cervera, A., Soehnlein, O. & Kenne, E. Neutrophils in chronic inflammatory diseases. Cell. Mol. Immunol. 19, 177–191 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Marzano, A. V. et al. Mechanisms of inflammation in neutrophil-mediated skin diseases. Front. Immunol. 10, 1059 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tang, H. N. et al. Plasticity of adipose tissue in response to fasting and refeeding in male mice. Nutr. Metab. 14, 3 (2017).

    Article  Google Scholar 

  45. Ding, H. et al. Fasting induces a subcutaneous-to-visceral fat switch mediated by microRNA-149-3p and suppression of PRDM16. Nat. Commun. 7, 11533 (2016).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  46. Xia, W. et al. Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation. Nat. Metab. 6, 273–289 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Shin, H. et al. Lipolysis in brown adipocytes is not essential for cold-induced thermogenesis in mice. Cell Metab. 26, 764–777 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yang, X. et al. Switching harmful visceral fat to beneficial energy combustion improves metabolic dysfunctions. JCI Insight 2, e89044 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Griffin, M. J. On the immunometabolic role of NF-κB in adipocytes. Immunometabolism https://doi.org/10.20900/immunometab20220003 (2022).

  50. Gao, D. et al. Interleukin-1β mediates macrophage-induced impairment of insulin signaling in human primary adipocytes. Am. J. Physiol. Endocrinol. Metab. 307, E289–E304 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Guo, Q. et al. NF-kappaB in biology and targeted therapy: new insights and translational implications. Signal Transduct. Target. Ther. 9, 53 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kahnt, A. S., Hafner, A. K. & Steinhilber, D. The role of human 5-Lipoxygenase (5-LO) in carcinogenesis—a question of canonical and non-canonical functions. Oncogene 43, 1319–1327 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Oyoshi, M. K. et al. Leukotriene B4-driven neutrophil recruitment to the skin is essential for allergic skin inflammation. Immunity 37, 747–758 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Afonso, P. V. et al. LTB4 is a signal-relay molecule during neutrophil chemotaxis. Dev. Cell 22, 1079–1091 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Werz, O., Klemm, J., Samuelsson, B. & Radmark, O. 5-Lipoxygenase is phosphorylated by p38 kinase-dependent MAPKAP kinases. Proc. Natl Acad. Sci. USA 97, 5261–5266 (2000).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  56. Lee, Y. S., Wollam, J. & Olefsky, J. M. An integrated view of immunometabolism. Cell 172, 22–40 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Stienstra, R. et al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc. Natl Acad. Sci. USA 108, 15324–15329 (2011).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  58. Hildebrandt, X., Ibrahim, M. & Peltzer, N. Cell death and inflammation during obesity: “know my methods, WAT(son)”. Cell Death Differ. 30, 279–292 (2023).

    Article  CAS  PubMed  Google Scholar 

  59. Sakamoto, T. et al. Macrophage infiltration into obese adipose tissues suppresses the induction of UCP1 level in mice. Am. J. Physiol. Endocrinol. Metab. 310, E676–E687 (2016).

    Article  PubMed  Google Scholar 

  60. Zhao, P. et al. TBK1 at the crossroads of inflammation and energy homeostasis in adipose tissue. Cell 172, 731–743 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wisessaowapak, C. et al. Protocol for differentiating murine 3T3-L1 and SVF-derived preadipocytes and isolating crude mitochondrial fractions. STAR Protoc. 6, 104045 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zhou, Y. et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun. 10, 1523 (2019).

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  63. Zhong, J. et al. adiposetissue.org: a knowledge portal integrating clinical and experimental data from human adipose tissue. Cell Metab. 37, 566–569 (2025).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the members of the Saltiel laboratory for discussions. S.S. was supported by American Diabetes Association Postdoc Fellowship 1-25-PDF-15. H.F. was supported by American Diabetes Association Postdoc Fellowship 1-25-PDF-21. C.X. was supported by a Maryam Ahmadian Fellowship. R.M.E. was supported by the NOMIS Foundation and NIH/NIDDK grants R01DK057978 and P30DK063491. This work was supported by a grant from the Larry L. Hillblom Foundation to R.M.E. and A.R.S., and US National Institute of Health (NIH/NIDDK) grants P30DK063491, R01DK122804, R01DK124496, R01DK125820 and R01DK128796 to A.R.S.

Author information

Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Department of Medicine and Pharmacology, University of California San Diego, San Diego, CA, USA

    Seunghwan Son, Cindy Xu, Haipeng Fu, Churaibhon Wisessaowapak, Joseph M. Valentine, Garam An, Janice Jang, Maddox Dinh, Wei Ying, Yuliya Skorobogatko & Alan R. Saltiel

  2. Gene Expression Laboratory, Salk Institute for Biological Studies, San Diego, CA, USA

    Yang Dai, Weiwei Fan, Ruth T. Yu, Michael Downes & Ronald M. Evans

Authors
  1. Seunghwan Son
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  2. Cindy Xu
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  3. Haipeng Fu
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Contributions

S.S. performed experimental design, experiments, data acquisition and interpretation, and wrote the manuscript. C.X., J.J. and M. Dinj performed the experiments. H.F. and C.W. performed experimental design and experiments. J.M.V. prepared primary adipocyte samples for RNA-seq. G.A. and W.Y. performed and analysed cell sorting of SVF cells from adipose tissue. Y.D., W.F., R.T.Y., M. Downes and R.M.E. performed and analysed RNA-seq experiments. Y.S. performed experimental design and provided critical data interpretation. A.R.S. conceptualized the study, performed data interpretation and wrote the manuscript.

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Correspondence to Seunghwan Son or Alan R. Saltiel.

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Extended data figures and tables

Extended Data Fig. 1 CL-316,243 injection or cold exposure induces neutrophil infiltration and inflammatory cytokine expression in white adipose tissue.

a. Absolute cell numbers of neutrophils, monocytes and macrophages in SVF of eWAT (top) or iWAT (bottom) from WT mice after CL-316,243 injection (0.5 mg kg−1) for the indicated times (0 h: n = 10,5; 1 h: n = 4,3; 12 h: n = 9,6; 24 h: n = 5,4). P values vs 0 h. b. Inflammatory genes in eWAT after CL for the indicated times (0 h: n = 8; 1 h: n = 6; 3 h: n = 7; 6 h: n = 5; 12 h: n = 8; 24 h: n = 5). P values vs 0 h. c. Quantification of cells in SVF of iWAT from WT mice exposed to cold for 18 h. (n = 3 per time point; each replicate pooled from two mice). P values vs 0 h. d-f. (d) Inflammatory genes in iWAT, (e) serum IL-6, (f) serum glycerol and NEFA levels after cold exposure for the indicated times. (n = 3,4 per time point). P values vs 0 h. Data are mean ± s.e.m. Each dot (n) represents one biological replicate (except c). Data are merged from three (a, b) or two (c, d-f) independent experiments. Statistics: one-way ANOVA with Tukey’s post hoc test (d, e, f (glycerol)); Welch’s one-way ANOVA with Dunnett’s T3 (f (NEFA)); Kruskal-Wallis one-way ANOVA with Dunn’s (a, b); unpaired two-sided Student’s t-test (c). Abbreviations. iWAT, inguinal white adipose tissue.

Source Data

Extended Data Fig. 2 Repeated CL-316,243 injection does not induce sustained neutrophil infiltration.

a-b. (a) Representative flow cytometry plots (top: neutrophils; middle: monocytes; bottom: macrophages. gated on CD45 + CD11b+Thy1.2-CD19-) and (b) quantification of neutrophils, monocytes and macrophages in SVF of eWAT (right) or iWAT (left) from WT mice 12 h after the final CL-316,243 injection (0.5 mg kg−1 day−1) (CLx1: 1 day; CLx2: 2 days; CLx4: 4 days; n = 4 per group). P values vs 0 h. c. Inflammatory genes expression in eWAT (left) or iWAT (right) from WT mice 12 h after the final CL injection (CLx1: 1 day; CLx2: 2 days; CLx4: 4 days). (left Y axis: IL-1β; right Y axis: IL-6, dotted line). (CLx0,x1,x2: n = 3; CLx4: n = 4 per time point). P values vs 0 h. Data are mean ± s.e.m. Each dot (n) represents one biological replicate. Data are merged from two (a-c) independent experiments. Statistics: one-way ANOVA with Tukey’s post hoc test (b, c); Welch’s one-way ANOVA with Dunnett’s T3 (b (neutrophil)).

Source Data

Extended Data Fig. 3 Lipolysis-dependent signals recruit neutrophils into white adipose tissue upon β3-adrenergic stimulation.

a. Serum glycerol in WT and ad-ATGL KO mice 0.5 h after CL-316,243 injection (0.5 mg kg−1). (n = 3 per group). P values WT vs ad-ATGL KO. b. Representative flow cytometry plots (top: neutrophils; middle: monocytes; bottom: macrophages. gated on CD45 + CD11b+Thy1.2-CD19-) and quantification of each population in iWAT SVF 12 h after CL injection. (CL 0 h: n = 3,2; CL 12 h: n = 3). P values WT vs ad-ATGL KO. c. Representative Ly6G (top) and F4/80 (bottom) staining of eWAT 12 h after CL injection. Scale bar: 100 µm. d. Inflammatory gene expression in iWAT after CL injection for the indicated times. (n = 4 per time point, except IL-1β, IL-6 at 0 h: n = 2). (normalized to WT 0 h). P values WT vs ad-ATGL KO or vs CL 0 h. e-g. (e, f) Inflammatory gene expression and (g) LTB4 levels in the supernatants from WT and ATGL KO PPDIVs treated with CL-316,243 (1 µM, 3 h) or TNFa (5 ng ml−1, 3 h). (n = 3 per group). (normalized to WT veh). P values WT vs ATGL KO. h-i. LTB4 levels in supernatants from (h) WT PPDIVs and bone marrow cells (BM), or (i) mature adipocytes (mAD) and stromal vascular fraction (SVF) isolated from eWAT of WT mice, treated with CL (1 µM, 3 h). (n = 3 per group). P values compare vehicle vs. CL. Data are mean ± s.e.m. Each dot (n) represents one biological replicate. Data are merged from two (b, d) or representative of two (a, c, e-g, h-i) independent experiments. Statistics: two-way ANOVA with Sidak’s post hoc test (a-i).

Source Data

Extended Data Fig. 4 LTB4 and p38 pathways mediate neutrophil recruitment into white adipose tissue upon β3-adrenergic stimulation.

a. Chemokines expression in WT PPDIVs pretreated for 30 min with SB203580 (10 µM) or SP600125 (10 µM) inhibitor, followed by CL-316,243 (1 µM, 3 h). (n = 4 per group). P values vs CL alone. b-c. Genes expression in WT PPDIVs pretreated for 30 min with SB203580 (10 µM), followed by CL (1 µM, 3 h). d-g. (d) IL-1β and IL-6 levels, (e) chemokines in eWAT, (f) plasma LTB4 (left), serum glycerol (right) and (g) immunoblots of eWAT from WT mice 6 h after Zileuton (5-LOX inhibitor, 50 mg kg−1) with CL injection. (n = 4 per group). P values veh+CL vs Zileuton+CL. h. Representative flow cytometry plots (top: neutrophils; bottom: monocytes. gated on CD45 + CD11b+Thy1.2-CD19-). i. Chemokines and cytokines in eWAT 3 h after MK886 (10 mg kg−1) with CL injection. (n = 4 per group). P values Veh+CL vs MK886 + CL. j-m. Analysis of WT mice 3 h or 6 h after CL injection with SB203580 (25 mg kg−1). (j) Serum LTB4 (3 h) and serum NEFA (6 h). (k) IL-6 levels in eWAT (3 h). (l) IL-1β gene (6 h) and (m) chemokines in eWAT (3 h and 6 h). (m. left Y axis: cxcl1; right Y axis: Cxcl2, Ccl2). (veh: n = 4; CL 3 h groups: n = 4; veh+CL 6 h: n = 7,8; SB + CL 6 h: n = 8). P values veh+CL vs SB + CL. Data are mean ± s.e.m. Each dot (n) represents one biological replicate. Data are merged from two (i, j (right), l, m) or representative of three (a), two (d-g, j (left), k) independent experiments. Statistics: two-way ANOVA with Sidak’s post hoc test (c, i); one-way ANOVA with Tukey’s (a, b, d, e (Ccl2), f, j, k, m (cxcl1)); Welch’s one-way ANOVA with Dunnett’s T3 (a (Ccl2), e, l, m).

Source Data

Extended Data Fig. 5 Infiltrated neutrophils are the major source of Interleukin-1β and limit excessive energy loss upon β3-adrenergic activation.

a. Representative flow cytometry plots (CD45 + CD11b+Thy1.2-CD19- cells) and quantification of each cells in spleen from diphtheria toxin (DT, 20 µg kg−1) treated Neu-WT and Neu-DTR mice 12 h after CL injection (0.5 mg kg−1). (Neu-WT: n = 8; Neu-DTR: n = 10). Quantification of cells in bone marrow 24 h after DT injection. (n = 3 per group). P values Neu-WT vs Neu-DTR. b. Serum NEFA and IL-6 in DT-treated mice after CL injection. (glycerol, 0 h: n = 3,4; 2 h: n = 6; 12 h: n = 10,7; 24 h: n = 6,10. IL-6, 0 h:n = 3,2; 2 h: n = 4,3; 12 h: n = 9,7; 24 h: n = 6,9). P values Neu-WT vs Neu-DTR. c. Inflammatory genes in eWAT (Adgre1) or iWAT (IL-1β, IL-6) from DT-treated mice 12 h after CL injection. (CL 0 h: n = 3,4; CL 12 h: n = 7,8. normalized to Neu-WT 0 h). P values Neu-WT vs Neu-DTR. d. IL-1β levels in supernatants from WT PPDIVs treated with CL-316,243 (1 µM, 12 h) or LPS (0.5 µg ml−1, 12 h), followed by ATP (5 mM, 1 h). (n = 2 per group). e-f. (e) Body weight and (f) food intake from DT-treated mice at indicated time points or 6 h after final CL injection. (CLx2: 2 days; CLx7: 7 days). Food intake was measured for 24 h before and after CL injection. (f, n = 6 per group). P values indicate comparisons between Neu-WT and Neu-DTR. g. Tissue weight of eWAT 6 h after second CL injection with or without DT. (n = 3,4 per group). P values Neu-WT vs Neu-DTR. h. IL-1β levels in eWAT from WT mice after CL injection for the indicated times (CL x2: 2 days injection). (0 h, 6 h: n = 4; 12 h, 24 h: n = 5; x2: n = 6). P values vs 0 h. i. IL-1β levels in eWAT from DT-treated mice 1 h after second CL injection. (CL 0 h: n = 2; CL x2: n = 4). P values Neu-WT vs Neu-DTR or relative vs 0 h. Data are mean ± s.e.m. Each dot (n) represents one biological replicate. Data are merged from three (a, b, c, h) or representative of two (d, f, g, i) independent experiments. Statistics: two-way ANOVA with Sidak’s post hoc test (a (bone marrow), b, c, e, f, g, i); one-way ANOVA with Tukey’s (h); unpaired two-sided Welch’s t-test (a).

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Extended Data Fig. 6 Neutrophil infiltration upon β3-adrenergic activation does not affect thermogenic gene expression in white adipose tissue.

a-b. Thermogenic genes in (a) iWAT and (b) eWAT from DT-treated Neu-WT and Neu-DTR mice 6 h after the final CL-316,243 injection (0.5 mg kg−1 day−1). DT was administered for 7 days (DT x7), CL was injected for 2 or 7 days (CLx2: 2 days; CLx7: 7 days). (DT x7: n = 4; CLx2: n = 4,6; CLx7: n = 6,7. normalized to Neu-WT DT x7). P values Neu-WT vs Neu-DTR. c-d. Thermogenic genes in (c) iWAT and (d) eWAT from WT mice 6 h after the final CL injection (0.5 mg kg−1 day−1, for 4 days), with vehicle or VX765 (50 mg kg−1, twice per day). (Veh: n = 7; Veh and VX765 + CL group: n = 8). P values vehicle vs VX765. e. Representative UCP1 immunohistochemistry images of iWAT from DT-treated mice 7 days after CL injection. Scale bar: 1 mm. Data are mean ± s.e.m. Each dot (n) represents one biological replicate. Data are merged from two (a-b, c-d) independent experiments. Statistics: two-way ANOVA with Sidak’s post hoc test (a, b); one-way ANOVA with Tukey’s (c, d); Welch’s one-way ANOVA with Dunnett’s T3 (c (UCP1), d (Dio2)). Abbreviations. UCP1, uncoupling protein 1.

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Extended Data Fig. 7 Neutrophil-derived IL-1β restrains lipolysis through catecholamine resistance in adipocytes.

a. Immunoblots of eWAT from WT mice 12 h after CL-316,243 injection (0.5 mg kg−1) with vehicle or VX765 (50 mg kg−1, twice per day) or IL-1β levels in eWAT from WT mice 3 h after the second CL injection (0.5 mg kg−1 day−1) with vehicle or VX765. (n = 4 per group). P values vehicle vs VX765. b. Chemokines and LTB4 levels from WT PPDIVs pretreated 30 min with VX765 (40 µM), followed by CL-316,243 (1 µM, 3 h). (veh: n = 3, VX765: n = 2, CL: n = 4; VX + CL: n = 3)). P values vehicle vs VX765. c-e. (c) Serum NEFA and glycerol, (d) IL-6 levels and (e) body weight, iWAT tissue weight after CL injection with vehicle or VX765 for the indicated times (CLx2-4: 2-4 days) (NEFA, 0 h/6 h/12 h: n = 4; 24 h: n = 8,7. Glycerol, 0 h: n = 3; 6 h: n = 7). P values vehicle vs VX765. f. Paired serum glycerol levels from the same mice at 30 min and 1 h after the second CL injection with vehicle or VX765 for the indicated times (n = 8 per group). P values 30 min vs 1 h. g. Analysis of DT-treated mice after the second CL injection. Serum glycerol and immunoblots of eWAT from 15 min after second CL injection. (0 min: n = 5,4; 15 min: n = 6,5; 30 min: n = 7,5; 60 min: n = 6,5). P values Neu-WT vs Neu-DTR. h. Glycerol release from ex vivo cultured eWAT of WT mice. eWAT was collected 24 h after CL injection with vehicle or VX765. Then treated in culture with vehicle or CL-316,243 (1 µM, 30 min). (0 h: n = 6,5; 0.5 h: n = 6,5). P values vehicle vs VX765. i. Fatty acid oxidation genes in both eWAT and iWAT 3 h after the second CL-injection with vehicle or VX765. (veh: n = 7,8; VX: n = 7,8). P values vehicle vs VX765. j-k. WT PPDIVs were pretreated 18 h with IL-1β (5 ng ml−1) or vehicle, followed by CL-316,243 (1 µM, 0.5 h). (j) Immunoblots and (k) glycerol release and fold change compared to vehicle or IL-1β. (n = 4 per group). P values vs groups. l-p. Genes expression in (l) 3T3-L1 adipocytes or (m, p) WT PPDIVs treated with IL-1β (5 ng ml−1, 3 h) or CL-316,243 (1 µM, 3 h) or TNFa (5 ng ml−1, 3 h). (veh: n = 2, IL-1β: n = 3, TNFa: n = 2; CL: n = 3). P values vs vehicle. n. Beta 3 adrenergic receptor gene in eWAT from WT mice 3 h after the second CL injection with vehicle or VX765. (n = 4 per group). P values vehicle vs VX765. o. Beta 3 adrenergic receptor gene expression in eWAT from DT-treated Neu-WT and Neu-DTR mice 6 h after the second CL injection. (n = 3,4 per group). P values Neu-WT vs Neu-DTR. Data are mean ± s.e.m. Each dot (n) represents one biological replicate. Data are merged from three (c-d), two (f-i) or representative of two (a, b, g (blot), j-p) independent experiments. Statistics: two-way ANOVA with Sidak’s post hoc test (c, d, g, h); two-way ANOVA with Fisher’s (e); one-way ANOVA with Tukey’s (b, n, o); Welch’s one-way ANOVA with Dunnett’s T3 (b (cxcl1), k); unpaired two-sided Student’s t-test (f); unpaired two-sided Welch’s t-test (a); two-sided Mann Whitney U test (i).

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Extended Data Fig. 8 Neutrophil-derived IL-1β limits lipolysis in vivo to prevent excessive energy loss.

a-c. Analysis of IgG or Ly6G-treated WT mice 1 h after the second CL-316,243 injection (0.5 mg kg−1 day−1). (a) eWAT tissue weight. (b) Serum glycerol (left) and NEFA (right) levels from the same mice over time. (c) Immunoblotting of spleen. (IgG: n = 3; Ly6G: n = 4). P values IgG vs Ly6G. d-g. Analysis of WT mice 1 h after the second CL injection with vehicle or MK886 (10 mg kg−1 day−1). (d) eWAT tissue weight. (e) Serum glycerol (left) and NEFA (right) levels from the same mice over time. (f) IL-1β level in eWAT. (g) immunoblotting of eWAT. (n = 4 per group). P values vehicle vs MK886. h-i. Analysis of WT mice under cold exposure (4 °C) for 24 h with vehicle or VX765 (50 mg kg−1, twice per day). (h) Serum glycerol (left) and NEFA (right) levels at indicated time. (4 h: n = 3,4; 24 h: n = 7,8). (i) Core rectal temperature measured at indicated time. (n = 4 per group). P vehicle vs VX765. Data are mean ± s.e.m. Each dot (n) represents one biological replicate. Data are merged from two (h) or representative of two (a-c, d-g, i) independent experiments. Statistics: two-way ANOVA with Sidak’s post hoc test (b, e, h, i); unpaired two-sided Student’s t-test (a, d, g, h (left)). Abbreviations. MK886, 5-Lipoxygenase-activating protein (FLAP) inhibitor.

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Extended Data Fig. 9 Inflammasome gene expression correlates with obesity-related traits and is increased in obese individuals.

a-d. (top) Spearman correlation of (a) IL1B, (b) IL18, (c) NLRP3 and (d) CASPASE 1 expression with obesity-related parameters (BMI, HOMA-IR, waist, hip, age) and circulating metabolic/inflammatory markers (insulin, glucose, triglycerides, LDL, CRP, HDL, cholesterol, HbA1c). Colours indicate -log10 P values. (n=up to 16 biologically independent cohorts). (bottom) Meta-analysis of genes expression comparing obese and non-obese cohorts. Data are shown as standardized mean difference (SMD) with 95% CI. Diamonds indicate pooled estimates from random-effects models. (n = 9 biologically independent datasets). Data was analysed through AT knowledge portal63. Statistics: two-sided Spearman correlation. ****p < 0.0001, ***p < 0.001, **p < 0.01, *p < 0.05.

Extended Data Fig. 10 Working model of neutrophil-derived IL-1β regulating lipolysis during β3-adrenergic stimulation.

β3-adrenergic activation transiently recruits neutrophils into white adipose tissue through secreting a lipolysis-p38-dependent Leukotriene B4. Infiltrated neutrophils secrete Interleukin-1β, which suppresses lipolysis and limits excessive energy loss by inducing catecholamine resistance in adipocytes. Created in BioRender. Son, S. (2025) https://BioRender.com/dq8j6v7.

Supplementary information

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Supplementary Figs. 1 and 2 and Supplementary Table 1, providing uncropped immunoblots, flow cytometry gating and primer sequences.

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Son, S., Xu, C., Fu, H. et al. Neutrophils preserve energy storage in sympathetically activated adipocytes. Nature (2025). https://doi.org/10.1038/s41586-025-09839-6

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