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Thermogenic adipocyte-derived zinc promotes sympathetic innervation in male mice

Nature Metabolism volume 5, pages 481–494 (2023)Cite this article

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Abstract

Sympathetic neurons activate thermogenic adipocytes through release of catecholamine; however, the regulation of sympathetic innervation by thermogenic adipocytes is unclear. Here, we identify primary zinc ion (Zn) as a thermogenic adipocyte-secreted factor that promotes sympathetic innervation and thermogenesis in brown adipose tissue and subcutaneous white adipose tissue in male mice. Depleting thermogenic adipocytes or antagonizing β3-adrenergic receptor on adipocytes impairs sympathetic innervation. In obesity, inflammation-induced upregulation of Zn chaperone protein metallothionein-2 decreases Zn secretion from thermogenic adipocytes and leads to decreased energy expenditure. Furthermore, Zn supplementation ameliorates obesity by promoting sympathetic neuron-induced thermogenesis, while sympathetic denervation abrogates this antiobesity effect. Thus, we have identified a positive feedback mechanism for the reciprocal regulation of thermogenic adipocytes and sympathetic neurons. This mechanism is important for adaptive thermogenesis and could serve as a potential target for the treatment of obesity.

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Fig. 1: UCP1-positive thermogenic adipocytes secrete Zn after β3-adrenergic receptor activation.
Fig. 2: Zn promotes sympathetic innervation and thermogenesis.
Fig. 3: Administration of Zn ameliorates obesity through promoting sympathetic innervation.
Fig. 4: Obesity suppresses Zn secretion through inflammation-induced MT2 expression.
Fig. 5: MT2 suppresses sympathetic innervation and thermogenesis.

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Data availability

There are no restrictions as to the availability of materials reported in the manuscript. The data that support the findings of this study are available from the corresponding author on request. The ion mass spectrometry and whole-mount immunostaining data generated in this study are accessible via Figshare (https://doi.org/10.6084/m9.figshare.21433002). Source data are provided with this paper.

References

  1. Bertholet, A. M. et al. Mitochondrial patch clamp of beige adipocytes reveals UCP1-positive and UCP1-negative cells both exhibiting futile creatine Cycling. Cell Metab. 25, 811–822 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Meyer, C. W. et al. Adaptive thermogenesis and thermal conductance in wild-type and UCP1-KO mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299, R1396–R1406 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cohen, P. et al. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell 156, 304–316 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hanssen, M. J. et al. Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. Nat. Med. 21, 863–865 (2015).

    Article  CAS  PubMed  Google Scholar 

  5. Hanssen, M. J. et al. Short-term cold acclimation recruits brown adipose tissue in obese humans. Diabetes 65, 1179–1189 (2016).

    Article  CAS  PubMed  Google Scholar 

  6. Ikeda, K. et al. UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nat. Med. 23, 1454–1465 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kazak, L. et al. Genetic depletion of adipocyte creatine metabolism inhibits diet-induced thermogenesis and drives obesity. Cell Metab. 26, 660–671 (2017).

    Article  Google Scholar 

  8. Zeng, X. et al. Innervation of thermogenic adipose tissue via a calsyntenin 3β–S100b axis. Nature 569, 229–235 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wang, P. et al. A leptin–BDNF pathway regulating sympathetic innervation of adipose tissue. Nature 583, 839–844 (2020).

    Article  CAS  PubMed  Google Scholar 

  10. Hu, B. et al. γδ T cells and adipocyte IL-17RC control fat innervation and thermogenesis. Nature 578, 610–614 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rios-Lugo, M. J., Madrigal-Arellano, C., Gaytán-Hernández, D., Hernández-Mendoza, H. & Romero-Guzmán, E. T. Association of serum zinc levels in overweight and obesity. Biol. Trace Elem. Res. 198, 51–57 (2020).

    Article  CAS  PubMed  Google Scholar 

  12. Torkanlou, K. et al. Reduced serum levels of zinc and superoxide dismutase in obese individuals. Ann. Nutr. Metab. 69, 232–236 (2016).

    Article  CAS  PubMed  Google Scholar 

  13. Norouzi, S., Adulcikas, J., Sohal, S. S. & Myers, S. Zinc stimulates glucose oxidation and glycemic control by modulating the insulin signaling pathway in human and mouse skeletal muscle cell lines. PLoS ONE 13, e0191727 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Song, Y., Leonard, S. W., Traber, M. G. & Ho, E. Zinc deficiency affects DNA damage, oxidative stress, antioxidant defenses, and DNA repair in rats. J. Nutr. 139, 1626–1631 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu, M. J. et al. Zinc deficiency augments leptin production and exacerbates macrophage infiltration into adipose tissue in mice fed a high-fat diet. J. Nutr. 143, 1036–1045 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Argani, H. et al. Effects of zinc supplementation on serum zinc and leptin levels, BMI, and body composition in hemodialysis patients. J. Trace Elem. Med. Biol. 28, 35–38 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. Khorsandi, H. et al. Zinc supplementation improves body weight management, inflammatory biomarkers and insulin resistance in individuals with obesity: a randomized, placebo-controlled, double-blind trial. Diabetol. Metab. Syndr. 11, 101 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Thoen, R. U. et al. Zinc supplementation reduces diet-induced obesity and improves insulin sensitivity in rats. Appl. Physiol. Nutr. Metab. 44, 580–586 (2019).

    Article  CAS  PubMed  Google Scholar 

  19. Jiang, H., Ding, X., Cao, Y., Wang, H. & Zeng, W. Dense intra-adipose sympathetic arborizations are essential for cold-induced beiging of mouse white adipose tissue. Cell Metab. 26, 686–692 (2017).

    Article  CAS  PubMed  Google Scholar 

  20. Chi, J. et al. Three-dimensional adipose tissue imaging reveals regional variation in beige fat biogenesis and PRDM16-dependent sympathetic neurite density. Cell Metab. 27, 226–236 (2018).

    Article  CAS  PubMed  Google Scholar 

  21. Ellis, C. D. et al. Zinc and the Msc2 zinc transporter protein are required for endoplasmic reticulum function. J. Cell Biol. 166, 325–335 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hogstrand, C., Kille, P., Nicholson, R. I. & Taylor, K. M. Zinc transporters and cancer: a potential role for ZIP7 as a hub for tyrosine kinase activation. Trends Mol. Med. 15, 101–111 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Ning, P. et al. A mitochondria-targeted ratiometric two-photon fluorescent probe for biological zinc ions detection. Biosens. Bioelectron. 77, 921–927 (2016).

    Article  CAS  PubMed  Google Scholar 

  24. Chyan, W., Zhang, D. Y., Lippard, S. J. & Radford, R. J. Reaction-based fluorescent sensor for investigating mobile Zn2+ in mitochondria of healthy versus cancerous prostate cells. Proc. Natl Acad. Sci. USA 111, 143–148 (2014).

    Article  CAS  PubMed  Google Scholar 

  25. Roh, H. C., Collier, S., Guthrie, J., Robertson, J. D. & Kornfeld, K. Lysosome-related organelles in intestinal cells are a zinc storage site in C. elegans. Cell Metab. 15, 88–99 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Breitbart, H., Rubinstein, S. & Gruberger, M. Calcium efflux mechanism in sperm mitochondria. Biochim. Biophys. Acta 1312, 79–84 (1996).

    Article  PubMed  Google Scholar 

  27. Akopova, O. V. & Sagach, V. F. Release of Ca2+ from mitochondria after mitochondrial membrane depolarisation. Ukr. Biokhim. Zh. 77, 62–69 (2005).

    CAS  Google Scholar 

  28. Yehuda-Shnaidman, E., Buehrer, B., Pi, J., Kumar, N. & Collins, S. Acute stimulation of white adipocyte respiration by PKA-induced lipolysis. Diabetes 59, 2474–2483 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nishito, Y. & Kambe, T. Zinc transporter 1 expression on the cell surface is elaborately controlled by cellular zinc levels. J. Biol. Chem. 294, 15686–15697 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kisiswa, L. et al. TNFα reverse signaling promotes sympathetic axon growth and target innervation. Nat. Neurosci. 16, 865–873 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Atwal, J. K., Massie, B., Miller, F. D. & Kaplan, D. R. The TrkB-Shc site signals neuronal survival and local axon growth via MEK and P13-kinase. Neuron 27, 265–277 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Chowanadisai, W., Graham, D. M., Keen, C. L., Rucker, R. B. & Messerli, M. A. Neurulation and neurite extension require the zinc transporter ZIP12 (slc39a12). Proc. Natl Acad. Sci. USA 110, 9903–9908 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kambe, T., Tsuji, T., Hashimoto, A. & Itsumura, N. The physiological, biochemical, and molecular roles of zinc transporters in zinc homeostasis and metabolism. Physiol. Rev. 95, 749–784 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. Kimura, T. & Kambe, T. The functions of metallothionein and ZIP and ZnT transporters: an overview and perspective. Int. J. Mol. Sci. 17, 336 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Deng, H. et al. SLC-30A9 is required for Zn2+ homeostasis, Zn2+ mobilization and mitochondrial health. Proc. Natl Acad. Sci. USA 118, e2023909118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ma, T. et al. A pair of transporters controls mitochondrial Zn2+ levels to maintain mitochondrial homeostasis. Protein Cell 13, 180–202 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Seale, P. et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab. 6, 38–54 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kajimura, S. et al. Initiation of myoblast to brown fat switch by a PRDM16–C/EBP-beta transcriptional complex. Nature 460, 1154–1158 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ohno, H., Shinoda, K., Spiegelman, B. M. & Kajimura, S. PPARγ agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab. 15, 395–404 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Reiterer, G. et al. Zinc deficiency increases plasma lipids and atherosclerotic markers in LDL-receptor-deficient mice. J. Nutr. 135, 2114–2118 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Beattie, J. H. et al. Obesity and hyperleptinemia in metallothionein (-I and -II) null mice. Proc. Natl Acad. Sci. USA 95, 358–363 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Fukunaka, A. et al. Zinc transporter ZIP13 suppresses beige adipocyte biogenesis and energy expenditure by regulating C/EBP-β expression. PLoS Genet. 13, e1006950 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Abramovitch-Dahan, C. et al. Amyloid-β attenuates metabotropic zinc sensing receptor, mZnR/GPR39, dependent Ca2+, ERK1/2 and clusterin signaling in neurons. J. Neurochem. 139, 221–233 (2016).

    Article  CAS  PubMed  Google Scholar 

  44. Lin, S. et al. Targeting parvalbumin promotes M2 macrophage polarization and energy expenditure in mice. Nat. Commun. 13, 3301 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang, P. et al. A leptin–BDNF pathway regulating sympathetic innervation of adipose tissue. Nature 583, 839–844 (2020).

    Article  CAS  PubMed  Google Scholar 

  46. Spinelli, J. B. et al. Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass. Science 358, 941–946 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sullivan, M. R. et al. Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability. eLife 8, e44235 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Reddy, A. et al. pH-gated succinate secretion regulates muscle remodeling in response to exercise. Cell 183, 62–75 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Luo, J. et al. A protocol for rapid generation of recombinant adenoviruses using the AdEasy system. Nat. Protoc. 2, 1236–1247 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Gong, X. M. et al. Gpnmb secreted from liver promotes lipogenesis in white adipose tissue and aggravates obesity and insulin resistance. Nat. Metab. 1, 570–583 (2019).

    Article  CAS  PubMed  Google Scholar 

  51. Vaughan, C. H., Zarebidaki, E., Ehlen, J. C. & Bartness, T. J. Analysis and measurement of the sympathetic and sensory innervation of white and brown adipose tissue. Methods Enzymol. 537, 199–225 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Fischer, A. W., Schlein, C., Cannon, B., Heeren, J. & Nedergaard, J. Intact innervation is essential for diet-induced recruitment of brown adipose tissue. Am. J. Physiol. Endocrinol. Metab. 316, E487–e503 (2019).

    Article  CAS  PubMed  Google Scholar 

  53. Mina, A. I. et al. CalR: a web-based analysis tool for indirect calorimetry experiments. Cell Metab. 28, 656–666 2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank S. Li from the School of Medicine for sharing DTR-STOPfl/fl mice and J. Liu from Shanghai Jiao Tong University Affiliated Sixth People’s Hospital for sharing Ucp1 KO mice. This work was supported by grants from the National Natural Science Foundation of China (81922015, 82170862, 81971078 and 82171166), Shanghai Scientific Research Project (19ZR1461700), Shuguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission (21SG21) and Fundamental Research Funds for the Central Universities.

Author information

Author notes

  1. These authors contributed equally: Junkun Jiang, Donglei Zhou, Anke Zhang, Wenjing Yu.

Authors and Affiliations

  1. Department of Endocrinology, Tongji Hospital Affiliated to Tongji University School of Medicine, Tongji University, Shanghai, China

    Junkun Jiang, Wenjing Yu, Huiwen Yuan, Chuan Zhang, Zelin Wang & Bing Luan

  2. Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China

    Donglei Zhou

  3. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    Donglei Zhou

  4. Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

    Anke Zhang

  5. Department of Metabolic Surgery, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China

    Lei Du & Xuyang Jia

  6. Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China

    Zhen-Ning Zhang

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Contributions

B.L. conceived and directed the study. J.J., A.Z., W.Y., H.Y., C.Z., Z.W., Z.-N.Z. and B.L. designed and performed experiments and analysed the data. D.Z., L.D. and X.J. helped with human sample preparation. J.J., Z.-N.Z. and B.L. wrote the manuscript with comments from all the authors. All authors provided input and reviewed the manuscript.

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Correspondence to Bing Luan.

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Nature Metabolism thanks Ana Domingos, Taiho Kambe and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Isabella Samuelson, in collaboration with the Nature Metabolism team.

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Extended data

Extended Data Fig. 1 Reciprocal regulation of UCP1-positive and TH-positive cells.

a, UCP1, TH protein expression and HSL phosphorylation in scWAT (Left) and BAT (Right) of mice under RT (25 °C) and cold exposure (4 °C) (n = 5 biological independent samples). b, TH and UCP1 staining in scWAT of mice under RT and 4 °C (n = 3 independent experiments). Scale bar (50 μm). c, Whitening morphology in scWAT and BAT of UCP1-DTR mice injected with DT (200 ng/day) under 4 °C. d, UCP1 and TH protein expression in BAT, Kidney and Heart of UCP1-DTR mice injected with DT under 4 °C (n = 3 biological independent samples). e, TH-positive sympathetic innervation staining in BAT of UCP1-DTR mice injected with DT under 4 °C (n = 3 biological independent samples). Scale bar (1000 μm). f, UCP1 and TH protein expression in BAT of mice injected with L748337 (5 mg/kg) under 4 °C (n = 3 biological independent samples). g, TH-positive sympathetic innervation staining in BAT of C57BL6 mice injected with L748337 (5 mg/kg) under 4 °C (n = 3 biological independent samples). Scale bar (1000 μm). h, Intracellular Zn levels in beige adipocytes, glutamatergic neurons and MIN6 cells. (n = 3 biological independent samples). Error bars represent ±SEM, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. n.s., not significant. P values were determined by unpaired two-tailed Student’s t-test (a, d, e, f, g, h).

Source data

Extended Data Fig. 2 Zn promotes thermogenesis in BAT.

a, Thermogenic genes expression in beige adipocytes treated with indicated concentration of Zn (n = 4 biological independent samples). b, TH-positive sympathetic innervation staining in BAT of C57BL6 mice injected with Zn (30 mg/kg/mice) (n = 3 biological independent samples). Scale bar (1000 μm). c, TH-positive sympathetic innervation staining in BAT of C57BL6 mice locally injected with Zn chelator TPEN (15 mg/kg) (n = 3 biological independent samples). Scale bar (1000 μm). d, Zip12 genes expression in primary sympathetic neurons (PSNs) transfected with Control-shRNA or ZIP12-shRNA (n = 3 biological independent samples). e-g, Body weight (e), food intake (f) and activity (g) of mice injected with different dose of Zn (n = 6 biological independent samples). h-j, Thermogenic genes expression (h, n = 7 biological independent samples), UCP1 protein expression and HSL phosphorylation (i, n = 4 biological independent samples), H&E staining (Top) and UCP1 staining (Down) (j, n = 3 independent experiments) in BAT of mice injected with Zn (30 mg/kg/mice). Scale bar (50 μm). k-m, Body weight (k), food intake (l) and activity (m) of mice locally injected with TPEN (15 mg/kg) in scWAT and BAT under 4 °C (n = 6 biological independent samples). n-p, Thermogenic genes expression (n, n = 5 biological independent samples), UCP1 protein expression and HSL phosphorylation (o, n = 4 biological independent samples), H&E staining (Top) and UCP1 staining (Down) (p, n = 3 independent experiments) in BAT of C57BL6 mice locally injected with TPEN (15 mg/kg) under 4 °C. Scale bar (50 μm). q-t, Oxygen consumption (q), Body weight (r), food intake (s) and activity (t) of UCP1 KO mice injected with Zn (30 mg/kg/mice) (n = 6 biological independent samples). Error bars represent ±SEM, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. n.s., not significant. P values were determined by unpaired two-tailed Student’s t-test (a-i, k-o, r-t), two-sided analysis of covariance (ANCOVA) (q).

Source data

Extended Data Fig. 3 Zn treatment ameliorates obesity.

a, Oil red staining of liver samples from HFD-fed mice treated with Zn supplementation in the drinking water (0.4 mg/ml) examined over three independent experiments. Scale bar (50 μm). b-c, Food intake (b) (n = 7 biological independent samples) and activity (c) (n = 6 biological independent samples) of HFD-fed mice with or without denervation in scWAT and BAT. Error bars represent ±SEM, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. n.s., not significant. P values were determined by unpaired two-tailed Student’s t-test (c) and two-way ANOVA (b).

Source data

Extended Data Fig. 4 Obesity induces MT2 expression through inflammation.

a, TH-positive sympathetic innervation staining in BAT of C57BL6 mice fed with HFD or regular diet (RD) (n = 3 biological independent samples). Scale bar (1000 μm). b, Znt, Zip and Metallothioneins (Mt1 and Mt2) genes expression in BAT of C57BL6 mice fed with HFD or RD (n = 6 biological independent samples). c, ZnT, ZIP and Metallothioneins genes expression in scWAT of lean and obese human individuals (n = 4 biological independent samples). d, Znt, Zip and Metallothioneins (Mt1 and Mt2) genes expression in beige adipocytes treated with TNFα (50 ng/ml) and IL1β (50 ng/ml) (n = 4 biological independent samples). Error bars represent ±SEM, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. n.s., not significant. P values were determined by unpaired two-tailed Student’s t-testV (a-d).

Source data

Extended Data Fig. 5 MT2 suppresses thermogenesis in BAT.

a-b, TH-positive sympathetic innervation staining in BAT (a, n = 3 biological independent samples) and TH protein expression in heart of WT and MT2 AKO under 4 °C (n = 4 biological independent samples). Scale bar (1000 μm). c-g, UCP1 protein expression and HSL phosphorylation (c, n = 4 biological independent samples), H&E staining (Top) and UCP1 staining (Down) (d, n = 3 independent experiments) in BAT as well as body weight (e), Food intake (f) and activity (g) (n = 6 biological independent samples) of WT and MT2 AKO mice under 4 °C. Scale bar (50 μm). h, Thermogenic genes expression in beige adipocytes from WT and MT2 AKO mice (n = 4 biological independent samples). i-k, Body weight (i), food intake (j) and activity (k) of WT and MT2 AKO mice with surgical transection of sympathetic neuron fibers in scWAT and BAT (n = 6 biological independent samples). l-q, Body weight and food intake (l, m, n = 8 biological independent samples), UCP1 and TH immunoblot (Down) in transplanted cells (n, n = 3 biological independent samples), oxygen consumption (o, n = 8 biological independent samples), thermogenic genes expression in endogenous scWAT (p, n = 8 biological independent samples) and BAT (q, n = 8 biological independent samples) of C57BL6 mice transplanted with WT beige adipocytes (Trans-WT) and MT2-KO beige adipocytes (Trans-KO) under 4 °C. r, Mt2 mRNA levels in scWAT, BAT, Liver and Kidney from Ad-GFP and Ad-MT2 injected mice (n = 5 biological independent samples). s, Co-staining of adenovirus infected cells (GFP positive) with adipocytes (Perilipin positive) and sympathetic neurons (TH positive) (n = 3 independent experiments). Scale bar (50 μm). t, TH-positive sympathetic innervation staining in BAT of C57BL6 mice locally-injected with Ad-GFP and Ad-MT2 in scWAT and BAT under 4 °C (n = 3 biological independent samples). Scale bar (1000 μm). u-z, Thermogenic genes expression (u, n = 7 biological independent samples), UCP1 protein expression and HSL phosphorylation (v, n = 4 biological independent samples), H&E staining (Top) and UCP1 staining (Down) (w, n = 3 independent experiments) in BAT as well as body weight (x), food intake (y) and activity (z) (n = 7 biological independent samples) of C57BL6 mice locally-injected with Ad-GFP and Ad-MT2 under 4 °C. Scale bar (50 μm). Error bars represent ±SEM, *p < 0.05, **p < 0.01, ***p < 0.001. n.s., not significant. P values were determined by unpaired two-tailed Student’s t-test (a-c, g-k, n, p-z), two-way ANOVA (e-f, l-m) and two-sided analysis of covariance (ANCOVA) (o).

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Jiang, J., Zhou, D., Zhang, A. et al. Thermogenic adipocyte-derived zinc promotes sympathetic innervation in male mice. Nat Metab 5, 481–494 (2023). https://doi.org/10.1038/s42255-023-00751-9

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