Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Animal Models

Irisin reverses high-fat diet-induced metabolic dysfunction via activation of brown adipose tissue in mice

International Journal of Obesity volume 49, pages 1066–1075 (2025)Cite this article

Subjects

Abstract

Background

High-fat diet (HFD) induces negative effects on the activity of interscapular brown adipose tissue (iBAT) and systemic energy metabolism. Irisin, a small hormonal agent known to modulate metabolism has been used for intervening HFD-induced obesity. However, its mechanism of action on iBAT function remains to be fully elucidated. This study sought to investigate whether irisin intervention could restore the thermogenic function of iBAT in mice with HFD-induced obesity, thereby regulating systemic metabolism.

Methods

Magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) were used to monitor changes of thermogenic capacity of iBAT and systemic metabolism in mice with HFD-induced obesity and iBAT deficiency during 2-week or 4-week irisin intervention. Pathological and molecular biology analyses were performed on tissue and blood samples.

Results

Prolonged HFD feeding in mice induced obesity and impaired the thermogenic capacity of iBAT. MRI results showed that irisin intervention for 4-week reduced lipid content in iBAT, increased uncoupling protein 1 (UCP 1) expression and enhanced glucose analogue uptake capacity. These improvements of functions in iBAT activity were accompanied by an improvement in systemic metabolism. The positive effects of irisin appears to be dependent on the length of intervention time. When iBAT was removed, the beneficial effects of irisin were partially suppressed, suggesting that irisin regulates metabolism through the restoration of the thermogenic function of iBAT.

Conclusions

HFD results in reduced thermogenic capacity of iBAT, while irisin intervention can effectively restore iBAT function, leading to improvement in overall glucose and lipid metabolism.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: MRI assessment of mice with obesity subjected to HFD for 16 weeks revealed a loss of functional activity in iBAT and systemic metabolism disfunction.
Fig. 2: Continuous MRI assesses the changes in dysfunctional iBAT during irisin intervention.
Fig. 3: Irisin intervention improved systemic glucose and lipid metabolism in mice with HFD.
Fig. 4: Continuous MRI assessment revealed irisin intervention reduced the deposition of lipids in the WAT and liver.
Fig. 5: Removal of iBAT eliminated the beneficial effects of irisin intervention on metabolism.

Similar content being viewed by others

Data availability

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Becher T, Palanisamy S, Kramer DJ, Eljalby M, Marx SJ, Wibmer AG, et al. Brown adipose tissue is associated with cardiometabolic health. Nat Med. 2021;27:58–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Liu X, Wang S, You Y, Meng M, Zheng Z, Dong M, et al. Brown adipose tissue transplantation reverses obesity in Ob/Ob mice. Endocrinology. 2015;156:2461–9.

    Article  CAS  PubMed  Google Scholar 

  3. Scheele C, Wolfrum C. Brown adipose crosstalk in tissue plasticity and human metabolism. Endocr Rev. 2020;41:53–65.

    Article  PubMed  Google Scholar 

  4. Sveidahl Johansen O, Ma T, Hansen JB, Markussen LK, Schreiber R, Reverte-Salisa L, et al. Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis. Cell. 2021;184:3502–18.e33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Jacobsson A, Stadler U, Glotzer MA, Kozak LP. Mitochondrial uncoupling protein from mouse brown fat. Molecular cloning, genetic mapping, and mRNA expression. J Biol Chem. 1985;260:16250–4.

    Article  CAS  PubMed  Google Scholar 

  6. Porter C, Herndon DN, Chondronikola M, Chao T, Annamalai P, Bhattarai N, et al. Human and mouse brown adipose tissue mitochondria have comparable UCP1 function. Cell Metab. 2016;24:246–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rangel-Azevedo C, Santana-Oliveira DA, Miranda CS, Martins FF, Mandarim-de-Lacerda CA, Souza-Mello V. Progressive brown adipocyte dysfunction: Whitening and impaired nonshivering thermogenesis as long-term obesity complications. J Nutr Biochem. 2022;105:109002.

    Article  CAS  PubMed  Google Scholar 

  8. Gross B, Pawlak M, Lefebvre P, Staels B. PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD. Nat Rev Endocrinol. 2017;13:36–49.

    Article  CAS  PubMed  Google Scholar 

  9. Turpin SM, Nicholls HT, Willmes DM, Mourier A, Brodesser S, Wunderlich CM, et al. Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance. Cell Metab. 2014;20:678–86.

    Article  CAS  PubMed  Google Scholar 

  10. Rozec B, Gauthier C. beta3-adrenoceptors in the cardiovascular system: putative roles in human pathologies. Pharmacol Ther. 2006;111:652–73.

    Article  CAS  PubMed  Google Scholar 

  11. Michel LYM, Farah C, Balligand JL. The Beta3 adrenergic receptor in healthy and pathological cardiovascular tissues. Cells. 2020;9:2584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cypess AM, Weiner LS, Roberts-Toler C, Franquet Elía E, Kessler SH, Kahn PA, et al. Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab. 2015;21:33–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Boström P, Wu J, Jedrychowski M, Korde A, Ye L, Lo J, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481:463–8.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Zhang Y, Xie C, Wang H, Foss RM, Clare M, George EV, et al. Irisin exerts dual effects on browning and adipogenesis of human white adipocytes. Am J Physiol Endocrinol Metab. 2016;311:E530–41.

    Article  PubMed  Google Scholar 

  15. Guo M, Yao J, Li J, Zhang J, Wang D, Zuo H, et al. Irisin ameliorates age-associated sarcopenia and metabolic dysfunction. J Cachexia Sarcopenia Muscle. 2023;14:391–405.

    Article  PubMed  Google Scholar 

  16. Zhang Y, Li R, Meng Y, Li S, Donelan W, Zhao Y, et al. Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. Diabetes. 2014;63:514–25.

    Article  CAS  PubMed  Google Scholar 

  17. Zhang HJ, Zhang XF, Ma ZM, Pan LL, Chen Z, Han HW, et al. Irisin is inversely associated with intrahepatic triglyceride contents in obese adults. J Hepatol. 2013;59:557–62.

    Article  CAS  PubMed  Google Scholar 

  18. Shimizu I, Aprahamian T, Kikuchi R, Shimizu A, Papanicolaou KN, MacLauchlan S, et al. Vascular rarefaction mediates whitening of brown fat in obesity. J Clin Invest. 2014;124:2099–112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Peng XG, Ju S, Fang F, Wang Y, Fang K, Cui X, et al. Comparison of brown and white adipose tissue fat fractions in ob, seipin, and Fsp27 gene knockout mice by chemical shift-selective imaging and (1)H-MR spectroscopy. Am J Physiol Endocrinol Metab. 2013;304:E160–7.

    Article  CAS  PubMed  Google Scholar 

  20. Chen Y, Ding J, Zhao Y, Ju S, Mao H, Peng XG. Irisin induces white adipose tissue browning in mice as assessed by magnetic resonance imaging. Exp Biol Med (Maywood). 2021;246:1597–606.

    Article  CAS  PubMed  Google Scholar 

  21. Zhao Y, Dai J, Jiang Y, Wu H, Cui Y, Li X, et al. Reducing white adipose tissue browning using p38α MAPK inhibitors ameliorates cancer-associated cachexia as assessed by magnetic resonance imaging. Nutrients. 2022;14:3013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kong X, Yao T, Zhou P, Kazak L, Tenen D, Lyubetskaya A, et al. Brown adipose tissue controls skeletal muscle function via the secretion of myostatin. Cell Metab. 2018;28:631–43.e3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lunati E, Marzola P, Nicolato E, Fedrigo M, Villa M, Sbarbati A. In vivo quantitative lipidic map of brown adipose tissue by chemical shift imaging at 4.7 Tesla. J Lipid Res. 1999;40:1395–400.

    Article  CAS  PubMed  Google Scholar 

  24. Seki T, Yang Y, Sun X, Lim S, Xie S, Guo Z, et al. Brown-fat-mediated tumour suppression by cold-altered global metabolism. Nature. 2022;608:421–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mirbolooki MR, Constantinescu CC, Pan ML, Mukherjee J. Quantitative assessment of brown adipose tissue metabolic activity and volume using 18F-FDG PET/CT and β3-adrenergic receptor activation. EJNMMI Res. 2011;1:30.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Leitner BP, Huang S, Brychta RJ, Duckworth CJ, Baskin AS, McGehee S, et al. Mapping of human brown adipose tissue in lean and obese young men. Proc Natl Acad Sci USA. 2017;114:8649–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Song A, Dai W, Jang MJ, Medrano L, Li Z, Zhao H, et al. Low- and high-thermogenic brown adipocyte subpopulations coexist in murine adipose tissue. J Clin Invest. 2020;130:247–57.

    Article  CAS  PubMed  Google Scholar 

  28. Crandall JP, Fraum TJ, Wahl RL. Brown adipose tissue: a protective mechanism against “preprediabetes”? J Nucl Med. 2022;63:1433–40.

    Article  CAS  PubMed  Google Scholar 

  29. Cobb T, Hwang I, Soukar M, Namkoong S, Cho US, Safdar M, et al. Iditarod, a Drosophila homolog of the Irisin precursor FNDC5, is critical for exercise performance and cardiac autophagy. Proc Natl Acad Sci USA. 2023;120:e2220556120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lee P, Linderman JD, Smith S, Brychta RJ, Wang J, Idelson C, et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab. 2014;19:302–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Martinez-Lopez N, Garcia-Macia M, Sahu S, Athonvarangkul D, Liebling E, Merlo P, et al. Autophagy in the CNS and periphery coordinate lipophagy and lipolysis in the brown adipose tissue and liver. Cell Metab. 2016;23:113–27.

    Article  CAS  PubMed  Google Scholar 

  32. Lee J, Ellis JM, Wolfgang MJ. Adipose fatty acid oxidation is required for thermogenesis and potentiates oxidative stress-induced inflammation. Cell Rep. 2015;10:266–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang J, Fang N, Xiong J, Du Y, Cao Y, Ji WK. An ESCRT-dependent step in fatty acid transfer from lipid droplets to mitochondria through VPS13D-TSG101 interactions. Nat Commun. 2021;12:1252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sponton CH, de Lima-Junior JC, Leiria LO. What puts the heat on thermogenic fat: metabolism of fuel substrates. Trends Endocrinol Metab. 2022;33:587–99.

    Article  CAS  PubMed  Google Scholar 

  35. Leiria LO, Wang CH, Lynes MD, Yang K, Shamsi F, Sato M, et al. 12-Lipoxygenase Regulates Cold Adaptation and Glucose Metabolism by Producing the Omega-3 Lipid 12-HEPE from Brown Fat. Cell Metab. 2019;30:768–83.e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Duta-Mare M, Sachdev V, Leopold C, Kolb D, Vujic N, Korbelius M, et al. Lysosomal acid lipase regulates fatty acid channeling in brown adipose tissue to maintain thermogenesis. Biochim Biophys Acta Mol Cell Biol Lipids. 2018;1863:467–78.

    Article  CAS  PubMed  Google Scholar 

  37. Cui L, Mirza AH, Zhang S, Liang B, Liu P. Lipid droplets and mitochondria are anchored during brown adipocyte differentiation. Protein Cell. 2019;10:921–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yu J, Zhang S, Cui L, Wang W, Na H, Zhu X, et al. Lipid droplet remodeling and interaction with mitochondria in mouse brown adipose tissue during cold treatment. Biochim Biophys Acta. 2015;1853:918–28.

    Article  CAS  PubMed  Google Scholar 

  39. Franz D, Karampinos DC, Rummeny EJ, Souvatzoglou M, Beer AJ, Nekolla SG, et al. Discrimination Between Brown and White Adipose Tissue Using a 2-Point Dixon Water-Fat Separation Method in Simultaneous PET/MRI. J Nucl Med. 2015;56:1742–7.

    Article  CAS  PubMed  Google Scholar 

  40. Hamilton G, Smith DL, Bydder M, Nayak KS, Hu HH. MR properties of brown and white adipose tissues. J Magn Reson Imaging. 2011;34:468–73.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Ouwerkerk R, Hamimi A, Matta J, Abd-Elmoniem KZ, Eary JF, Abdul Sater Z, et al. Proton MR Spectroscopy Measurements of White and Brown Adipose Tissue in Healthy Humans: Relaxation Parameters and Unsaturated Fatty Acids. Radiology. 2021;299:396–406.

    Article  PubMed  Google Scholar 

  42. Lundström E, Strand R, Forslund A, Bergsten P, Weghuber D, Ahlström H, et al. Automated segmentation of human cervical-supraclavicular adipose tissue in magnetic resonance images. Sci Rep. 2017;7:3064.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Chouchani ET, Kazak L, Spiegelman BM. New advances in adaptive thermogenesis: UCP1 and Beyond. Cell Metab. 2019;29:27–37.

    Article  CAS  PubMed  Google Scholar 

  44. Ikeda K, Kang Q, Yoneshiro T, Camporez JP, Maki H, Homma M, et al. UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nat Med. 2017;23:1454–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kazak L, Chouchani ET, Jedrychowski MP, Erickson BK, Shinoda K, Cohen P, et al. A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell. 2015;163:643–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang T, Sharma AK, Wu C, Maushart CI, Ghosh A, Yang W, et al. Single-nucleus transcriptomics identifies separate classes of UCP1 and futile cycle adipocytes. Cell Metab. 2024;36:2130–45.e7.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work is funded by National Natural Science Foundation of China (81871412 and 82272064), Jiangsu Provincial Science and Technique Program (BK20221461), Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX21_0159, KYCX22_0297, and KYCX23_0323).

Author information

Authors and Affiliations

  1. Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China

    Jingyue Dai, Yufei Zhao, Yue Chen, Yang Jiang, Xingzhe Tang, Ying Cui & Xin-Gui Peng

  2. Department of Pharmacy, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu, 215002, China

    Rui Sun

  3. Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, 30322, USA

    Hui Mao

  4. Department of Radiology, Nanjing Lishui People’s Hospital, Zhongda Hospital Lishui Branch, Southeast University, Nanjing, 211200, China

    Xin-Gui Peng

Authors
  1. Jingyue Dai
    View author publications

    Search author on:PubMed Google Scholar

  2. Yufei Zhao
    View author publications

    Search author on:PubMed Google Scholar

  3. Yue Chen
    View author publications

    Search author on:PubMed Google Scholar

  4. Yang Jiang
    View author publications

    Search author on:PubMed Google Scholar

  5. Rui Sun
    View author publications

    Search author on:PubMed Google Scholar

  6. Xingzhe Tang
    View author publications

    Search author on:PubMed Google Scholar

  7. Ying Cui
    View author publications

    Search author on:PubMed Google Scholar

  8. Hui Mao
    View author publications

    Search author on:PubMed Google Scholar

  9. Xin-Gui Peng
    View author publications

    Search author on:PubMed Google Scholar

Contributions

The contributions of all authors are presented as follows. Jingyue Dai: research design and conceptualization, background research, practical performance, data analysis, writing - original draft. Yufei Zhao, Xingzhe Tang, Rui Sun: validation, practical performance. Yue Chen: research design and conceptualization, background research. Yang Jiang, Ying Cui: data collection and analysis. Hui Mao: experimental design, writing - review & editing. Xin-Gui Peng: research design and conceptualization, supervision, project administration, funding acquisition, writing - review & editing. All authors revised and edited the manuscript. The authors extend thanks to Dr. Xiaoxuan Xu, Prof. Yanli An and Prof. Fengchao Zang for their invaluable assistance in methodological support.

Corresponding author

Correspondence to Xin-Gui Peng.

Ethics declarations

Competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethics Approval and Consent to Participate

All animal experiments were performed in accordance with the relevant guidelines and regulations approved by the Institutional Animal Care and Use Committee of the Medical School of Southeast University (approval ID: 20210601020).

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dai, J., Zhao, Y., Chen, Y. et al. Irisin reverses high-fat diet-induced metabolic dysfunction via activation of brown adipose tissue in mice. Int J Obes 49, 1066–1075 (2025). https://doi.org/10.1038/s41366-025-01739-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-025-01739-z

Search

Advanced search

Quick links