Skip to main content
Springer Nature Link
Log in

Liraglutide induced browning of visceral white adipose through regulation of miRNAs in high-fat-diet-induced obese mice

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Objective

See More

Obesity is characterized by excessive accumulation of white adipose tissue (WAT). Conversely, brown adipose tissue is protective against obesity. We recently reported liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), could inhibit high-fat-diet-induced obesity by browning of WAT. However, the molecular mechanism involved is not well defined. Hence, we aimed to explore whether GLP-1RA could promote brown remodeling in WAT by regulating miRNAs.

Methods

After the obesity model was successfully constructed, C57BL/6J mice were treated with liraglutide (200 μg/kg/d) or equivoluminal saline subcutaneously for 12 weeks. Then, the deposition of abdominal fat was measured by CT scanning. At the end of the treatments, glucose and insulin tolerance in mice were assessed. Serum lipid levels were monitored and epididymal WAT (eWAT) were collected for analysis. Quantitative real-time PCR and western blot analyses were conducted to evaluate the expression of genes and miRNAs associated with white fat browning.

Results

Liraglutide significantly reduced body weight and visceral fat mass. Levels of lipid profile were also improved. Liraglutide upregulated the expression of browning-related genes in eWAT. Meanwhile, the expression level of miRNAs (miR-196a and miR-378a) positively associated with the browning of WAT were increased, while the expression of miR-155, miR-199a, and miR-382 negatively related with browning of WAT were decreased.

Conclusion

Our findings suggest that liraglutide could promote brown remodeling of visceral WAT by bi-regulating miRNAs; this might be one of the mechanisms underlying its effect on weight loss.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+
from $39.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

Data availability

All data generated or analyzed during this study are included within the article.

Abbreviations

GLP-1RA:

glucagon-like peptide-1 receptor agonists

AT:

adipose tissue

WAT:

white adipose tissue

eWAT:

epididymal white adipose tissue

BAT:

brown adipose tissue

UCP1:

unique Uncoupling protein 1

FGF21:

fibroblast growth factor 21

ND:

normal diet

HFD:

high-fat diet

TG:

triglycerides

TC:

total cholesterol

LDL:

low-density lipoprotein

PGC-1α:

Peroxisome proliferator-activated receptor-gamma coactivator-1alpha

PRDM16:

positive regulatory domain containing 16

CIDEA:

cell death-inducing DNA fragmentation factorα-like effector A

MAPK:

mitogen-activated protein kinase.

References

  1. X. Jin, T. Qiu, L. Li, R. Yu, X. Chen, C. Li, C.G. Proud, T. Jiang, Pathophysiology of obesity and its associated diseases. Acta. Pharm. Sin. B 13, 2403–2424 (2023). https://doi.org/10.1016/j.apsb.2023.01.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. F. Shamsi, C.H. Wang, Y.H. Tseng, The evolving view of thermogenic adipocytes - ontogeny, niche and function. Nat. Rev. Endocrinol. 17, 726–744 (2021). https://doi.org/10.1038/s41574-021-00562-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. S. Heinonen, R. Jokinen, A. Rissanen, K.H. Pietiläinen, White adipose tissue mitochondrial metabolism in health and in obesity. Obes. Rev. 21, e12958 (2020). https://doi.org/10.1111/obr.12958

    Article  PubMed  Google Scholar 

  4. D. Da Eira, S. Jani, R.B. Ceddia, An obesogenic diet impairs uncoupled substrate oxidation and promotes whitening of the brown adipose tissue in rats. J. Physiol. 601, 69–82 (2023). https://doi.org/10.1113/jp283721

    Article  CAS  PubMed  Google Scholar 

  5. N. Vujović, M.J. Piron, J. Qian, S.L. Chellappa, A. Nedeltcheva, D. Barr, S.W. Heng, K. Kerlin, S. Srivastav, W. Wang, B. Shoji, M. Garaulet, M.J. Brady, F. Scheer, Late isocaloric eating increases hunger, decreases energy expenditure, and modifies metabolic pathways in adults with overweight and obesity. Cell Metab. 34, 1486–1498.e7 (2022). https://doi.org/10.1016/j.cmet.2022.09.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Y. Li, P.C. Schwalie, A. Bast-Habersbrunner, S. Mocek, J. Russeil, T. Fromme, B. Deplancke, M. Klingenspor, Systems-genetics-based inference of a core regulatory network underlying white fat browning. Cell Rep. 29, 4099–4113.e5 (2019). https://doi.org/10.1016/j.celrep.2019.11.053

    Article  CAS  PubMed  Google Scholar 

  7. V.M. Lima, J. Liu, B.B. Brandão, C.A. Lino, C.S. Balbino Silva, M.A.C. Ribeiro, T.E. Oliveira, C.C. Real, D. de Paula Faria, C. Cederquist, Z.P. Huang, X. Hu, M.L. Barreto-Chaves, J.C.B. Ferreira, W.T. Festuccia, M.A. Mori, C.R. Kahn, D.Z. Wang, G.P. Diniz, miRNA-22 deletion limits white adipose expansion and activates brown fat to attenuate high-fat diet-induced fat mass accumulation. Metabolism 117, 154723 (2021). https://doi.org/10.1016/j.metabol.2021.154723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Y.F. Lv, J. Yu, Y.L. Sheng, M. Huang, X.C. Kong, W.J. Di, J. Liu, H. Zhou, H. Liang, G.X. Ding, Glucocorticoids suppress the browning of adipose tissue via miR-19b in male mice. Endocrinology 159, 310–322 (2018). https://doi.org/10.1210/en.2017-00566

    Article  CAS  PubMed  Google Scholar 

  9. H. Zhang, M. Guan, K.L. Townsend, T.L. Huang, D. An, X. Yan, R. Xue, T.J. Schulz, J. Winnay, M. Mori, M.F. Hirshman, K. Kristiansen, J.S. Tsang, A.P. White, A.M. Cypess, L.J. Goodyear, Y.H. Tseng, MicroRNA-455 regulates brown adipogenesis via a novel HIF1an-AMPK-PGC1α signaling network. EMBO Rep. 16, 1378–1393 (2015). https://doi.org/10.15252/embr.201540837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. L. He, M. Tang, T. Xiao, H. Liu, W. Liu, G. Li, F. Zhang, Y. Xiao, Z. Zhou, F. Liu, F. Hu, Obesity-associated miR-199a/214 cluster inhibits adipose browning via PRDM16-PGC-1α transcriptional network. Diabetes 67, 2585–2600 (2018). https://doi.org/10.2337/db18-0626

    Article  PubMed  Google Scholar 

  11. N. Arias, L. Aguirre, A. Fernández-Quintela, M. González, A. Lasa, J. Miranda, M.T. Macarulla, M.P. Portillo, MicroRNAs involved in the browning process of adipocytes. J. Physiol. Biochem. 72, 509–521 (2016). https://doi.org/10.1007/s13105-015-0459-z

    Article  CAS  PubMed  Google Scholar 

  12. M. Mori, H. Nakagami, G. Rodriguez-Araujo, K. Nimura, Y. Kaneda, Essential role for miR-196a in brown adipogenesis of white fat progenitor cells. PLoS Biol. 10, e1001314 (2012). https://doi.org/10.1371/journal.pbio.1001314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Y. Chen, F. Siegel, S. Kipschull, B. Haas, H. Fröhlich, G. Meister, A. Pfeifer, miR-155 regulates differentiation of brown and beige adipocytes via a bistable circuit. Nat. Commun. 4, 1769 (2013). https://doi.org/10.1038/ncomms2742

    Article  CAS  PubMed  Google Scholar 

  14. A. Astrup, S. Rossner, L. Van Gaal, A. Rissanen, L. Niskanen, M. Al Hakim, J. Madsen, M.F. Rasmussen, M.E. Lean; N.N.S. Group, Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet 374, 1606–1616 (2009). https://doi.org/10.1016/S0140-6736(09)61375-1

    Article  CAS  PubMed  Google Scholar 

  15. M.C. Thomas, M.T. Coughlan, M.E. Cooper, The postprandial actions of GLP-1 receptor agonists: the missing link for cardiovascular and kidney protection in type 2 diabetes. Cell Metab. 35, 253–273 (2023). https://doi.org/10.1016/j.cmet.2023.01.004

    Article  CAS  PubMed  Google Scholar 

  16. J. Chen, A. Mei, Y. Wei, C. Li, H. Qian, X. Min, H. Yang, L. Dong, X. Rao, J. Zhong, GLP-1 receptor agonist as a modulator of innate immunity. Front. Immunol. 13, 997578 (2022). https://doi.org/10.3389/fimmu.2022.997578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Food and Drug Administration, Saxenda (Liraglutide 3.0 Mg) Prescribing Information, (Food and Drug Administration, Springer Field, Maryland, 2014)

  18. D. Beiroa, M. Imbernon, R. Gallego, A. Senra, D. Herranz, F. Villarroya, M. Serrano, J. Fernø, J. Salvador, J. Escalada, C. Dieguez, M. Lopez, G. Frühbeck, R. Nogueiras, GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 63, 3346–3358 (2014). https://doi.org/10.2337/db14-0302

    Article  CAS  PubMed  Google Scholar 

  19. L. Lynch, A.E. Hogan, D. Duquette, C. Lester, A. Banks, K. LeClair, D.E. Cohen, A. Ghosh, B. Lu, M. Corrigan, D. Stevanovic, E. Maratos-Flier, D.J. Drucker, D. O’Shea, M. Brenner, iNKT cells induce FGF21 for thermogenesis and are required for maximal weight loss in GLP1 therapy. Cell Metab. 24, 510–519 (2016). https://doi.org/10.1016/j.cmet.2016.08.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. P.L. Valenzuela, P. Carrera-Bastos, A. Castillo-García, D.E. Lieberman, A. Santos-Lozano, A. Lucia, Obesity and the risk of cardiometabolic diseases. Nat. Rev. Cardiol. 20, 475–494 (2023). https://doi.org/10.1038/s41569-023-00847-5

    Article  PubMed  Google Scholar 

  21. D.M. Rubino, F.L. Greenway, U. Khalid, P.M. O’Neil, J. Rosenstock, R. Sørrig, T.A. Wadden, A. Wizert, W.T. Garvey, Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes: The STEP 8 Randomized Clinical Trial. JAMA 327, 138–150 (2022). https://doi.org/10.1001/jama.2021.23619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. A.S. Kelly, P. Auerbach, M. Barrientos-Perez, I. Gies, P.M. Hale, C. Marcus, L.D. Mastrandrea, N. Prabhu, S. Arslanian, A randomized, controlled trial of liraglutide for adolescents with obesity. N. Eng. J. Med. 382, 2117–2128 (2020). https://doi.org/10.1056/NEJMoa1916038

    Article  CAS  Google Scholar 

  23. D. Papamargaritis, C.W. le Roux, J.J. Holst, M.J. Davies, New therapies for obesity. Cardiovasc. Res. (2022). https://doi.org/10.1093/cvr/cvac176

  24. K. Raun, P. von Voss, C.F. Gotfredsen, V. Golozoubova, B. Rolin, L.B. Knudsen, Liraglutide, a long-acting glucagon-like peptide-1 analog, reduces body weight and food intake in obese candy-fed rats, whereas a dipeptidyl peptidase-IV inhibitor, vildagliptin, does not. Diabetes 56, 8–15 (2007). https://doi.org/10.2337/db06-0565

    Article  CAS  PubMed  Google Scholar 

  25. X. Pi-Sunyer, A. Astrup, K. Fujioka, F. Greenway, A. Halpern, M. Krempf, D.C. Lau, C.W. le Roux, R. Violante Ortiz, C.B. Jensen, J.P. Wilding, A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N. Eng. J. Med. 373, 11–22 (2015). https://doi.org/10.1056/NEJMoa1411892

    Article  CAS  Google Scholar 

  26. R.Z. Ye, G. Richard, N. Gévry, A. Tchernof, A.C. Carpentier, Fat cell size: measurement methods, pathophysiological origins, and relationships with metabolic dysregulations. Endocr. Rev. 43, 35–60 (2022). https://doi.org/10.1210/endrev/bnab018

    Article  PubMed  Google Scholar 

  27. T. Skurk, C. Alberti-Huber, C. Herder, H. Hauner, Relationship between adipocyte size and adipokine expression and secretion. J. Clin. Endocrinol. Metab. 92, 1023–1033 (2007). https://doi.org/10.1210/jc.2006-1055

    Article  CAS  PubMed  Google Scholar 

  28. Y. Wan, X. Bao, J. Huang, X. Zhang, W. Liu, Q. Cui, D. Jiang, Z. Wang, R. Liu, Q. Wang, Novel GLP-1 analog supaglutide reduces HFD-induced obesity associated with increased Ucp-1 in white adipose tissue in mice. Front. Physiol. 8, 294 (2017). https://doi.org/10.3389/fphys.2017.00294

    Article  PubMed  PubMed Central  Google Scholar 

  29. S. Kajimura, B.M. Spiegelman, P. Seale, Brown and beige fat: physiological roles beyond heat generation. Cell Metab. 22, 546–559 (2015). https://doi.org/10.1016/j.cmet.2015.09.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. A. Bartelt, C. John, N. Schaltenberg, J.F.P. Berbée, A. Worthmann, M.L. Cherradi, C. Schlein, J. Piepenburg, M.R. Boon, F. Rinninger, M. Heine, K. Toedter, A. Niemeier, S.K. Nilsson, M. Fischer, S.L. Wijers, W. van Marken Lichtenbelt, L. Scheja, P.C.N. Rensen, J. Heeren, Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport. Nat. Commun. 8, 15010 (2017). https://doi.org/10.1038/ncomms15010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. J. Wu, P. Cohen, B.M. Spiegelman, Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev. 27, 234–250 (2013). https://doi.org/10.1101/gad.211649.112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. F. Xu, B. Lin, X. Zheng, Z. Chen, H. Cao, H. Xu, H. Liang, J. Weng, GLP-1 receptor agonist promotes brown remodelling in mouse white adipose tissue through SIRT1. Diabetologia 59, 1059–1069 (2016). https://doi.org/10.1007/s00125-016-3896-5

    Article  CAS  PubMed  Google Scholar 

  33. H.J. Jun, Y. Joshi, Y. Patil, R.C. Noland, J.S. Chang, NT-PGC-1α activation attenuates high-fat diet-induced obesity by enhancing brown fat thermogenesis and adipose tissue oxidative metabolism. Diabetes 63, 3615–3625 (2014). https://doi.org/10.2337/db13-1837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. K.J. Chung, A. Chatzigeorgiou, M. Economopoulou, R. Garcia-Martin, V.I. Alexaki, I. Mitroulis, M. Nati, J. Gebler, T. Ziemssen, S.E. Goelz, J. Phieler, J.H. Lim, K.P. Karalis, T. Papayannopoulou, M. Blüher, G. Hajishengallis, T. Chavakis, A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity. Nat. Immunol. 18, 654–664 (2017). https://doi.org/10.1038/ni.3728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. M. Uldry, W. Yang, J. St-Pierre, J. Lin, P. Seale, B.M. Spiegelman, Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab. 3, 333–341 (2006). https://doi.org/10.1016/j.cmet.2006.04.002

    Article  CAS  PubMed  Google Scholar 

  36. D. Cuevas-Ramos, R. Mehta, C.A. Aguilar-Salinas, Fibroblast growth factor 21 and browning of white adipose tissue. Front. Physiol. 10, 37 (2019). https://doi.org/10.3389/fphys.2019.00037

    Article  PubMed  PubMed Central  Google Scholar 

  37. S. Jash, S. Banerjee, M.J. Lee, S.R. Farmer, V. Puri, CIDEA transcriptionally regulates UCP1 for britening and thermogenesis in human fat cells. iScience 20, 73–89 (2019). https://doi.org/10.1016/j.isci.2019.09.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. J. Wang, Y. Zhou, D. Long, Y. Wu, F. Liu, GLP-1 receptor agonist, liraglutide, protects podocytes from apoptosis in diabetic nephropathy by promoting white fat browning. Biochem. Biophys. Res. Commun. 664, 142–151 (2023). https://doi.org/10.1016/j.bbrc.2023.04.012

    Article  CAS  PubMed  Google Scholar 

  39. L. Zhao, C. Zhu, M. Lu, C. Chen, X. Nie, B. Abudukerimu, K. Zhang, Z. Ning, Y. Chen, J. Cheng, F. Xia, N. Wang, M.D. Jensen, Y. Lu, The key role of a glucagon-like peptide-1 receptor agonist in body fat redistribution. J. Endocrinol. 240, 271–286 (2019). https://doi.org/10.1530/joe-18-0374

    Article  CAS  PubMed  Google Scholar 

  40. X. Zhang, D.C. Yeung, M. Karpisek, D. Stejskal, Z.G. Zhou, F. Liu, R.L. Wong, W.S. Chow, A.W. Tso, K.S. Lam, A. Xu, Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 57, 1246–1253 (2008). https://doi.org/10.2337/db07-1476

    Article  CAS  PubMed  Google Scholar 

  41. P.Y. Ma, X.Y. Li, Y.L. Wang, D.Q. Lang, L. Liu, Y.K. Yi, Q. Liu, C.Y. Shen, Natural bioactive constituents from herbs and nutraceuticals promote browning of white adipose tissue. Pharmacol. Res. 178, 106175 (2022). https://doi.org/10.1016/j.phrs.2022.106175

    Article  CAS  PubMed  Google Scholar 

  42. N. Huang, J. Wang, W. Xie, Q. Lyu, J. Wu, J. He, W. Qiu, N. Xu, Y. Zhang, MiR-378a-3p enhances adipogenesis by targeting mitogen-activated protein kinase 1. Biochem. Biophys. Res. Commun. 457, 37–42 (2015). https://doi.org/10.1016/j.bbrc.2014.12.055

    Article  CAS  PubMed  Google Scholar 

  43. W.H. Choi, J. Ahn, C.H. Jung, Y.J. Jang, T.Y. Ha, β-lapachone prevents diet-induced obesity by increasing energy expenditure and stimulating the browning of white adipose tissue via downregulation of miR-382 expression. Diabetes 65, 2490–2501 (2016). https://doi.org/10.2337/db15-1423

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported in part by grants from the National Natural Science Foundation of China (82000809, 81870548), the Social Development Project of Jiangsu Province (BE2018692), the Natural Science Foundation of Jiangsu Province, China (BK20191222), and the Social Development Project of Zhenjiang City (SH2019041), Jiangsu Province.

Author information

Author notes

  1. These authors contributed equally: Li Zhao, Wenxin Li, Panpan Zhang.

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China

    Li Zhao, Wenxin Li, Dong Wang, Ling Yang & Guoyue Yuan

  2. Department of Endocrinology, Taicang Hospital of Traditional Chinese Medicine, Taicang, Jiangsu, China

    Panpan Zhang

Authors
  1. Li Zhao
    View author publications

    Search author on:PubMed Google Scholar

  2. Wenxin Li
    View author publications

    Search author on:PubMed Google Scholar

  3. Panpan Zhang
    View author publications

    Search author on:PubMed Google Scholar

  4. Dong Wang
    View author publications

    Search author on:PubMed Google Scholar

  5. Ling Yang
    View author publications

    Search author on:PubMed Google Scholar

  6. Guoyue Yuan
    View author publications

    Search author on:PubMed Google Scholar

Contributions

L.Z. and G.Y. conceived and designed the study. L.Z. and W.L. performed the analysis, prepared the figures, and drafted the manuscript. W.L. and P.Z. performed the experiment, collected the data. D.W., L.Y., and G.Y. conceived the study and participated in its design and coordination. All the authors discussed the results and approved the final manuscript.

Corresponding authors

Correspondence to Li Zhao or Guoyue Yuan.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Ethical approval

The study was approved by the Biomedical Research Ethics Committee of Affiliated Hospital of Jiangsu University, Zhenjiang, China, and performed in accordance with the Declaration of Helsinki.

Additional information

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

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

Zhao, L., Li, W., Zhang, P. et al. Liraglutide induced browning of visceral white adipose through regulation of miRNAs in high-fat-diet-induced obese mice. Endocrine 85, 222–232 (2024). https://doi.org/10.1007/s12020-024-03734-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1007/s12020-024-03734-2

Keywords