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.

  • Original Article
  • Published:

Animal Models

Dietary luteolin activates browning and thermogenesis in mice through an AMPK/PGC1α pathway-mediated mechanism

International Journal of Obesity volume 40, pages 1841–1849 (2016)Cite this article

Subjects

Abstract

Background:

Two brown-like adipocytes, including classical brown adipocytes from brown adipose tissues and beige cells from white adipose tissues, regulate thermogenesis. The developmental and functional induction of brown-like cells provides a defense against obesity and associated metabolic diseases. Our previous study suggests dietary luteolin can improve diet-induced obesity and insulin resistance in mice. Here we further elucidated the action of the natural flavonoid on energy expenditure and adaptive thermogenesis.

Methods:

Five-week-old male C57BL/6 mice were fed low-fat diet (LFD), high-fat diet (HFD) and HFD supplemented with 0.01% luteolin. After 12 weeks, their energy expenditure were detected using a combined indirect calorimetry system. Moreover, thermogenic program and associated molecular regulators were assessed in adipose tissues. In another independent study, even-aged mice were fed LFD and luteolin-containing LFD for 12 weeks, and their energy expenditure and thermogenic program were also investigated. Finally, differentiated primary brown and subcutaneous adipocytes were used to identify the critical participation of AMPK/PGC1α signaling in luteolin-regulated browning and thermogenesis.

Results:

In mice fed either HFD or LFD, dietary luteolin supplement increased oxygen consumption, carbon dioxide production and respiratory exchange ratio. The enhancement in energy expenditure was accompanied by the upregulation of thermogenic genes in brown and subcutaneous adipose tissues. Meanwhile, several important AMPK/PGC1α signaling molecules were activated by dietary luteolin in the tissues. Further, luteolin treatment directly elevated thermogenic gene expressions and activated AMPK/PGC1α signaling in differentiated primary brown and subcutaneous adipocytes, whereas AMPK inhibitor Compound C reversed the efficiencies.

Conclusions:

Dietary luteolin activated browning and thermogenesis through an AMPK/PGC1α pathway-mediated mechanism.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Spiegelman BM, Flier JS . Obesity and the regulation of energy balance. Cell 2001; 104: 531–543.

    Article  CAS  Google Scholar 

  2. Rosen ED, Spiegelman BM . What we talk about when we talk about fat. Cell 2014; 156: 20–44.

    Article  CAS  Google Scholar 

  3. Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012; 150: 366–376.

    Article  CAS  Google Scholar 

  4. Harms M, Seale P . Brown and beige fat: development, function and therapeutic potential. Nat Med 2013; 19: 1252–1263.

    Article  CAS  Google Scholar 

  5. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009; 360: 1509–1517.

    Article  CAS  Google Scholar 

  6. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T et al. Functional brown adipose tissue in healthy adults. N Engl J Med 2009; 360: 1518–1525.

    Article  CAS  Google Scholar 

  7. Kajimura S, Saito M . A new era in brown adipose tissue biology: molecular control of brown fat development and energy homeostasis. Annu Rev Physiol 2014; 76: 225–249.

    Article  CAS  Google Scholar 

  8. Lopez-Lazaro M . Distribution and biological activities of the flavonoid luteolin. Mini Rev Med Chem 2009; 9: 31–59.

    Article  CAS  Google Scholar 

  9. Xu N, Zhang L, Dong J, Zhang X, Chen YG, Bao B et al. Low-dose diet supplement of a natural flavonoid, luteolin, ameliorates diet-induced obesity and insulin resistance in mice. Mol Nutr Food Res 2014; 58: 1258–1268.

    Article  CAS  Google Scholar 

  10. Kwon EY, Jung UJ, Park T, Yun JW, Choi MS . Luteolin attenuates hepatic steatosis and insulin resistance through the interplay between the liver and adipose tissue in diet-induced obese mice. Diabetes 2015; 64: 1658–1669.

    Article  CAS  Google Scholar 

  11. Puhl AC, Bernardes A, Silveira RL, Yuan J, Campos JL, Saidemberg DM et al. Mode of peroxisome proliferator-activated receptor gamma activation by luteolin. Mol Pharmacol 2012; 81: 788–799.

    Article  CAS  Google Scholar 

  12. Park HS, Kim SH, Kim YS, Ryu SY, Hwang JT, Yang HJ et al. Luteolin inhibits adipogenic differentiation by regulating PPARgamma activation. Biofactors 2009; 35: 373–379.

    Article  CAS  Google Scholar 

  13. Ding L, Jin D, Chen X . Luteolin enhances insulin sensitivity via activation of PPARgamma transcriptional activity in adipocytes. J Nutr Biochem 2010; 21: 941–947.

    Article  CAS  Google Scholar 

  14. Fernandez-Marcos PJ, Auwerx J . Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr 2011; 93: 884S–890S.

    Article  CAS  Google Scholar 

  15. Hardie DG, Ross FA, Hawley SA . AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 2012; 13: 251–262.

    Article  CAS  Google Scholar 

  16. Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 2009; 458: 1056–1060.

    Article  CAS  Google Scholar 

  17. Suwa M, Nakano H, Kumagai S . Effects of chronic AICAR treatment on fiber composition, enzyme activity, UCP3, and PGC-1 in rat muscles. J Appl Physiol 2003; 95: 960–968.

    Article  CAS  Google Scholar 

  18. Jager S, Handschin C, St-Pierre J, Spiegelman BM . AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci USA 2007; 104: 12017–12022.

    Article  Google Scholar 

  19. Xiao N, Mei F, Sun Y, Pan G, Liu B, Liu K . Quercetin, luteolin, and epigallocatechin gallate promote glucose disposal in adipocytes with regulation of AMP-activated kinase and/or sirtuin 1 activity. Planta Med 2014; 80: 993–1000.

    Article  CAS  Google Scholar 

  20. Dong J, Zhang X, Zhang L, Bian HX, Xu N, Bao B et al. Quercetin reduces obesity-associated ATM infiltration and inflammation in mice: a mechanism including AMPKalpha1/SIRT1. J Lipid Res 2014; 55: 363–374.

    Article  CAS  Google Scholar 

  21. Tseng YH, Kriauciunas KM, Kokkotou E, Kahn CR . Differential roles of insulin receptor substrates in brown adipocyte differentiation. Mol Cell Biol 2004; 24: 1918–1929.

    Article  CAS  Google Scholar 

  22. Klein J, Fasshauer M, Ito M, Lowell BB, Benito M, Kahn CR . beta(3)-adrenergic stimulation differentially inhibits insulin signaling and decreases insulin-induced glucose uptake in brown adipocytes. J Biol Chem 1999; 274: 34795–34802.

    Article  CAS  Google Scholar 

  23. Zhang Z, Zhang H, Li B, Meng X, Wang J, Zhang Y et al. Berberine activates thermogenesis in white and brown adipose tissue. Nat Commun 2014; 5: 5493.

    Article  CAS  Google Scholar 

  24. McDonald ME, Li C, Bian H, Smith BD, Layne MD, Farmer SR . Myocardin-related transcription factor A regulates conversion of progenitors to beige adipocytes. Cell 2015; 160: 105–118.

    Article  CAS  Google Scholar 

  25. Rosenwald M, Perdikari A, Rulicke T, Wolfrum C . Bi-directional interconversion of brite and white adipocytes. Nat Cell Biol 2013; 15: 659–667.

    Article  CAS  Google Scholar 

  26. Lee YH, Petkova AP, Mottillo EP, Granneman JG . In vivo identification of bipotential adipocyte progenitors recruited by beta3-adrenoceptor activation and high-fat feeding. Cell Metab 2012; 15: 480–491.

    Article  CAS  Google Scholar 

  27. Cousin B, Cinti S, Morroni M, Raimbault S, Ricquier D, Penicaud L et al. Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. J Cell Sci 1992; 103: 931–942.

    CAS  Google Scholar 

  28. Okla M, Wang W, Kang I, Pashaj A, Carr T, Chung S . Activation of Toll-like receptor 4 (TLR4) attenuates adaptive thermogenesis via endoplasmic reticulum stress. J Biol Chem 2015; 290: 26476–26490.

    Article  CAS  Google Scholar 

  29. Mekjavic IB, Eiken O . Contribution of thermal and nonthermal factors to the regulation of body temperature in humans. J Appl Physiol 2006; 100: 2065–2072.

    Article  Google Scholar 

  30. Uldry M, Yang W, St-Pierre J, Lin J, Seale P, Spiegelman BM . Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab 2006; 3: 333–341.

    Article  CAS  Google Scholar 

  31. Kajimura S, Seale P, Tomaru T, Erdjument-Bromage H, Cooper MP, Ruas JL et al. Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex. Genes Dev 2008; 22: 1397–1409.

    Article  CAS  Google Scholar 

  32. Canto C, Auwerx J . PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol 2009; 20: 98–105.

    Article  CAS  Google Scholar 

  33. Hallberg M, Morganstein DL, Kiskinis E, Shah K, Kralli A, Dilworth SM et al. A functional interaction between RIP140 and PGC-1alpha regulates the expression of the lipid droplet protein CIDEA. Mol Cell Biol 2008; 28: 6785–6795.

    Article  CAS  Google Scholar 

  34. Hansen JB, Jorgensen C, Petersen RK, Hallenborg P, De Matteis R, Boye HA et al. Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation. Proc Natl Acad Sci USA 2004; 101: 4112–4117.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by projects from National Natural Science Foundation of China (Grant Numbers 311171315 and 31471320 to JL, and 31401204 to BB); The Fundamental Research Funds for the Central Universities, China (Grant Number 2014HGCH0005 to JL); Anhui Science and Technology Research Projects of China (Grant Number 1401b042018 to JL); and the Anhui Provincial Natural Science Foundation (Grant Number 1408085QC48 to BB).

Author contributions

XZ conceived and designed the experiments, performed the study and wrote the manuscript. Q-XZ, XW and LZ participated in the study and contributed to data analysis. WQ and BB contributed to data analysis and revised manuscript. JL reviewed/approved the research protocol, edited the manuscript and has taken full responsibility for the work as a whole, including the study design, access to data and the decision to submit and publish the manuscript.

Author information

Authors and Affiliations

  1. Department of Biological Sciences, School of Biotechnology and Food Engineering, Hefei University of Technology, Hefei, China

    X Zhang, Q-X Zhang, X Wang, L Zhang, W Qu, B Bao, C-A Liu & J Liu

Authors
  1. X Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Q-X Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. X Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C-A Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Liu.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on International Journal of Obesity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, X., Zhang, QX., Wang, X. et al. Dietary luteolin activates browning and thermogenesis in mice through an AMPK/PGC1α pathway-mediated mechanism. Int J Obes 40, 1841–1849 (2016). https://doi.org/10.1038/ijo.2016.108

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2016.108

This article is cited by

Search

Advanced search

Quick links