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.

  • Letter
  • Published:

AMPK activation protects against diet-induced obesity through Ucp1-independent thermogenesis in subcutaneous white adipose tissue

Nature Metabolism volume 1, pages 340–349 (2019)Cite this article

Subjects

Abstract

Obesity results from a chronic imbalance between energy intake and energy output but remains difficult to prevent or treat in humans. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an important regulator of energy homeostasis1,2,3 and is a molecular target of drugs used for the treatment of metabolic diseases, including obesity4,5. Here we show that mice expressing a gain-of-function AMPK mutant6 display a change in morphology of subcutaneous white adipocytes that is reminiscent of browning. However, despite a dramatic increase in mitochondrial content, Ucp1 expression is undetectable in these adipocytes. In response to a high-fat diet (HFD), expression of skeletal muscle–associated genes is induced in subcutaneous white adipocytes from the gain-of-function AMPK mutant mice. Chronic genetic AMPK activation results in protection against diet-induced obesity due to an increase in whole-body energy expenditure, most probably because of a substantial increase in the oxygen consumption rate of white adipose tissue. These results suggest that AMPK activation enriches, or leads to the emergence of, a population of subcutaneous white adipocytes that produce heat via Ucp1-independent uncoupling of adenosine triphosphate (ATP) production on a HFD. Our findings indicate that AMPK activation specifically in adipose tissue may have therapeutic potential for the treatment of obesity.

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

Fig. 1: AMPK activation protects against diet-induced obesity by increasing energy expenditure.
Fig. 2: AMPK activation protects against diet-induced obesity through a brown adipose tissue–independent mechanism.
Fig. 3: AMPK activation increases subcutaneous white adipose mitochondrial content and Ucp1-independent respiration.
Fig. 4: AMPK activation induces a skeletal muscle–like gene signature in WATsc in mice fed a HFD.

Similar content being viewed by others

Data availability

The datasets that support the findings of this study are available from the corresponding author upon request. RNA-sequence datasets used in this study are available from Gene Expression Omnibus with the accession number GSE120429.

References

  1. Carling, D. AMPK signalling in health and disease. Curr. Opin. Cell Biol. 45, 31–37 (2017).

    Article  CAS  Google Scholar 

  2. Hardie, D. G. AMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels. Annu. Rev. Nutr. 34, 31–55 (2014).

    Article  CAS  Google Scholar 

  3. Steinberg, G. R. & Kemp, B. E. AMPK in health and disease. Physiol. Rev. 89, 1025–1078 (2009).

    Article  CAS  Google Scholar 

  4. Cool, B. et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 3, 403–416 (2006).

  5. Xiao, B. et al. Structural basis of AMPK regulation by small molecule activators. Nat. Commun. 4, 3017 (2013).

    Article  Google Scholar 

  6. Woods, A. et al. Liver-specific activation of AMPK prevents steatosis on a high fructose diet. Cell Rep. 18, 3043–3051 (2017).

    Article  CAS  Google Scholar 

  7. Andersson, U. et al. AMP-activated protein kinase plays a role in the control of food intake. J. Biol. Chem. 279, 12005–12008 (2004).

    Article  CAS  Google Scholar 

  8. Minokoshi, Y. et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569–574 (2004).

    Article  CAS  Google Scholar 

  9. Nicholls, D. G. & Locke, R. M. Thermogenic mechanisms in brown fat. Physiol. Rev. 64, 1–64 (1984).

    Article  CAS  Google Scholar 

  10. Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

    Article  CAS  Google Scholar 

  11. Feldmann, H. M., Golozoubova, V., Cannon, B. & Nedergaard, J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell. Metab. 9, 203–209 (2009).

    Article  CAS  Google Scholar 

  12. García-Ruiz, E. et al. The intake of high-fat diets induces the acquisition of brown adipocyte gene expression features in white adipose tissue. Int. J. Obes. 39, 1619–1629 (2015).

    Article  Google Scholar 

  13. Gordon, C. J. Thermal physiology of laboratory mice: defining thermoneutrality. J. Therm. Biol. 37, 654–685 (2012).

    Article  Google Scholar 

  14. Walden, T. B., Hansen, I. R., Timmons, J. A., Cannon, B. & Nedergaard, J. Recruited vs. nonrecruited molecular signatures of brown, “brite,” and white adipose tissues. Am. J. Physiol. Endocrinol. Metab. 302, E19–E31 (2012).

    Article  CAS  Google Scholar 

  15. Wu, J., Cohen, P. & Spiegelman, B. M. Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev. 27, 234–250 (2013).

  16. Harms, M. & Seale, P. Brown and beige fat: development, function and therapeurtic potential. Nat. Med. 19, 1252–1263 (2013).

    Article  CAS  Google Scholar 

  17. Wu, J. et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150, 366–376 (2012).

    Article  CAS  Google Scholar 

  18. Granneman, J. G., Burnazi, M., Zhu, Z. & Schwamb, L. A. White adipose tissue contributes to UCP1-independent thermogenesis. Am. J. Physiol. Endocrinol. Metab. 285, E1230–E1236 (2003).

    Article  CAS  Google Scholar 

  19. Ukropec, J., Anunciado, R. P., Ravussin, Y., Hulver, M. W. & Kozak, L. P. UCP1-independent thermogenesis in white adipose tissue of cold-acclimated Ucp1-/- mice. J. Biol. Chem. 281, 31894–31908 (2006).

  20. Kazak, L. et al. A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell 163, 643–655 (2015).

    Article  CAS  Google Scholar 

  21. Fitch, C. D. & Chevli, R. Inhibition of creatine and phosphocreatine accumulation in skeletal muscle and heart. Metabolism 29, 686–690 (1980).

    Article  CAS  Google Scholar 

  22. Block, B. A., O’Brien, J. & Meissner, G. Characterization of the sarcoplasmic reticulum proteins in the thermogenic muscles of fish. J. Cell. Biol. 127, 1275–1287 (1994).

    Article  CAS  Google Scholar 

  23. da Costa, D. C. & Landeira-Fernandez, A. M. Thermogenic activity of the Ca2+-ATPase from blue marlin heater organ: regulation by KCl and temperature. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, R1460–R1468 (2009).

    Article  Google Scholar 

  24. 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  Google Scholar 

  25. Inagaki, T., Sakai, J. & Kajimura, S. Transcriptional and epigenetic control of brown and beige adipose cell fate and function. Nat. Rev. Mol. Cell Biol. 17, 480–495 (2106).

    Article  Google Scholar 

  26. Sanchez-Gurmaches, J., Hung, C. M. & Guertin, D. A. Emerging complexities in adipocyte origins andidentity. Trends Cell Biol. 26, 313–326 (2016).

    Article  CAS  Google Scholar 

  27. Eguchi, J. et al. Transcriptional control of adipose lipid handling by IRF4. Cell. Metab. 13, 249–259 (2011).

    Article  CAS  Google Scholar 

  28. Jeffery, E. et al. Characterization of Cre recombinase models for the study of adipose tissue. Adipocyte 3, 206–211 (2014).

    Article  CAS  Google Scholar 

  29. Berry, R. & Rodeheffer, M. S. Characterization of the adipocyte cellular lineage in vivo. Nat. Cell Biol. 15, 302–308 (2013).

    Article  CAS  Google Scholar 

  30. Yang, Q. et al. AMPK/α-ketoglutarate axis dynamically mediates DNA demethylation in the Prdm16 promoter and brown adipogenesis. Cell Metab. 24, 542–554 (2016).

  31. Wu, L. et al. AMP-activated protein kinase (AMPK) regulates energy metabolism through modulating thermogenesis in adipose tissue. Front. Physiol. 9, 122 (2018).

    Article  Google Scholar 

  32. Mottillo, E. P. et al. Lack of adipocyte AMPK exacerbates insulin resistance and hepatic steatosis through brown and beige adipose tissue function. Cell Metab. 24, 118–129 (2016).

Download references

Acknowledgements

This work was funded by the Medical Research Council UK (grant MC-A654-5QB10 to D.C.). A.E.P. was funded by a BBSRC-CASE Studentship Award (BB/L502662/1). L.W. was funded by a British Heart Foundation Studentship Award. We would like to thank the MRC London Institute of Medical Sciences Whole Animal Physiology Team for their assistance.

Author information

Authors and Affiliations

  1. MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital, London, UK

    Alice E. Pollard, Luís Martins, Phillip J. Muckett, Sanjay Khadayate, Rebeca Fiadeiro, Laura Wilson, Chad Whilding, Lucy Penfold, Alessandro Sardini, Angela Woods & David Carling

  2. Discovery Sciences IMED Biotech Unit, AstraZeneca, Cambridge, UK

    Alice E. Pollard, Aurélie Bornot, David M. Smith, Jon A. Read & Michael A. Snowden

  3. Discovery Sciences IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden

    Maryam Clausen, Therese Admyre, Mikael Bjursell & Mohammad Bohlooly-Y

  4. Department of Cell and Developmental Biology and UCL Consortium for Mitochondrial Research, University College London, London, UK

    Vassilios N. Kotiadis & Michael R. Duchen

  5. Drug Safety and Metabolism IMED Biotech Unit, AstraZeneca, Babraham, UK

    Daniel Sutton

  6. Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital, London, UK

    David Carling

Authors
  1. Alice E. Pollard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luís Martins
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Phillip J. Muckett
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sanjay Khadayate
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aurélie Bornot
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maryam Clausen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Therese Admyre
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mikael Bjursell
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rebeca Fiadeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Laura Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Chad Whilding
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Vassilios N. Kotiadis
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Michael R. Duchen
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Daniel Sutton
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Lucy Penfold
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Alessandro Sardini
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Mohammad Bohlooly-Y
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. David M. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Jon A. Read
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Michael A. Snowden
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Angela Woods
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. David Carling
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.E.P., L.M., P.J.M., T.A., M.B., L.W. and R.F. carried out the in vivo and in vitro studies. S.K., A.B. and M.C. carried out the RNA sequencing and analysis. C.W. and D.S. helped with immunohistochemistry analysis. A.S. and M.B.Y. helped with the metabolic phenotyping. L.P. and A.W. helped perform phenotypic analysis of mice. A.E.P., L.M., W.K. and M.R.D. carried out the cellular respiration studies. A.E.P., L.M., A.W., D.M.S., J.A.R., M.A.S. and D.C. designed and planned the study. All authors contributed to the preparation of the manuscript.

Corresponding authors

Correspondence to Angela Woods or David Carling.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Supplementary information

Supplementary Information

Supplementary Figures 1–7 and Supplementary Table 1

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pollard, A.E., Martins, L., Muckett, P.J. et al. AMPK activation protects against diet-induced obesity through Ucp1-independent thermogenesis in subcutaneous white adipose tissue. Nat Metab 1, 340–349 (2019). https://doi.org/10.1038/s42255-019-0036-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s42255-019-0036-9

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing