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.

Integrative Biology

Defective regulation of adipose tissue autophagy in obesity

International Journal of Obesity volume 37, pages 1473–1480 (2013)Cite this article

Subjects

Abstract

Objectives:

Autophagy is a highly regulated process that has an important role in the control of a wide range of cellular functions, such as organelle recycling, nutrient availability and tissue differentiation. A recent study has shown an increased autophagic activity in the adipose tissue of obese subjects, and a role for autophagy in obesity-associated insulin resistance was proposed. Body mass reduction is the most efficient approach to tackle insulin resistance in over-weight subjects; however, the impact of weight loss in adipose tissue autophagy is unknown.

Subjects:

Adipose tissue autophagy was evaluated in mice and humans.

Results:

First, a mouse model of diet-induced obesity and diabetes was maintained on a 15-day, 40% caloric restriction. At baseline, markers of autophagy were increased in obese mice as compared with lean controls. Upon caloric restriction, autophagy increased in the lean mice, whereas it decreased in the obese mice. The reintroduction of ad libitum feeding was sufficient to rapidly reduce autophagy in the lean mice and increase autophagy in the obese mice. In the second part of the study, autophagy was evaluated in the subcutaneous adipose tissue of nine obese-non-diabetic and six obese-diabetic subjects undergoing bariatric surgery for body mass reduction. Specimens were collected during the surgery and approximately 1 year later. Markers of systemic inflammation, such as tumor necrosis factor-1α, interleukin (IL)-6 and IL-1β were evaluated. As in the mouse model, human obesity was associated with increased autophagy, and body mass reduction led to an attenuation of autophagy in the adipose tissue.

Conclusion:

Obesity and caloric overfeeding are associated with the defective regulation of autophagy in the adipose tissue. The studies in obese-diabetic subjects undergoing improved metabolic control following calorie restriction suggest that autophagy and inflammation are regulated independently.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

References

  1. Kahn SE, Hull RL, Utzschneider KM . Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 2006; 444: 840–846.

    Article  CAS  Google Scholar 

  2. Gregor MF, Hotamisligil GS . Inflammatory mechanisms in obesity. Annu Rev Immunol 2011; 29: 415–445.

    Article  CAS  Google Scholar 

  3. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004; 306: 457–461.

    Article  Google Scholar 

  4. Hotamisligil GS . Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 2010; 140: 900–917.

    Article  CAS  Google Scholar 

  5. Cnop M, Foufelle F, Velloso LA . Endoplasmic reticulum stress, obesity and diabetes. Trends Mol Med 2012; 18: 59–68.

    Article  CAS  Google Scholar 

  6. Hotamisligil GS . Inflammation and endoplasmic reticulum stress in obesity and diabetes. Int J Obes (Lond) 2008; 32 (Suppl 7): S52–S54.

    Article  CAS  Google Scholar 

  7. Yang L, Li P, Fu S, Calay ES, Hotamisligil GS . Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab 2010; 11: 467–478.

    Article  CAS  Google Scholar 

  8. Kundu M, Thompson CB . Autophagy: basic principles and relevance to disease. Annu Rev Pathol 2008; 3: 427–455.

    Article  CAS  Google Scholar 

  9. Mizushima N, Levine B, Cuervo AM, Klionsky DJ . Autophagy fights disease through cellular self-digestion. Nature 2008; 451: 1069–1075.

    Article  CAS  Google Scholar 

  10. Mizushima N, Klionsky DJ . Protein turnover via autophagy: implications for metabolism. Annu Rev Nutr 2007; 27: 19–40.

    Article  CAS  Google Scholar 

  11. Delgado M, Singh S, De Haro S, Master S, Ponpuak M, Dinkins C et al. Autophagy and pattern recognition receptors in innate immunity. Immunol Rev 2009; 227: 189–202.

    Article  CAS  Google Scholar 

  12. Botti J, Djavaheri-Mergny M, Pilatte Y, Codogno P . Autophagy signaling and the cogwheels of cancer. Autophagy 2006; 2: 67–73.

    Article  CAS  Google Scholar 

  13. Kroemer G, Marino G, Levine B . Autophagy and the integrated stress response. Mol Cell 2010; 40: 280–293.

    Article  CAS  Google Scholar 

  14. Kovsan J, Bluher M, Tarnovscki T, Kloting N, Kirshtein B, Madar L et al. Altered autophagy in human adipose tissues in obesity. J Clin Endocrinol Metab 2011; 96: E268–E277.

    Article  CAS  Google Scholar 

  15. Tang F, Watkins JW, Bermudez M, Gray R, Gaban A, Portie K et al. A life-span extending form of autophagy employs the vacuole-vacuole fusion machinery. Autophagy 2008; 4: 874–886.

    Article  CAS  Google Scholar 

  16. Rubinsztein DC, Marino G, Kroemer G . Autophagy and aging. Cell 2011; 146: 682–695.

    Article  CAS  Google Scholar 

  17. Gastrointestinal surgery for severe obesity: National Institutes of Health Consensus Development Conference Statement. Am J Clin Nutr 1992; 55 (2 Suppl): 615S–619S.

  18. Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, Adeli K et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 2012; 8: 445–544.

    Article  CAS  Google Scholar 

  19. Rossmeisl M, Rim JS, Koza RA, Kozak LP . Variation in type 2 diabetes--related traits in mouse strains susceptible to diet-induced obesity. Diabetes 2003; 52: 1958–1966.

    Article  CAS  Google Scholar 

  20. De Souza CT, Araujo EP, Stoppiglia LF, Pauli JR, Ropelle E, Rocco SA et al. Inhibition of UCP2 expression reverses diet-induced diabetes mellitus by effects on both insulin secretion and action. FASEB J 2007; 21: 1153–1163.

    Article  CAS  Google Scholar 

  21. Ost A, Svensson K, Ruishalme I, Brannmark C, Franck N, Krook H et al. Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes. Mol Med 2010; 16: 235–246.

    Article  Google Scholar 

  22. Zhang Y, Goldman S, Baerga R, Zhao Y, Komatsu M, Jin S . Adipose-specific deletion of autophagy-related gene 7 (atg7) in mice reveals a role in adipogenesis. Proc Natl Acad Sci USA 2009; 106: 19860–19865.

    Article  CAS  Google Scholar 

  23. Goldman S, Zhang Y, Jin S . Autophagy and adipogenesis: implications in obesity and type II diabetes. Autophagy 2010; 6: 179–181.

    Article  Google Scholar 

  24. Moscat J, Diaz-Meco MT . Feedback on fat: p62-mTORC1-autophagy connections. Cell 2011; 147: 724–727.

    Article  CAS  Google Scholar 

  25. Codogno P, Meijer AJ . Autophagy: a potential link between obesity and insulin resistance. Cell Metab 2010; 11: 449–451.

    Article  CAS  Google Scholar 

  26. Kopp HP, Kopp CW, Festa A, Krzyzanowska K, Kriwanek S, Minar E et al. Impact of weight loss on inflammatory proteins and their association with the insulin resistance syndrome in morbidly obese patients. Arterioscler Thromb Vasc Biol 2003; 23: 1042–1047.

    Article  CAS  Google Scholar 

  27. Lima MM, Pareja JC, Alegre SM, Geloneze SR, Kahn SE, Astiarraga BD et al. Acute effect of roux-en-y gastric bypass on whole-body insulin sensitivity: a study with the euglycemic-hyperinsulinemic clamp. J Clin Endocrinol Metab 2010; 95: 3871–3875.

    Article  CAS  Google Scholar 

  28. van de Sande-Lee S, Pereira FR, Cintra DE, Fernandes PT, Cardoso AR, Garlipp CR et al. Partial reversibility of hypothalamic dysfunction and changes in brain activity after body mass reduction in obese subjects. Diabetes 2011; 60: 1699–1704.

    Article  CAS  Google Scholar 

  29. Geloneze SR, Geloneze B, Morari J, Matos-Souza JR, Lima MM, Chaim EA et al. PGC1alpha gene Gly482Ser polymorphism predicts improved metabolic, inflammatory and vascular outcomes following bariatric surgery. Int J Obes (Lond) 2012; 36: 363–368.

    Article  CAS  Google Scholar 

  30. Gregor MF, Yang L, Fabbrini E, Mohammed BS, Eagon JC, Hotamisligil GS et al. Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. Diabetes 2009; 58: 693–700.

    Article  CAS  Google Scholar 

  31. Cancello R, Tordjman J, Poitou C, Guilhem G, Bouillot JL, Hugol D et al. Increased infiltration of macrophages in omental adipose tissue is associated with marked hepatic lesions in morbid human obesity. Diabetes 2006; 55: 1554–1561.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr ER Roman, Mr JG Ferraz and Mr M Cruz from the University of Campinas for technical assistance. We thank Dr N Conran for editing the English grammar. The support for the study was provided by Fundação de Amparo a Pesquisa do Estado de Sao Paulo and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico.

Author information

Authors and Affiliations

  1. Laboratory of Cell Signaling, University of Campinas, Campinas, Brazil,

    C E Nuñez, V S Rodrigues, F S Gomes, R F de Moura, S C Victorio, B Bombassaro, L A Velloso & E P Araujo

  2. Department of Nursing, University of Campinas, Campinas, Brazil

    F S Gomes & E P Araujo

  3. Department of Surgery, University of Campinas, Campinas, Brazil

    E A Chaim & J C Pareja

  4. Laboratory of Investigation on Metabolism and Diabetes, University of Campinas, Campinas, Brazil,

    B Geloneze

Authors
  1. C E Nuñez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V S Rodrigues
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F S Gomes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R F de Moura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S C Victorio
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B Bombassaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E A Chaim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J C Pareja
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. B Geloneze
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. L A Velloso
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. E P Araujo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E P Araujo.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nuñez, C., Rodrigues, V., Gomes, F. et al. Defective regulation of adipose tissue autophagy in obesity. Int J Obes 37, 1473–1480 (2013). https://doi.org/10.1038/ijo.2013.27

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2013.27

Keywords

  • beclin
  • p62
  • mTOR
  • PERK
  • GPR78
  • CHOP

This article is cited by

Search

Advanced search

Quick links