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:

Adipocyte and Cell Biology

Decreased adiponectin links elevated adipose tissue autophagy with adipocyte endocrine dysfunction in obesity

International Journal of Obesity volume 40, pages 912–920 (2016)Cite this article

Subjects

Abstract

Background/Objectives:

Adipose tissue (AT) autophagy gene expression is elevated in human obesity, correlating with increased metabolic risk, but mechanistic links between the two remain unclear. Thus, the objective of this study was to assess whether elevated autophagy may cause AT endocrine dysfunction, emphasizing the putative role of adiponectin in fat–liver endocrine communication.

Subjects/Methods:

We utilized a large (N=186) human AT biobank to assess clinical associations between human visceral AT autophagy genes, adiponectin and leptin, by multivariate models. A broader view of adipocytokines association with elevated autophagy was assessed using adipocytokine array. Finally, to establish causality, ex vivo studies utilizing a murine AT–hepatocyte cell line co-culture system was used.

Results:

Circulating high-molecular-weight adiponectin and leptin levels were associated with human omental-AT expression of ATG5 mRNA, associations that remained significant (β=−0.197, P=0.011; β=0.267, P<0.001, respectively) in a multivariate model adjusted for age, sex, body mass index and interleukin-6 (IL-6). A similar association was observed with omental-AT LC3A mRNA levels. Bafilomycin-A1 (Baf A) pretreatment of AT explants from high-fat-fed (HFF) mice had no effect on the secretion of some AT-derived endocrine factors, but partially or fully reversed obesity-related changes in secretion of a subset of adipocytokines by >30%, including the obesity-associated upregulation of IL-6, vascular endothelial growth factor, tumor necrosis factor alpha (TNFα) and certain insulin-like growth factor-binding proteins, and the HFF-induced downregulated secretion of IL-10 and adiponectin. Similarly, decreased adiponectin and increased leptin secretion from cultured adipocytes stimulated with TNFα+IL-1β was partially reversed by small interfering RNA-mediated knockdown of ATG7. AT explants from HFF mice co-cultured with Hepa1c hepatoma cells impaired insulin-induced Akt and GSK3 phosphorylation. This effect was significantly reversed by pretreating explants with Baf A, but not if adiponectin was immunodepleted from the conditioned media.

Conclusions:

Reduced secretion of adiponectin may link obesity-associated elevated AT autophagy/lysosomal activity with adipose endocrine dysfunction.

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

Similar content being viewed by others

References

  1. Stienstra R, Haim Y, Riahi Y, Netea M, Rudich A, Leibowitz G . Autophagy in adipose tissue and the beta cell: implications for obesity and diabetes. Diabetologia 2014; 57: 1505–1516.

    Article  CAS  Google Scholar 

  2. Maixner N, Kovsan J, Harman-Boehm I, Bluher M, Bashan N, Rudich A . Autophagy in adipose tissue. Obes Facts 2012; 5: 710–721.

    Article  Google Scholar 

  3. 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 

  4. Kosacka J, Kern M, Klöting N, Paeschke S, Rudich A, Haim Y et al. Autophagy in adipose tissue of patients with obesity and type 2 diabetes. Mol Cell Endocrinol 2015; 409: 21–32.

    Article  CAS  Google Scholar 

  5. 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 

  6. 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 

  7. Nunez CE, Rodrigues VS, Gomes FS, Moura RF, Victorio SC, Bombassaro B et al. Defective regulation of adipose tissue autophagy in obesity. Int J Obes 2013; 37: 1473–1480.

    Article  CAS  Google Scholar 

  8. Jansen HJ, van Essen P, Koenen T, Joosten LA, Netea MG, Tack CJ et al. Autophagy activity is up-regulated in adipose tissue of obese individuals and modulates proinflammatory cytokine expression. Endocrinology 2012; 153: 5866–5874.

    Article  CAS  Google Scholar 

  9. Yoshizaki T, Kusunoki C, Kondo M, Yasuda M, Kume S, Morino K et al. Autophagy regulates inflammation in adipocytes. Biochem Biophys Res Commun 2012; 417: 352–357.

    Article  CAS  Google Scholar 

  10. Soussi H, Reggio S, Alili R, Prado C, Mutel S, Pini M et al. DAPK2 downregulation associates with attenuated adipocyte autophagic clearance in human obesity. Diabetes 2015; 64: 3452–3463.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  12. Singh R, Xiang Y, Wang Y, Baikati K, Cuervo AM, Luu YK et al. Autophagy regulates adipose mass and differentiation in mice. J Clin Invest 2009; 119: 3329–3339.

    Article  CAS  Google Scholar 

  13. 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 

  14. Xu X, Grijalva A, Skowronski A, van Eijk M, Serlie MJ, Ferrante AW Jr . Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation. Cell Metab 2013; 18: 816–830.

    Article  CAS  Google Scholar 

  15. Kovsan J, Osnis A, Maissel A, Mazor L, Tarnovscki T, Hollander L et al. Depot-specific adipocyte cell lines reveal differential drug-induced responses of white adipocytes–relevance for partial lipodystrophy. Am J Physiol Endocrinol Metab 2009; 296: E315–E322.

    Article  CAS  Google Scholar 

  16. Haim Y, Bluher M, Slutsky N, Goldstein N, Kloting N, Harman-Boehm I et al. Elevated adipose tissue autophagy gene expression in humans: a potential non-cell-cycle-dependent function of E2F1. Autophagy 2015; 11: 2074–2088.

    Article  CAS  Google Scholar 

  17. Nov O, Shapiro H, Ovadia H, Tarnovscki T, Dvir I, Shemesh E et al. Interleukin-1beta regulates fat-liver crosstalk in obesity by auto-paracrine modulation of adipose tissue inflammation and expandability. PloS ONE 2013; 8: e53626.

    Article  CAS  Google Scholar 

  18. Nov O, Kohl A, Lewis EC, Bashan N, Dvir I, Ben-Shlomo S et al. Interleukin-1beta may mediate insulin resistance in liver-derived cells in response to adipocyte inflammation. Endocrinology 2010; 151: 4247–4256.

    Article  CAS  Google Scholar 

  19. Bashan N, Dorfman K, Tarnovscki T, Harman-Boehm I, Liberty IF, Bluher M et al. Mitogen-activated protein kinases, inhibitory-kappaB kinase, and insulin signaling in human omental versus subcutaneous adipose tissue in obesity. Endocrinology 2007; 148: 2955–2962.

    Article  CAS  Google Scholar 

  20. Bluher M, Bashan N, Shai I, Harman-Boehm I, Tarnovscki T, Avinaoch E et al. Activated Ask1-MKK4-p38MAPK/JNK stress signaling pathway in human omental fat tissue may link macrophage infiltration to whole-body Insulin sensitivity. J Clin Endocrinol Metab 2009; 94: 2507–2515.

    Article  Google Scholar 

  21. Harman-Boehm I, Bluher M, Redel H, Sion-Vardy N, Ovadia S, Avinoach E et al. Macrophage infiltration into omental versus subcutaneous fat across different populations: effect of regional adiposity and the comorbidities of obesity. J Clin Endocrinol Metab 2007; 92: 2240–2247.

    Article  CAS  Google Scholar 

  22. Shapiro H, Pecht T, Shaco-Levy R, Harman-Boehm I, Kirshtein B, Kuperman Y et al. Adipose tissue foam cells are present in human obesity. J Clin Endocrinol Metab 2013; 98: 1173–1181.

    Article  CAS  Google Scholar 

  23. 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 

  24. Choi AM, Ryter SW, Levine B . Autophagy in human health and disease. N Engl J Med 2013; 368: 651–662.

    Article  CAS  Google Scholar 

  25. Chen ZH, Kim HP, Sciurba FC, Lee SJ, Feghali-Bostwick C, Stolz DB et al. Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease. PloS ONE 2008; 3: e3316.

    Article  Google Scholar 

  26. Zhou L, Liu F . Autophagy: roles in obesity-induced ER stress and adiponectin downregulation in adipocytes. Autophagy 2010; 6: 1196–1197.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported in part by grants from Deutsche Forschungsgemeinschaft (DFG): SFB 1052/1: ‘Obesity mechanisms’ (projects B1 and B2 to AR and MB), and by the Israel Science Foundation (ISF 928/14, to AR). AR is Chair of the Fraida Foundation in Diabetes Research.

Author information

Authors and Affiliations

  1. Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel

    N Slutsky, M Vatarescu, Y Haim, N Goldstein, N Bashan & A Rudich

  2. Soroka Academic Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel

    B Kirshtein & I Harman-Boehm

  3. Department of Epidemiology, Ben-Gurion University of the Negev, Beer-Sheva, Israel

    Y Gepner & I Shai

  4. Department of Medicine, University of Leipzig, Leipzig, Germany

    M Blüher

  5. National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel

    A Rudich

Authors
  1. N Slutsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Vatarescu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Haim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N Goldstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B Kirshtein
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. I Harman-Boehm
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Y Gepner
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. I Shai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. N Bashan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Blüher
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A Rudich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Rudich.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Slutsky, N., Vatarescu, M., Haim, Y. et al. Decreased adiponectin links elevated adipose tissue autophagy with adipocyte endocrine dysfunction in obesity. Int J Obes 40, 912–920 (2016). https://doi.org/10.1038/ijo.2016.5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2016.5

This article is cited by

Search

Advanced search

Quick links