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.

Animal Models

Effect of resveratrol on visceral white adipose tissue inflammation and insulin sensitivity in a mouse model of sleep apnea

Abstract

Background:

Sleep fragmentation (SF) increases food intake and the risk of obesity, and recruits macrophages to visceral white adipose tissue (VWAT) promoting tissue inflammation and insulin resistance. Administration of resveratrol (Resv) has been associated with significant improvements in high-fat diet-induced obesity, inflammation and insulin resistance.

Methods:

Male mice were subjected to SF or sleep control conditions for 8 weeks, and treated with either Resv or vehicle (Veh). Fasting plasma levels of glucose, insulin and leptin were obtained and VWAT insulin sensitivity tests were performed (phosphorylated AKT/total AKT), along with flow-cytometric assessments for VWAT macrophages (M1 and M2) and T-cell lymphocytes (CD4+, CD8+ and T regulatory cell (Treg)).

Results:

SF-Veh and SF-Resv mice showed increased food consumption and weight gain. However, although SF-Veh mice exhibited increased fasting insulin and leptin levels, and reduced VWAT p-AKT/AKT responses to insulin, such alterations were abrogated in SF-Resv-treated mice. Increases in M1, reduced M2 counts and increased tumor necrosis factor-α release emerged in SF-Veh macrophages compared with all other three groups. Similarly, increased CD8+ and reduced Treg lymphocyte counts were apparent in SF-Veh.

Conclusions:

Resveratrol does not reverse the SF-induced increases in food intake and weight gain, but markedly attenuates VWAT inflammation and insulin resistance, thereby providing a potentially useful adjunctive therapy in the context of sleep disorders manifesting metabolic morbidity.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4

References

  1. Wang Y, Carreras A, Lee SH, Hakim F, Zhang SXL, Nair D et al. Chronic fragmented sleep promotes obesity in mice. Obesity 2014; 22: 758–762.

    Article  CAS  PubMed  Google Scholar 

  2. Khalyfa A, Wang Y, Zhang SX, Qiao Z, Abdelkarim A, Gozal D . Sleep fragmentation in mice induces nicotinamide adenine dinucleotide phosphate oxidase 2-dependent mobilization, proliferation, and differentiation of adipocyte progenitors in visceral white adipose tissue. Sleep 2014; 37: 999–1009.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Zhang SX, Khalyfa A, Wang Y, Carreras A, Hakim F, Neel BA et al. Sleep fragmentation promotes NADPH oxidase 2-mediated adipose tissue inflammation leading to insulin resistance in mice. Int J Obes 2014; 38: 619–624.

    Article  CAS  Google Scholar 

  4. Nair D, Zhang SX, Ramesh V, Hakim F, Kaushal N, Wang Y et al. Sleep fragmentation induces cognitive deficits via nicotinamide adenine dinucleotide phosphate oxidase-dependent pathways in mouse. Am J Resp Critic Care Med 2011; 184: 1305–1312.

    Article  CAS  Google Scholar 

  5. Ramesh V, Nair D, Zhang SX, Hakim F, Kaushal N, Kayali F et al. Disrupted sleep without sleep curtailment induces sleepiness and cognitive dysfunction via the tumor necrosis factor-alpha pathway. J Neuroinflammation 2012; 9: 91.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Kaushal N, Ramesh V, Gozal D . TNF-α and temporal changes in sleep architecture in mice exposed to sleep fragmentation. PLoS One 2012; 7: e45610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Möller-Levet CS, Archer SN, Bucca G, Laing EE, Slak A, Kabiljo R et al. Effects of insufficient sleep on circadian rhythmicity and expression amplitude of the human blood transcriptome. Proc Natl Acad Sci USA 2013; 110: E1132–E1141.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Stamatakis KA, Punjabi NM . Effects of sleep fragmentation on glucose metabolism in normal subjects. Chest 2010; 137: 95–101.

    Article  CAS  PubMed  Google Scholar 

  9. van den Berg SW, Jansen EH, Kruijshoop M, Beekhof PK, Blaak E, van der Kallen CJ et al. Paraoxonase 1 phenotype distribution and activity differs in subjects with newly diagnosed Type 2 diabetes (the CODAM Study). Diabet Med 2008; 25: 186–193.

    Article  CAS  PubMed  Google Scholar 

  10. van den Berg SW, Dollé ME, Imholz S, van der A DL, van 't Slot R, Wijmenga C et al. Genetic variations in regulatory pathways of fatty acid and glucose metabolism are associated with obesity phenotypes: a population-based cohort study. Int J Obes (Lond) 2009; 33: 1143–1152.

    Article  CAS  Google Scholar 

  11. Hubbard BP, Sinclair DA . Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci. 2014; 35: 146–154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hausenblas HA, Schoulda JA, Smoliga JM . Resveratrol treatment as an adjunct to pharmacological management in Type 2 diabetes mellitus - systematic review and meta-analysis. Mol Nutr Food Res 2014.

  13. Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 2008; 8: 157–168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006; 444: 337–342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 2006; 127: 1109–1122.

    Article  CAS  PubMed  Google Scholar 

  16. Ramesh V, Kaushal N, Gozal D . Sleep fragmentation differentially modifies EEG delta power during slow wave sleep in socially isolated and paired mice. Sleep Sci 2009; 2: 64–75.

    Google Scholar 

  17. Sargis RM, Neel BA, Brock CO, Lin Y, Hickey AT, Carlton DA et al. The novel endocrine disruptor tolylfluanid impairs insulin signaling in primary rodent and human adipocytes through a reduction in insulin receptor substrate-1levels. Biochim Biophys Acta 2012; 1822: 952–960.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hakim F, Wang Y, Carreras A, Hirotsu C, Zhang J, Peris E et al. Chronic sleep disruption during the sleep period induces hypothalamic endoplasmic reticulum stress and PTP1b-mediated leptin resistance in mice. Sleep 2014 (in press).

  19. Zhu J, Yong W, Wu X, Yu Y, Lv J, Liu C et al. Anti-inflammatory effect of resveratrol on TNF-alpha-induced MCP-1 expression in adipocytes. Biochem Biophys Res Commun. 2008; 369: 471–477.

    Article  CAS  PubMed  Google Scholar 

  20. Gonzales AM, Orlando RA . Curcumin and resveratrol inhibit nuclear factor-kappaB-mediated cytokine expression in adipocytes. Nutr Metab (Lond) 2008; 5: 17.

    Article  Google Scholar 

  21. Olholm J, Paulsen SK, Cullberg KB, Richelsen B, Pedersen SB . Anti-inflammatory effect of resveratrol on adipokine expression and secretion in human adipose tissue explants. Int J Obes (Lond) 2010; 34: 1546–1553.

    Article  CAS  Google Scholar 

  22. Jimenez-Gomez Y, Mattison JA, Pearson KJ, Martin-Montalvo A, Palacios HH, Sossong AM et al. Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet. Cell Metab 2013; 18: 533–545.

    Article  CAS  PubMed  Google Scholar 

  23. Wright DC . Exercise- and resveratrol-mediated alterations in adipose tissue metabolism. Appl Physiol Nutr Metab 2014; 39: 109–116.

    Article  CAS  PubMed  Google Scholar 

  24. Schneider Y, Duranton B, Gossé F, Schleiffer R, Seiler N, Raul F . Resveratrol inhibits intestinal tumorigenesis and modulates host-defense-related gene expression in an animal model of human familial adenomatous polyposis. Nutr Cancer 2001; 39: 102–107.

    Article  CAS  PubMed  Google Scholar 

  25. Norata GD, Marchesi P, Passamonti S, Pirillo A, Violi F, Catapano AL . Anti-inflammatory and anti-atherogenic effects of cathechin, caffeic acid and trans-resveratrol in apolipoprotein E deficient mice. Atherosclerosis 2007; 191: 265–271.

    Article  CAS  PubMed  Google Scholar 

  26. Qureshi AA, Guan XQ, Reis JC, Papasian CJ, Jabre S, Morrison DC et al. Inhibition of nitric oxide and inflammatory cytokines in LPS-stimulated murine macrophages by resveratrol, a potent proteasome inhibitor. Lipids Health Dis 2012; 11: 76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cho SJ, Jung UJ, Choi MS . Differential effects of low-dose resveratrol on adiposity and hepatic steatosis in diet-induced obese mice. Br J Nutr 2012; 108: 2166–2175.

    Article  CAS  PubMed  Google Scholar 

  28. Bakker GC, van Erk MJ, Pellis L, Wopereis S, Rubingh CM, Cnubben NH et al. An antiinflammatory dietary mix modulates inflammation and oxidative and metabolic stress in overweight men: a nutrigenomics approach. Am J Clin Nutr 2010; 91: 1044–1059.

    Article  CAS  PubMed  Google Scholar 

  29. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr . Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796–1808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Di Gregorio GB, Yao-Borengasser A, Rasouli N, Varma V, Lu T, Miles LM et al. Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: association with cytokine expression, insulin resistance, and reduction by pioglitazone. Diabetes 2005; 54: 2305–2313.

    Article  CAS  PubMed  Google Scholar 

  31. Hernandez ED, Lee SJ, Kim JY, Duran A, Linares JF, Yajima T et al. A Macrophage NBR1-MEKK3 Complex Triggers JNK-Mediated Adipose Tissue Inflammation in Obesity. Cell Metab 2014; 20: 499–511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cipolletta D . Adipose tissue-resident regulatory T cells: phenotypic specialization, functions and therapeutic potential. Immunology 2014; 142: 517–525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Garg SK, Delaney C, Shi H, Yung R . Changes in adipose tissue macrophages and T cells during aging. Crit Rev Immunol 2014; 34: 1–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lee BC, Lee J . Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance. Biochim Biophys Acta. 2014; 1842: 446–462.

    Article  CAS  PubMed  Google Scholar 

  35. Lal G, Bromberg JS . Epigenetic mechanisms of regulation of Foxp3 expression. Blood 2009; 114: 3727–3735.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Akasheh RT, Pang J, York JM, Fantuzzi G . New pathways to control inflammatory responses in adipose tissue. Curr Opin Pharmacol 2013; 13: 613–617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Farghali H, Kutinová Canová N, Lekić N . Resveratrol and related compounds as antioxidants with an allosteric mechanism of action in epigenetic drug targets. Physiol Res 2013; 62: 1–13.

    CAS  PubMed  Google Scholar 

  38. Qin W, Zhang K, Clarke K, Weiland T, Sauter ER . Methylation and miRNA effects of resveratrol on mammary tumors vs normal tissue. Nutr Cancer 2014; 66: 270–277.

    Article  CAS  PubMed  Google Scholar 

  39. Kim J, Bhattacharjee R, Khalyfa A, Kheirandish-Gozal L, Capdevila OS, Wang Y et al. DNA methylation in inflammatory genes among children with obstructive sleep apnea. Am J Respir Crit Care Med 2012; 185: 330–338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tan HL, Gozal D, Wang Y, Bandla HP, Bhattacharjee R, Kulkarni R et al. Alterations in circulating T-cell lymphocyte populations in children with obstructive sleep apnea. Sleep 2013; 36: 913–922.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Herbert T. Abelson Endowed Chair in Pediatrics to DG.

Author Contributions

AC participated in the conceptual framework of the project, performed experiments, analyzed data and drafted components of the manuscript. SXZ, EP, ZQ, IA performed experiments. YW analyzed data and served as blinded observer. DG conceptualized the project, provided critical input in all phases of the experiments, analyzed data, drafted the ulterior versions of the manuscript and is responsible for the financial support of the project and the manuscript content. All authors have reviewed and approved the final version of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to D Gozal.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Carreras, A., Zhang, S., Peris, E. et al. Effect of resveratrol on visceral white adipose tissue inflammation and insulin sensitivity in a mouse model of sleep apnea. Int J Obes 39, 418–423 (2015). https://doi.org/10.1038/ijo.2014.181

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2014.181

This article is cited by

Search

Quick links