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Inflammation

, Volume 41, Issue 2, pp 626–642 | Cite as

Inhibitory Effects of Toll-Like Receptor 4, NLRP3 Inflammasome, and Interleukin-1β on White Adipocyte Browning

  • Meshail Okla
  • Walid Zaher
  • Musaad Alfayez
  • Soonkyu Chung
ORIGINAL ARTICLE

Abstract

Adipose tissue expansion is accompanied by infiltration and accumulation of pro-inflammatory macrophages, which links obesity to pathologic conditions such as type 2 diabetes. However, little is known regarding the role of pro-inflammatory adipose tissue remodeling in the thermogenic activation of brown/beige fat. Here, we investigated the effect of pattern recognition receptors (PRR) activation in macrophages, especially the toll-like receptor 4 (TLR4) and Nod-like receptor 3 (NLRP3), on white adipocyte browning. We report that TLR4 activation by lipopolysaccharide repressed white adipocyte browning in response to β3-adrenergic receptor activation and caused ROS production and mitochondrial dysfunction, while genetic deletion of TLR4 protected mitochondrial function and thermogenesis. In addition, activation of NLRP3 inflammasome in macrophages attenuated UCP1 induction and mitochondrial respiration in cultures of primary adipocytes, while the absence of NLRP3 protected UCP1 in adipocytes. The effect of NLRP3 inflammasome activation on browning was mediated by IL-1β signaling, as blocking IL-1 receptor in adipocytes protected thermogenesis. We also report that IL-1β interferes with thermogenesis via oxidative stress stimulation and mitochondrial dysfunction as we observed a statistically significant increase in ROS production, decrease in SOD enzyme activity, and increase in mitochondrial depolarization in adipocytes treated with IL-1β. Collectively, we demonstrated that inflammatory response to obesity, such as TLR4 and NLRP3 inflammasome activation as well as IL-1β secretion, attenuates β3-adrenoreceptor-induced beige adipocyte formation via oxidative stress and mitochondrial dysfunction. Our findings provide insights into targeting innate inflammatory system for enhancement of the adaptive thermogenesis against obesity.

KEY WORDS

TLR4 NLRP3 inflammasome IL-1β uncoupling protein 1 beige adipocytes brown adipocytes β3-adrenergic receptor 

Abbreviations

NLRP3

NOD-like receptor protein 3

TLR4

Toll-like receptor 4

WAT

White adipose tissue

PRR

Pattern recognition receptors

β3-AR

Beta 3-adrenergic receptor

ROS

Reactive oxygen species

UCP1

Uncoupling protein 1

IL-1β

Interleukin-1 beta

BMP7

Bone morphogenetic protein 7

LPS

Lipopolysaccharide

CL

CL 316,243

hASCs

Human adipose-derived stem cells

EMSC

Ear mesenchymal stem cells

sWAT

Subcutaneous white adipose tissue

mtDNA

Mitochondrial DNA

OCR

Oxygen consumption rate

SOD

Superoxide dismutase

hIL-1β-CM

Human interleukin-1 beta-conditioned medium

mIL-1β-CM

Mouse interleukin-1 beta-conditioned medium

NAC

n-Acetylcysteine

Bt2-cAMP

Dibutyryl-cAMP

IL-1RA

IL-1 receptor antagonist

MQ

Macrophages

Notes

Acknowledgements

The authors wish to acknowledge the College of Medicine Research Center (CMRC) at King Saud University (KSU) and the Stem cell lab in the College of Medicine at KSU for providing access to their facilities to perform mitochondrial depolarization and oxidative stress experiments. Also, the authors wish to thank Rabih Halwani at the College of Medicine in KSU for permitting the use of Muse flow cytometry.

Author Contributions

M.O. designed and performed experiments, analyzed data, and wrote the manuscript. W.Z. and M.A. critically reviewed the manuscript. S.C. provided scientific guidance, participated in discussions and manuscript preparation, and helped in interpreting the significance of the results.

Funding

This study was supported by the National Institute of Health (Grant 1P20GM104320, project 5; to S. C.) in the USA, International Scientific Partnership Program (ISPP, no. 0103) at King Saud University (KSU) in Saudi Arabia, and Deanship of Scientific Research (Project No. R6-17-02-36) at King Saud University in Saudi Arabia.

Compliance with Ethical Standards

All protocols and procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Nebraska-Lincoln in Nebraska, United States, and by the Institutional Review Board (IRB) at King Saud University in Riyadh, Saudi Arabia.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Supplementary material

10753_2017_718_MOESM1_ESM.docx (362 kb)
ESM 1 (DOCX 361 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Department of Nutrition and Health SciencesUniversity of Nebraska-LincolnLincolnUSA
  2. 2.Department of Community Health Sciences, College of Applied Medical SciencesKing Saud UniversityRiyadhSaudi Arabia
  3. 3.College of Medicine Research Center, College of MedicineKing Saud UniversityRiyadhSaudi Arabia
  4. 4.Department of Anatomy, College of MedicineKing Saud UniversityRiyadhSaudi Arabia
  5. 5.Stem Cell Unit, Department of Anatomy, College of MedicineKing Saud UniversityRiyadhSaudi Arabia

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