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

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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.

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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

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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.

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.

Author information

Authors and Affiliations

  1. Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE, USA

    Meshail Okla & Soonkyu Chung

  2. Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, 183T11, P.O. Box 22452, Riyadh, 11495, Saudi Arabia

    Meshail Okla

  3. College of Medicine Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia

    Walid Zaher

  4. Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia

    Walid Zaher

  5. Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh, Saudi Arabia

    Musaad Alfayez

Authors
  1. Meshail Okla
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  2. Walid Zaher
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  3. Musaad Alfayez
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  4. Soonkyu Chung
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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.

Corresponding author

Correspondence to Meshail Okla.

Ethics declarations

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.

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Okla, M., Zaher, W., Alfayez, M. et al. Inhibitory Effects of Toll-Like Receptor 4, NLRP3 Inflammasome, and Interleukin-1β on White Adipocyte Browning. Inflammation 41, 626–642 (2018). https://doi.org/10.1007/s10753-017-0718-y

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