Activation of pattern recognition receptors in brown adipocytes induces inflammation and suppresses uncoupling protein 1 expression and mitochondrial respiration

Pattern recognition receptors (PRR), Toll-like receptors (TLR), and nucleotide-oligomerization domain-containing proteins (NOD) play critical roles in mediating inflammation and modulating functions in white adipocytes in obesity. However, the role of PRR activation in brown adipocytes, which are re...

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Published in:American Journal of Physiology: Cell Physiology 2014-05, Vol.306 (10), p.C918-C930
Main Authors: Bae, Jiyoung, Ricciardi, Carolyn J, Esposito, Debora, Komarnytsky, Slavko, Hu, Pan, Curry, Benjamin J, Brown, Patricia L, Gao, Zhanguo, Biggerstaff, John P, Chen, Jiangang, Zhao, Ling
Format: Article
Language:English
Subjects:
Adipocytes - drug effects
Adipocytes - metabolism
Adipocytes - pathology
Adipose Tissue, Brown - drug effects
Adipose Tissue, Brown - metabolism
Adipose Tissue, Brown - pathology
Animals
Body fat
Cell Line
Cytokines - genetics
Cytokines - metabolism
Diet, High-Fat
Electron Transport - drug effects
Gene Expression Regulation
Inflammation - genetics
Inflammation - metabolism
Inflammation - pathology
Ion Channels - genetics
Ion Channels - metabolism
Isoproterenol - pharmacology
Male
Mice
Mitochondria - drug effects
Mitochondria - metabolism
Mitochondrial Proteins - genetics
Mitochondrial Proteins - metabolism
Mitogen-Activated Protein Kinases - genetics
Mitogen-Activated Protein Kinases - metabolism
NF-kappa B - genetics
NF-kappa B - metabolism
Nod1 Signaling Adaptor Protein - genetics
Nod1 Signaling Adaptor Protein - metabolism
Nod2 Signaling Adaptor Protein - genetics
Nod2 Signaling Adaptor Protein - metabolism
Obesity
Obesity - genetics
Obesity - metabolism
Obesity - pathology
Pattern recognition
Promoter Regions, Genetic
Protein expression
RNA, Messenger - genetics
RNA, Messenger - metabolism
Rodents
Signal Transduction
T cell receptors
Tissues
Toll-Like Receptor 2 - genetics
Toll-Like Receptor 2 - metabolism
Toll-Like Receptor 4 - genetics
Toll-Like Receptor 4 - metabolism
Uncoupling Protein 1
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Summary:Pattern recognition receptors (PRR), Toll-like receptors (TLR), and nucleotide-oligomerization domain-containing proteins (NOD) play critical roles in mediating inflammation and modulating functions in white adipocytes in obesity. However, the role of PRR activation in brown adipocytes, which are recently found to be present in adult humans, has not been studied. Here we report that mRNA of TLR4, TLR2, NOD1, and NOD2 is upregulated, paralleled with upregulated mRNA of inflammatory cytokines and chemokines in the brown adipose tissue (BAT) of the obese mice. During brown adipocyte differentiation, mRNA and protein expression of NOD1 and TLR4, but not TLR2 and NOD2, is also increased. Activation of TLR4, TLR2, or NOD1 in brown adipocytes induces activation of NF-κB and MAPK signaling pathways, leading to inflammatory cytokine/chemokine mRNA expression and/or protein secretion. Moreover, activation of TLR4, TLR2, or NOD1 attenuates both basal and isoproterenol-induced uncoupling protein 1 (UCP-1) expression without affecting mitochondrial biogenesis and lipid accumulation in brown adipocytes. Cellular bioenergetics measurements confirm that attenuation of UCP-1 expression by PRR activation is accompanied by suppression of both basal and isoproterenol-stimulated oxygen consumption rates and isoproterenol-induced uncoupled respiration from proton leak; however, maximal respiration and ATP-coupled respiration are not changed. Further, the attenuation of UCP-1 by PRR activation appears to be mediated through downregulation of the UCP-1 promoter activities. Taken together, our results demonstrate the role of selected PRR activation in inducing inflammation and downregulation of UCP-1 expression and mitochondrial respiration in brown adipocytes. Our results uncover novel targets in BAT for obesity treatment and prevention.
ISSN:0363-6143
1522-1563
DOI:10.1152/ajpcell.00249.2013