Activation of pattern recognition receptors in brown adipocytes induces inflammation and suppresses uncoupling protein 1 expression and mitochondrial respiration. American Journal of Physiology. Cell Physiology. May 15, 2014. Epub 2014 Mar 13. Bae J1, Ricciardi CJ1, Esposito D2, Komarnytsky S2, Hu P1, Curry BJ1, Brown PL1, Gao Z3, Biggerstaff JP4, Chen J5, Zhao L6.
1Department of Nutrition, University of Tennessee, Knoxville, Tennessee; 2Plants for Human Health Institute, North Carolina Research Campus, North Carolina State University, Kannapolis, North Carolina; Department of Food, Bioprocessing, and Nutrition Sciences, North Carolina State University, Raleigh, North Carolina; 3Pennington Biomedical Research Center, Baton Rouge, Louisiana; 4Department of Nutrition, University of Tennessee, Knoxville, Tennessee; Center for Environmental Biotechnology, University of Tennessee, Knoxville, Tennessee; 5Department of Nutrition, University of Tennessee, Knoxville, Tennessee; Department of Public Health, University of Tennessee, Knoxville, Tennessee; 6Department of Nutrition, University of Tennessee, Knoxville, Tennessee.
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.
Copyright © 2014 the American Physiological Society.
PMID: 24627558 [PubMed – in process]