title: Activation of pattern recognition receptors in brown adipocytes induces inflammation and suppresses uncoupling protein 1 expression and mitochondrial respiration.
abstract: 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.
authors.affiliation: Department of Nutrition, University of Tennessee, Knoxville, Tennessee;
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Bae
authors.affiliation: Department of Nutrition, University of Tennessee, Knoxville, Tennessee;
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Ricciardi
authors.affiliation: Plants 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; and.
authors.forename: Debora
authors.initials: D
authors.lastname: Esposito
authors.affiliation: Plants 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; and.
authors.forename: Slavko
authors.initials: S
authors.lastname: Komarnytsky
authors.affiliation: Department of Nutrition, University of Tennessee, Knoxville, Tennessee;
authors.forename: Pan
authors.initials: P
authors.lastname: Hu
authors.affiliation: Department of Nutrition, University of Tennessee, Knoxville, Tennessee;
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Curry
authors.affiliation: Department of Nutrition, University of Tennessee, Knoxville, Tennessee;
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Brown
authors.affiliation: Pennington Biomedical Research Center, Baton Rouge, Louisiana.
authors.forename: Zhanguo
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Department of Nutrition, University of Tennessee, Knoxville, Tennessee; Center for Environmental Biotechnology, University of Tennessee, Knoxville, Tennessee;
authors.forename: John P
authors.initials: JP
authors.lastname: Biggerstaff
authors.affiliation: Department of Nutrition, University of Tennessee, Knoxville, Tennessee; Department of Public Health, University of Tennessee, Knoxville, Tennessee;
authors.forename: Jiangang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Nutrition, University of Tennessee, Knoxville, Tennessee; ling.zhao@utk.edu.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D004579:Electron Transport / Q000187:drug effects; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D000071256:Uncoupling Protein 1
chemical_list: D016207:Cytokines; D007473:Ion Channels; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D012333:RNA, Messenger; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D020928:Mitogen-Activated Protein Kinases; D007545:Isoproterenol
keywords: UCP-1; brown adipocytes; brown adipose tissue; inflammation; pattern recognition receptor