title: Activation of Toll-like receptor 4 (TLR4) attenuates adaptive thermogenesis via endoplasmic reticulum stress.
abstract: Adaptive thermogenesis is the cellular process transforming chemical energy into heat in response to cold. A decrease in adaptive thermogenesis is a contributing factor to obesity. However, the molecular mechanisms responsible for the compromised adaptive thermogenesis in obese subjects have not yet been elucidated. In this study we hypothesized that Toll-like receptor 4 (TLR4) activation and subsequent inflammatory responses are key regulators to suppress adaptive thermogenesis. To test this hypothesis, C57BL/6 mice were either fed a palmitate-enriched high fat diet or administered with chronic low-dose LPS before cold acclimation. TLR4 stimulation by a high fat diet or LPS were both associated with reduced core body temperature and heat release. Impairment of thermogenic activation was correlated with diminished expression of brown-specific markers and mitochondrial dysfunction in subcutaneous white adipose tissue (sWAT). Defective sWAT browning was concomitant with elevated levels of endoplasmic reticulum (ER) stress and autophagy. Consistently, TLR4 activation by LPS abolished cAMP-induced up-regulation of uncoupling protein 1 (UCP1) in primary human adipocytes, which was reversed by silencing of C/EBP homologous protein (CHOP). Moreover, the inactivation of ER stress by genetic deletion of CHOP or chemical chaperone conferred a resistance to the LPS-induced suppression of adaptive thermogenesis. Collectively, our data indicate the existence of a novel signaling network that links TLR4 activation, ER stress, and mitochondrial dysfunction, thereby antagonizing thermogenic activation of sWAT. Our results also suggest that TLR4/ER stress axis activation may be a responsible mechanism for obesity-mediated defective brown adipose tissue activation.
authors.affiliation: From the Department of Nutrition and Health Sciences, the University of Nebraska-Lincoln, Lincoln, Nebraska 68583.
authors.forename: Meshail
authors.initials: M
authors.lastname: Okla
authors.affiliation: From the Department of Nutrition and Health Sciences, the University of Nebraska-Lincoln, Lincoln, Nebraska 68583.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: From the Department of Nutrition and Health Sciences, the University of Nebraska-Lincoln, Lincoln, Nebraska 68583.
authors.forename: Inhae
authors.initials: I
authors.lastname: Kang
authors.affiliation: From the Department of Nutrition and Health Sciences, the University of Nebraska-Lincoln, Lincoln, Nebraska 68583.
authors.forename: Anjeza
authors.initials: A
authors.lastname: Pashaj
authors.affiliation: From the Department of Nutrition and Health Sciences, the University of Nebraska-Lincoln, Lincoln, Nebraska 68583.
authors.forename: Timothy
authors.initials: T
authors.lastname: Carr
authors.affiliation: From the Department of Nutrition and Health Sciences, the University of Nebraska-Lincoln, Lincoln, Nebraska 68583 schung4@unl.edu.
authors.forename: Soonkyu
authors.identifier: http://orcid.org/0000-0001-6279-7017
authors.initials: S
authors.lastname: Chung
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D059865:Endoplasmic Reticulum Stress; D017353:Gene Deletion; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D022722:Thermogenesis; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D000071256:Uncoupling Protein 1
chemical_list: C497250:Ddit3 protein, mouse; D007473:Ion Channels; D008070:Lipopolysaccharides; D024101:Mitochondrial Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D051742:Transcription Factor CHOP
keywords: Toll-like receptor 4 (TLR4); UCP1; WAT browning; adaptive thermogenesis; adipose tissue metabolism; beige adipocyte; endoplasmic reticulum stress (ER stress); metabolic syndrome; reactive oxygen species (ROS)