Nutrition and Health Sciences, Department of


Document Type


Date of this Version



Published in The Journal of Biological Chemistry 290:44 (October 30, 2015), pp. 26476–26490. doi 10.1074/jbc.M115.677724


Copyright © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. Used by permission.


Background: Human obesity is associated with defective brown adipose tissue (BAT) activation.

Results: Toll-like receptor 4(TLR4) activation by high fat diet or lipopolysaccharide impairs adaptive thermogenesis.

Conclusion: Obesity-mediated TLR4 activation represses adaptive thermogenesis through endoplasmic reticulum (ER) stress-mediated mitochondrial dysfunction.

Significance: Inhibition of TLR4/ER stress axis is a novel target to augment BAT activity.

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 upregulation 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 LPSinduced 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