Activation of Toll-like receptor 4 (TLR4) attenuates adaptive thermogenesis via endoplasmic reticulum stress

Meshail Okla, Wei Wang, Inhae Kang, Anjeza Pashaj, Timothy Carr, Soonkyu Chung

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


Adaptive thermogenesis is the cellular process transforming chemical energy into heat in response to cold. A decrease in adaptive thermogenesis isacontributing factortoobesity. 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 dietorLPS were both associated with reduced core body temperature and heat release. Impairment of thermogenic activation was correlated with diminished expressionofbrown-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 maybea responsible mechanism for obesity-mediated defective brown adipose tissue activation.

Original languageEnglish (US)
Pages (from-to)26476-26490
Number of pages15
JournalJournal of Biological Chemistry
Issue number44
StatePublished - Oct 30 2015

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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