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

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

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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
Volume290
Issue number44
DOIs
StatePublished - Oct 30 2015

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Toll-Like Receptor 4
Endoplasmic Reticulum Stress
Thermogenesis
Chemical activation
White Adipose Tissue
Subcutaneous Fat
Transcription Factor CHOP
Tissue
Chemical Phenomena
Hot Temperature
Brown Adipose Tissue
Palmitates
Acclimatization
Autophagy
High Fat Diet
Fats
Body Temperature
Inbred C57BL Mouse
Adipocytes
Up-Regulation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Activation of Toll-like receptor 4 (TLR4) attenuates adaptive thermogenesis via endoplasmic reticulum stress. / Okla, Meshail; Wang, Wei; Kang, Inhae; Pashaj, Anjeza; Carr, Timothy P; Chung, Soonkyu.

In: Journal of Biological Chemistry, Vol. 290, No. 44, 30.10.2015, p. 26476-26490.

Research output: Contribution to journalArticle

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