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High‐Fat Diet‐Induced Obesity Suppresses Adaptive Thermogenesis via Toll‐Like Receptor (TLR) 4‐Mediated Endoplasmic Reticulum Stress
Author(s) -
Okla Meshail,
Wang Wei,
Chung Soonkyu
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.291.2
Subject(s) - thermogenesis , endocrinology , medicine , unfolded protein response , endoplasmic reticulum , tlr4 , knockout mouse , brown adipose tissue , white adipose tissue , biology , receptor , adipose tissue , microbiology and biotechnology
Adaptive thermogenesis is a cellular process that dissipates energy as heat, thus defending against obesity, in response to various activators such as cold. Obese subjects are less responsive to thermogenic signaling cues compared to lean subjects. Elevated levels of metabolic endotoxemia and circulating free fatty acids associated with obesity induce innate immune system and TLR4 activation, leading to the development of metabolic disorders. However, whether TLR4 activation plays a role in the adaptive thermogenesis impairment observed in obesity has not been investigated. In this study, we hypothesized that TLR4 activation in a high‐fat (HF) diet‐induced obesity model impairs adaptive thermogenesis. To test this hypothesis, C57BL/6 mice were fed either a low‐fat (LF) or HF diet for 12 weeks, followed by cold acclimation. HF diet‐mediated TLR4 activation concurred with a significant decrease in adaptive thermogenesis, brown‐specific markers, and mitochondrial‐specific markers in subcutaneous white adipose tissue (WAT). To verify the role of TLR4 in WAT browning, chronic low‐dose LPS was administrated to wild type and TLR4 knockout mice. LPS‐injected wild type mice were immune to both cold‐induced WAT browning and β3‐adrenergic receptor agonist (CL‐316,243)‐induced WAT browning, whereas TLR4 knockout mice were able to arouse thermogenesis. Chronic TLR4 activation in our mice resulted in ROS production and ER stress elevation. To understand the molecular link between TLR4 and ER stress in thermogenesis attenuation, ER stress was inactivated by either genetic deletion of CHOP or intraperitoneal injection of a chemical chaperone (PBA). Blunting ER stress protected the mice from TLR4‐induced mitochondrial degradation and rescued WAT browning. Taken together, our results indicate that TLR4 is a pivotal player in thermogenesis impairment observed in obesity. It mediates ROS production and ER stress activation, leading to mitochondrial degradation and WAT browning inhibition. In this study, we identified a novel TLR4/ER stress signaling axis associated with antagonizing WAT browning. Targeting this TLR4/ER stress axis might be efficacious in preventing defective thermogenesis observed in obesity. Support or Funding Information NIH 1P20GM104320