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Toll-like receptor 4 knockout mice are protected against endoplasmic reticulum stress induced by a high-fat diet
Nicolas Pierre1, Louise Deldicque, Caroline Barbé
1Institute of Neuroscience, Université catholique de Louvain, Louvain-la-Neuve, Belgium.
Abstract:
The purpose of this study was to investigate whether toll-like receptor 4 (TLR4) is implicated in the development of endoplasmic reticulum stress (ER stress) observed after a high-fat diet (HFD) in liver, skeletal muscle and adipose tissue. TLR4(-/-) and C57BL/6J wild-type mice (WT) were fed with chow or HFD (45% calories from fat) during 18 weeks. An oral glucose tolerance-test was performed. The animals were sacrificed in a fasted state and the tissues were removed. TLR4 deletion protected from body weight gain and glucose intolerance induced by HFD whereas energy intake was higher in transgenic mice suggesting larger energy expenditure. HFD induced an ER stress in skeletal muscle, liver and adipose tissue of WT mice as assessed by BiP, CHOP, spliced and unspliced XBP1 and phospho-eIF2α. TLR4(-/-) mice were protected against HFD-induced ER stress. Then, we investigated the main signaling downstream of TLR4 namely the NF-κB pathway, expecting to identify the mechanism by which TLR4 is able to activate ER stress. The mRNA levels of cytokines regulated by NF-κB namely TNFα, IL-1β and IL-6, were not changed after HFD and phospho-IκB-α (ser 32) was not changed. Our results indicate that TLR4 is essential for the development of ER stress related to HFD. Nevertheless, the NFκ-B pathway does not seem to be directly implicated. The reduced fat storage in TLR4(-/-) mice could explain the absence of an ER stress after HFD.
Insights
Toll-like receptor 4 (TLR4) deficiency prevents high-fat diet-induced endoplasmic reticulum (ER) stress and glucose intolerance in mice. This suggests TLR4 plays a crucial role in diet-induced metabolic dysfunction.
Area of Science:
- Metabolic diseases
- Immunology
- Cellular stress responses
Background:
- High-fat diets (HFD) induce metabolic dysfunction and endoplasmic reticulum (ER) stress.
- Toll-like receptor 4 (TLR4) is a key immune receptor involved in inflammatory responses.
Purpose of the Study:
- To investigate the role of TLR4 in HFD-induced ER stress in liver, skeletal muscle, and adipose tissue.
- To determine if TLR4 deletion protects against HFD-induced metabolic disturbances.
Main Methods:
- Comparison of TLR4 knockout mice and wild-type mice fed a HFD or control diet for 18 weeks.
- Assessment of body weight, glucose tolerance, energy expenditure, and ER stress markers (BiP, CHOP, XBP1, eIF2α).
- Analysis of the NF-κB pathway activation.
Main Results:
- TLR4 deletion protected against HFD-induced weight gain and glucose intolerance.
- HFD induced ER stress in wild-type mice, which was prevented in TLR4 knockout mice.
- NF-κB pathway activation was not significantly altered, suggesting it's not the primary mediator.
Conclusions:
- TLR4 is essential for the development of ER stress associated with HFD.
- Reduced fat accumulation in TLR4 knockout mice may underlie the protection against ER stress.
- The NF-κB pathway does not appear to be directly involved in TLR4-mediated ER stress in this context.
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