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Journal of Neuroinflammation

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Open Access 01-12-2018 | Research

TLR4 inhibitor TAK-242 attenuates the adverse neural effects of diet-induced obesity

Authors: V. Alexandra Moser, Mariana F. Uchoa, Christian J. Pike

Published in: Journal of Neuroinflammation | Issue 1/2018

Abstract

Background

Obesity exerts negative effects on brain health, including decreased neurogenesis, impaired learning and memory, and increased risk for Alzheimer’s disease and related dementias. Because obesity promotes glial activation, chronic neuroinflammation, and neural injury, microglia are implicated in the deleterious effects of obesity. One pathway that is particularly important in mediating the effects of obesity in peripheral tissues is toll-like receptor 4 (TLR4) signaling. The potential contribution of TLR4 pathways in mediating adverse neural outcomes of obesity has not been well addressed. To investigate this possibility, we examined how pharmacological inhibition of TLR4 affects the peripheral and neural outcomes of diet-induced obesity.

Methods

Male C57BL6/J mice were maintained on either a control or high-fat diet for 12 weeks in the presence or absence of the specific TLR4 signaling inhibitor TAK-242. Outcomes examined included metabolic indices, a range of behavioral assessments, microglial activation, systemic and neuroinflammation, and neural health endpoints.

Results

Peripherally, TAK-242 treatment was associated with partial inhibition of inflammation in the adipose tissue but exerted no significant effects on body weight, adiposity, and a range of metabolic measures. In the brain, obese mice treated with TAK-242 exhibited a significant reduction in microglial activation, improved levels of neurogenesis, and inhibition of Alzheimer-related amyloidogenic pathways. High-fat diet and TAK-242 were associated with only very modest effects on a range of behavioral measures.

Conclusions

These results demonstrate a significant protective effect of TLR4 inhibition on neural consequences of obesity, findings that further define the role of microglia in obesity-mediated outcomes and identify a strategy for improving brain health in obese individuals.

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Title: TLR4 inhibitor TAK-242 attenuates the adverse neural effects of diet-induced obesity
Authors: V. Alexandra Moser
Mariana F. Uchoa
Christian J. Pike
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-018-1340-0

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

TLR4 inhibitor TAK-242 attenuates the adverse neural effects of diet-induced obesity

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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