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TBK1 激酶活性丧失可保护小鼠免受饮食诱导的代谢功能障碍。

Loss of Tbk1 kinase activity protects mice from diet-induced metabolic dysfunction.

机构信息

Division of Surgical Oncology, Department of Surgery and the Hamon Center for Therapeutic Oncology Research, USA.

Touchstone Diabetes Center, Department of Internal Medicine, USA.

出版信息

Mol Metab. 2018 Oct;16:139-149. doi: 10.1016/j.molmet.2018.06.007. Epub 2018 Jun 11.

DOI:10.1016/j.molmet.2018.06.007
PMID:29935921
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6157474/
Abstract

OBJECTIVE

TANK Binding Kinase 1 (TBK1) has been implicated in the regulation of metabolism through studies with the drug amlexanox, an inhibitor of the IκB kinase (IKK)-related kinases. Amlexanox induced weight loss, reduced fatty liver and insulin resistance in high fat diet (HFD) fed mice and has now progressed into clinical testing for the treatment and prevention of obesity and type 2 diabetes. However, since amlexanox is a dual IKKε/TBK1 inhibitor, the specific metabolic contribution of TBK1 is not clear.

METHODS

To distinguish metabolic functions unique to TBK1, we examined the metabolic profile of global Tbk1 mutant mice challenged with an obesogenic diet and investigated potential mechanisms for the improved metabolic phenotype.

RESULTS AND CONCLUSION

We report that systemic loss of TBK1 kinase function has an overall protective effect on metabolic readouts in mice on an obesogenic diet, which is mediated by loss of an inhibitory interaction between TBK1 and the insulin receptor.

摘要

目的

通过使用 IκB 激酶（IKK）相关激酶抑制剂 amlexanox 的研究，TANK 结合激酶 1（TBK1）被牵连到代谢的调节中。amlexanox 可诱导高脂肪饮食（HFD）喂养的小鼠体重减轻、减少脂肪肝和胰岛素抵抗，现已进入肥胖和 2 型糖尿病治疗和预防的临床测试。然而，由于 amlexanox 是一种双重 IKKε/TBK1 抑制剂，因此 TBK1 的特定代谢贡献尚不清楚。

方法

为了区分 TBK1 特有的代谢功能，我们检查了肥胖饮食挑战的全局 Tbk1 突变小鼠的代谢谱，并研究了改善代谢表型的潜在机制。

结果和结论

我们报告称，TBK1 激酶功能的系统性丧失对肥胖饮食小鼠的代谢读数具有整体保护作用，这是由 TBK1 和胰岛素受体之间的抑制性相互作用丧失介导的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/53732d5c49b7/figs4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/23a2e63ac25e/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/b73ba935fe3d/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/4cf0fd0414a6/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/c6c763aba538/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/ef715f71d92e/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/95c4df698510/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/17f4d94ce7d1/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/7f505bb8906a/figs1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/79da679cfc72/figs2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/d8b721891572/figs3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/53732d5c49b7/figs4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/23a2e63ac25e/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/b73ba935fe3d/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/4cf0fd0414a6/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/c6c763aba538/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/ef715f71d92e/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/95c4df698510/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/17f4d94ce7d1/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/7f505bb8906a/figs1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/79da679cfc72/figs2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/d8b721891572/figs3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/22fc/6157474/53732d5c49b7/figs4.jpg

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