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Loss of Tbk1 kinase activity protects mice from diet-induced metabolic dysfunction
Victoria H Cruz1, Emily N Arner1, Katherine W Wynne1
1Division of Surgical Oncology, Department of Surgery and the Hamon Center for Therapeutic Oncology Research, USA.
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.
Insights
Loss of TANK Binding Kinase 1 (TBK1) protects against metabolic dysfunction in mice fed an obesogenic diet. This protective effect is due to TBK1 no longer inhibiting the insulin receptor.
Area of Science:
- Biochemistry
- Metabolic disease research
- Molecular biology
Background:
- TANK Binding Kinase 1 (TBK1) is implicated in metabolic regulation.
- Amlexanox, a dual IKKε/TBK1 inhibitor, shows promise for obesity and type 2 diabetes treatment.
- The specific metabolic role of TBK1 remains unclear due to amlexanox's dual action.
Purpose of the Study:
- To elucidate the unique metabolic functions of TBK1.
- To investigate the metabolic profile of mice lacking TBK1 kinase function.
- To identify mechanisms underlying TBK1's metabolic influence.
Main Methods:
- Examined the metabolic profile of global Tbk1 mutant mice.
- Challenged mice with an obesogenic diet.
- Investigated the interaction between TBK1 and the insulin receptor.
Main Results:
- Systemic loss of TBK1 kinase function conferred a protective metabolic phenotype in mice on an obesogenic diet.
- This protection was mediated by the absence of an inhibitory interaction between TBK1 and the insulin receptor.
- TBK1 kinase activity negatively impacts metabolic health.
Conclusions:
- TBK1 plays a critical role in metabolic regulation.
- Disrupting the TBK1-insulin receptor interaction may offer therapeutic benefits for metabolic diseases.
- Targeting TBK1 could be a strategy for treating obesity and type 2 diabetes.
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