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Reversal of prolonged obesity-associated cerebrovascular dysfunction by inhibiting microglial Tak1
Qing Shen1,2,3, Zhuo Chen1,2,3, Faming Zhao1,2,3
1Key Laboratory of Environmental Health, Ministry of Education, Department of Toxicology, School of Public Health, Tongji Medical College, Wuhan, China.
Abstract:
Prolonged obesity is associated with cerebrovascular dysfunction; however, the underlying mechanisms remain largely unclear. In the present study, using a prolonged obesity mouse model that suffers from basilar artery (BA) abnormalities, we find that microglial transforming growth factor β-activated kinase 1 (Tak1) is over-activated in the brainstem. Both pharmacological inhibition primarily in the brainstem and genetic microglia-selective deletion of Tak1 ameliorated BA vascular dysfunction. Conversely, microglia-specific activation of Tak1 in the brainstem was sufficient to cause an impairment in BA function in chow-fed mice. Mechanistically, Tak1 activation leads to increased interleukin-18 (IL-18) production, whereas blockade of IL-18 receptor in the brain helped protect against cerebrovascular dysfunction despite prolonged obesity. Microglia-selective deletion of Tak1 also protects against ischemic stroke in prolonged obesity. Taken together, these findings provide evidence that microglial Tak1 in the brain, and particularly the brainstem, contributes to the pathogenesis of obesity-associated cerebrovascular dysfunction.
Insights
Obesity impairs brain blood vessels. Researchers found that blocking microglial transforming growth factor β-activated kinase 1 (Tak1) in the brainstem improved basilar artery function and protected against stroke in obese mice.
Area of Science:
- Neuroscience
- Immunology
- Cardiovascular Science
Background:
- Prolonged obesity is linked to cerebrovascular dysfunction.
- Mechanisms underlying obesity-related brain vascular issues are not fully understood.
Purpose of the Study:
- To investigate the role of microglial transforming growth factor β-activated kinase 1 (Tak1) in obesity-associated cerebrovascular dysfunction.
- To explore therapeutic targets for preventing obesity-related brain vascular damage.
Main Methods:
- Utilized a prolonged obesity mouse model with basilar artery (BA) abnormalities.
- Employed pharmacological inhibition and genetic deletion of Tak1 specifically in microglia within the brainstem.
- Investigated the downstream effects of Tak1 activation, including interleukin-18 (IL-18) production.
Main Results:
- Over-activation of microglial Tak1 was observed in the brainstem of obese mice.
- Pharmacological inhibition and genetic deletion of Tak1 in microglia ameliorated BA vascular dysfunction.
- Microglia-specific Tak1 activation induced BA dysfunction in non-obese mice.
- Blocking the IL-18 receptor protected against cerebrovascular dysfunction in obese mice.
- Microglia-selective Tak1 deletion reduced ischemic stroke incidence in obese mice.
Conclusions:
- Microglial Tak1 in the brainstem significantly contributes to the pathogenesis of obesity-associated cerebrovascular dysfunction.
- Targeting microglial Tak1 and IL-18 signaling presents a potential therapeutic strategy for cerebrovascular complications of obesity.
