Reversal of prolonged obesity-associated cerebrovascular dysfunction by inhibiting microglial Tak1.

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.

• Authors: Qing Shen, Zhuo Chen, Faming Zhao, Susu Pan, Tingting Zhang, Xueer Cheng, Lei Zhang, Shanshan Zhang, Junxia Qi, Juxue Li, Dongsheng Cai, Guo Zhang
• Journal: Nature neuroscience (Nat Neurosci) Vol. 23 Issue 7 Pg. 832-841 (07 2020) ISSN: 1546-1726 [Electronic] United States
• PMID: 32451485 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7

Topics

• Animals
• Basilar Artery (pathology)
• Brain (blood supply)
• Brain Stem (metabolism)
• Cerebrovascular Circulation (physiology)
• Diet, High-Fat (adverse effects)
• MAP Kinase Kinase Kinases (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Microglia (metabolism)
• Obesity (metabolism)
• Stroke (metabolism)