Abstract
Altered autonomic regulation of the heart may contribute to the increased risk of cardiac diseases in obesity. The mechanisms behind the abnormal autonomic activities remain to be addressed. In this study, mice fed regular diet (RD) or high fat diet (HFD) for 6 weeks were used to test the effect of parasympathetic nervous system (PSNS) on the heart. The body weight, plasma insulin, and total cholesterols were significantly increased in HFD mice compared to RD mice. Functionally, the response in heart rate to vagal stimulation, but not the response to the direct stimulation of muscarinic receptors, was significantly attenuated in HFD mice compared with RD mice. These results suggest a reduced cholinergic activity at PSNS ganglia and/or terminals in HFD mice. Vesicular acetylcholine transporter (VAChT) is critical for acetylcholine storing and release at cholinergic neurons and terminals. Western blot showed that the protein level of VAChT was significantly reduced in atria samples from HFD mice compared with RD mice. Furthermore, in vitro experiments using a cholinergic cell line, SN56, showed that the treatment with insulin significantly increased VAChT ubiquitination. Prolonged treatment with insulin decreased VAChT protein level and VAChT trafficking. Together, these results suggest that reduced VAChT level, at least partially due to the insulin‐induced increase in ubiquitination‐mediated VAChT degradation, may contribute to the attenuated cholinergic activity at parasympathetic ganglia and/or terminals in the heart in HFD mice. This work was supported by AHA grant No.0835256N, NIH INBRE grant No. P20 RR016479, and the BBS bridge grant.
Published Version
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