The Impact of High Fat Diet on Brainstem Vagal Regulation

ABSTRACT:
Current understanding of cardiac parasympathetic (or vagal) activity unequivocally demonstrates that the vagal
activity to the heart and homeostatic reflex changes in cardiac vagal activity are mediated by cardiac vagal motor
neurons (CVNs) in the brainstem. Therefore, CVNs play an essential role in normal cardiovascular function.
Despite our understanding of CVN neurophysiology in health, the potential for CVN dysfunction in diseases is
still unclear. This is particularly true of our understanding of the complex interplay between diet and
cardiovascular function. In some estimates, Americans are consuming 600 more calories from fat per day then
any time in the recent past. This increased consumption of foods high in fat significantly elevated the risk of
developing cardiovascular diseases. A distinctive hallmark of cardiovascular disease risk is low cardiac vagal
signaling, and the extend of this imbalance correlates strongly with increasing risk morbidity and mortality.
Preliminary data from our laboratory demonstrate that CVN activity is significantly reduced and inhibitory
neurotransmission to CVNs is increased during early consumption of foods high in fat. This reduced CVN activity
parallels a significant reduction in cardiac vagal contribution to resting heart rate. The reduction in vagal activity
can be abolished through genetic knock down of a specific subunit of the receptors that mediate inhibition in
CVNs. Critically, PKC inhibition also abolishes the influence of high fat diet on vagal function, and this increased
PKCδ activity is likely mediated by increased activity of the alpha-1 adrenoreceptor on CVNs. Our overall
hypothesis guiding this proposal is that high fat diet-induced increase in functional expression of inhibitory
receptors in CVNs results in a progressive decline in overall vagal activity. However, critical questions remain,
including how quickly does the increased inhibition of CVNs occur and what role does the PKCδ isoform play in
this inhibition. Therefore, this proposal will 1) quantitively determine the timing of cardiac vagal signaling after
high fat diet, and 2) establish the role of PKCδ in the effects of early HFD on CVN function. The anticipated
results of these experiments will provide fundamental details in our understanding of cardiac vagal regulation
and mechanisms responsible for vagal regulation of heart rate. Identifying the early mechanistic consequences
of HFD on vagal activity could lead to the discovery of biomarkers, and early testing of new therapeutics targeting
disease mechanisms, rather than symptoms.

Grant Number: 5R01HL157366-05
NIH Institute/Center: NIH
Principal Investigator: CARIE BOYCHUK