Grants and Contracts Details
Description
Obesity affects >30% of the U.S. population and is a major risk factor for the pathogenesis of hypertension
[1]. Compelling evidence from both human and animal studies indicates that elevated sympathetic nerve
activity (SNA) to the hindlimb and renal vasculature contributes to obesity-induced hypertension [2]. One signal
linking elevated SNA to obesity-induced hypertension is hyperinsulinemia. Acute increases in circulating
insulin levels elevates SNA whereas chronic hyperinsuliunemia produces hypertension. Despite these
observations, the neural mechanisms underlying elevated SNA and ABP during hyperinsulinemia and obesity
are poorly understood.
Basal sympathetic outflow arises from the tonic drive of sympathetic-regulatory neurons in the rostral
ventrolateral medulla (RVLM) to preganglionic neurons in the thoracic and lumbar spinal cord [81. Altered
activity of RVLM neurons has also been implicated in several forms of hypertension [9-12] including a rodent
model of obesity hypertension published recently from our laboratory [13]. The goal of this fellowship is to
identify the neural mechanisms by which insulin elevates SNA and ABP in obesity. Myfireliminarv data
indicate that RVLM neurons contribute to the sympathoexcitatory actions of insulin. I hypothesize that diet-
induced obesity elevates circulating insulin which is sensed by neurons of the hypothalamic arcuate nucleus
(ARC) to activate a descending polysynaptic pathway to the RVLM. Subsequent activation of glutamate,
angiotensin ll-typel, or meianocortin-4 receptors in the RVLM increases the neuronal discharge of RVLM
sympathetic regulatory neurons. This increased excitatory drive to preganglionic neurons in the spinal cord
elevates SNA and ABP. Specific Aim #1 will identify specific receptors in the RVLM that mediate the elevated
SNA during hyperinsulinemia. Specific Aim #2 will identify the brain region that detects circulating insulin levels
and contributes to activation of RVLM neurons and SNA during hyperinsulinemia. Specific Aim #3 will identify
the cellular mechanisms within RVLM that elevate SNA and ABP in diet-induced obesity. The proposed
experiments will provide new insight into the neural mechanisms and circuitry mediating the
sympathoexcitatory effects of insulin and identify how these cellular mechanisms ultimately contribute to
obesity-induced hypertension. I
Status | Finished |
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Effective start/end date | 7/1/08 → 6/30/10 |
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