Fellowship Bardgett: Neural Mechanisms of Sympathetic Activation During Hyperinsulinemia and Obesity-Induced Hpertension

  • Stocker, Sean (PI)
  • Bardgett, Megan (CoI)

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
StatusFinished
Effective start/end date7/1/086/30/10

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.