# Sympathetic Mechanisms in the Cardiovascular and Metabolic Alterations of Obesity

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $601,970

## Abstract

Project Summary:
The presence of obesity increases the risk for hypertension and diabetes, in part due to the development of
insulin resistance. Obesity is also associated with sympathetic activation and our overarching hypothesis
is that sympathetic activation contributes to insulin resistance with impairment of its vascular and
metabolic actions. Our preliminary studies suggest that 1) Blood pressure can be normalized by autonomic
blockade in obese hypertensives, 2) Sympathetic activation provides no metabolic benefit because the
increase in resting energy expenditure associated with obesity is due to an increase in fat free mass
rather than sympathetic activation. On the contrary, autonomic blockade: 3) Improves insulin sensitivity in
obese hypertensives, 4) Reverses their impaired NO-mediated dilation, and 5) Reduces plasma
isoprostanes, a measure of oxidative stress. Furthermore, these abnormalities are interrelated in
negative feedback loops, whereby inflammation/oxidative stress impairs nitric oxide mechanisms,
which in turn reduces insulin-mediated vasodilation important for substrate delivery, thus contributing to
insulin resistance; insulin resistance leads to compensatory increases in insulin levels, which contributes to
further sympathetic activation.
 Current treatment guidelines do not specifically address the treatment of obesity hypertension, and do
not target sympathetic activation as a first line approach. It is important, therefore, to determine whether or
not targeting sympathetic activation offers unique advantages in the treatment of obesity hypertension over
current approaches. We propose a proof-of-concept mechanistic study comparing the metabolic, vascular,
and anti-inflammatory effects of sympathetic inhibition, calcium channel blockade and angiotensin receptor
blockade in obesity hypertension. We will test the hypotheses that sympathetic activation contributes to 1)
metabolic insulin resistance, which impairs the suppression of endogenous glucose production and the
stimulation of glucose uptake normally provided by insulin, 2) vascular insulin resistance, which impairs
insulin-mediated vasodilation and microvascular recruitment that normally promote glucose uptake, and 3)
inflammation and oxidative stress, which contribute to insulin resistance and hypertension.
 The proposed studies will gauge the contribution of sympathetic activation to the cardiovascular
and metabolic complications of obesity, and provide the mechanistic insight to determine whether or not we
should foster the efforts currently under way to develop novel therapies targeting sympathetic
activation for hypertension.

## Key facts

- **NIH application ID:** 10192815
- **Project number:** 5R01HL149386-03
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Italo Biaggioni
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $601,970
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10192815

## Citation

> US National Institutes of Health, RePORTER application 10192815, Sympathetic Mechanisms in the Cardiovascular and Metabolic Alterations of Obesity (5R01HL149386-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10192815. Licensed CC0.

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