# Neuronal Mechanisms of Obesity-Induced Hypertension

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2024 · —

## Abstract

The high prevalence of obesity among the veterans is a major challenge for the VA healthcare system. This is
because obesity is associated with increased sympathetic nerve traffic leading to hypertension, a major risk
factor for end-organ damage, stroke, myocardial infarction and congestive heart failure. However, the cellular
and molecular etiology of obesity-associated cardiovascular risks remain poorly understood. We and others
have previously demonstrated the importance of the brain mechanisms in the pathophysiology of obesity-
induced sympathetic activation and hypertension. Brain action of leptin and the melanocortinergic system have
emerged as major drivers of the increase in sympathetic nerve traffic and blood pressure in obesity. Studies
from our lab also revealed the importance of the mechanistic target of rapamycin complex 1 (mTORC1) in the
control of sympathetic nerve activity and blood pressure. Moreover, we provide compelling preliminary data
demonstrating that disruption of mTORC1 signaling in the leptin receptor (LepRb)-containing neurons interfere
selectively with the ability of leptin to increase renal sympathetic activity and blood pressure. Notably,
mTORC1 disruption in the LepRb neurons protect mice from the sympathetic overdrive and hypertension
evoked by diet-induced obesity without affecting weigh gain and adiposity. Moreover, we identified serine
peptidase inhibitor A3N (SerpinA3N) as a novel gene downstream to mTORC1 signaling. This led us to
hypothesize that mTORC1 signaling and SerpinA3N in the LepRb neurons mediate obesity-induced
sympathetic nerve activation and hypertension. We will test our hypothesis by examining the transcription
mechanisms that regulate SerpinA3N gene. In addition, we will investigate the role of SerpinA3N in the control
of sympathetic nerve traffic, arterial pressure and obesity-associated hypertension and sympathetic nerve
activation. We will also dissect the neurocircuit underlying the protection conferred by disruption of mTORC1
signaling in LepRb neurons on obesity-induced hypertension and sympathetic nerve activation. This research
will advance understanding of the mechanisms underlying the sympathetic overdrive and hypertension
associated with obesity that has become common in the VA population.

## Key facts

- **NIH application ID:** 10765667
- **Project number:** 5I01BX004249-06
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** KAMAL RAHMOUNI
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765667

## Citation

> US National Institutes of Health, RePORTER application 10765667, Neuronal Mechanisms of Obesity-Induced Hypertension (5I01BX004249-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10765667. Licensed CC0.

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