# Forebrain-hypothalamic mechanisms in obesity-induced hypertension

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2020 · $487,115

## Abstract

PROJECT SUMMARY:
Obesity is a growing health epidemic and is directly linked to the development of hypertension. Accumulating
evidence from humans and animal models indicate that excessive central sympathetic nerve activity (SNA)
plays a pathogenic role in obesity-associated hypertension. However, the central nervous system (CNS)
networks and molecular mechanisms that lead to sustained elevations in SNA and arterial blood pressure
during obesity remain unclear. There is mounting evidence that endoplasmic reticulum (ER) stress and
activation of the transcription factor nuclear factor-κ-B (NFκB) are involved in obesity. Our recently published
observations, as well as exciting preliminary data, are in support of this and point to forebrain-hypothalamic
networks as a culprit. Key findings, during diet-induced obesity in mice, have revealed robust ER stress and
downstream activation of NFκB in the paraventricular nucleus of the hypothalamus (PVN) - a key CNS region
involved in sympathetic and cardiovascular regulation. We also provide novel evidence that these
pathophysiological alterations are mediated through an excitatory neural circuit involving the subfornical organ
(SFO), a CNS circumventricular region located outside of the blood-brain-barrier that integrates circulating
factors with the control of the autonomic nervous system. Using an approach that combines genomic
interventions, neuroanatomical circuit analysis, chemogenetic manipulations, innovative imaging techniques,
and integrative physiology, we will test the overall hypothesis that ER stress-induced NFκB activation in a
forebrain-hypothalamic circuit involving the SFO and PVN mediates hypertension development during obesity.
Using a murine model of obesity-induced hypertension, in Aim 1, we will dissect out the role of SFO excitatory
signaling in PVN ER stress. Based on our evidence that ER stress intersects directly with NFκB activation, in
Aim 2, we will interrogate ER stress-NFκB interactions in the PVN during obesity-related hypertension. In Aim
3, we will investigate the functional role of the SFO-PVN axis, as related to ER stress and NFκB activation, in
mediating obesity-induced sympathetic overactivity and hypertension development. We will use an array of
designer receptors engineered against designer drugs technology, intersectional viral techniques to target
select neuron populations, transgenic mouse models, longitudinal in vivo bioluminescence imaging, molecular
biology, state-of-the-art scanning electron microscopy techniques, and integrative cardiovascular/autonomic
physiology to accomplish the proposed studies. Overall, this project will expand our knowledge of the
underlying neurocircuitry and molecular mechanisms that contribute to hypertension development in obese
conditions.

## Key facts

- **NIH application ID:** 9860934
- **Project number:** 5R01HL141393-03
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Colin Neal Young
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $487,115
- **Award type:** 5
- **Project period:** 2018-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9860934

## Citation

> US National Institutes of Health, RePORTER application 9860934, Forebrain-hypothalamic mechanisms in obesity-induced hypertension (5R01HL141393-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9860934. Licensed CC0.

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