# Interaction between leptin and angiotensin in the pathogenesis of obesity-hypertension

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $385,000

## Abstract

Project Summary / Abstract
The renin-angiotensin system (RAS) exists as a circulating hormone system but also as a local
autocrine/paracrine signaling mechanism in tissues such as the brain. The RAS is active in regions of the
brain which are recognized contributors to blood pressure control, including the subfornical organ,
paraventricular nucleus, area postrema, medulla, and others. Although generally considered a major
contributor to metabolic but not cardiovascular control, the arcuate nucleus (ARC) also exhibits expression of
the RAS. We and others have determined that the brain RAS strongly contributes to energy balance,
especially through the control of sympathetic nervous activity (SNA) and subsequently, resting metabolic rate
(RMR). Together these data led to the general hypothesis that the RAS within the ARC may differentially
contribute to metabolic versus cardiovascular control. The overall objective of the current proposal is therefore
to understand the role of the RAS in the neurocircuitry of the ARC which contributes to metabolic versus
cardiovascular control physiology. New unpublished data from our group demonstrate that that the angiotensin
II type 1A receptor (AT1A) specifically localized to cells that express the leptin receptor (LepR) are critically
involved in the control of RMR and thereby weight gain in response to high fat diet. Importantly AT1A
expressed in LepR-expressing cells are also involved in the RMR, but not blood pressure (BP) responses to
deoxycorticosterone acetate (DOCA)-salt treatment. Localization and gene profiling studies indicate that AT1A
are only expressed in the subset of LepR-expressing cells which also express agouti related peptide (AgRP),
but not proopiomelanocortin (POMC). These data lead us to propose three aims. Aim 1 will evaluate the
cardiovascular and metabolic consequences of selectively disrupting AT1A expression within AgRP-expressing
cells. Aim 2 will examine the role of AT1A in the AgRP neuron in the pathogenesis of selective leptin resistance
(SLR). SLR describes the selective loss of metabolic, but not cardiovascular, responses to leptin which occur
after prolonged obesity. SLR has been proposed as a possible explanation for the high comorbidity of
hypertension and obesity (i.e. – obesity-associated hypertension). Our discovery that the ARC RAS
specifically acts to modulate metabolic (but not cardiovascular) sensitivity therefore supports the novel concept
that AT1A receptor modulation within AgRP cells may explain the molecular mechanism of SLR. Aim 3 will
examine a novel hypothesis that LepR activation in AgRP cells activates a RAS-mediated autocrine signaling
pathway, which may represent the molecular mechanism of the cross-talk between the LepR and AT1A in these
cells. We will use an array of newly-developed genetically-modified animal models, state-of-the-art methods
for the measurement of BP, SNA, and RMR, and well-established collaborations with recognized experts in
leptin, SL...

## Key facts

- **NIH application ID:** 9842567
- **Project number:** 5R01HL134850-05
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Justin L Grobe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842567

## Citation

> US National Institutes of Health, RePORTER application 9842567, Interaction between leptin and angiotensin in the pathogenesis of obesity-hypertension (5R01HL134850-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9842567. Licensed CC0.

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