# Hypothalamic signaling mechanisms linking angiotensin and melanocortin pathways for metabolic control

> **NIH NIH P01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $391,276

## Abstract

Summary / Abstract
Obesity represents a major risk factor for the development of hypertension and other cardiovascular disorders,
and current therapeutic approaches to prevent and reverse obesity are insufficient. Studies from the NIH and
others have demonstrated that human obesity, and resistance to weight loss, is related to the suppression of
energy expenditure at rest (termed resting metabolic rate, or RMR). While clinical studies utilizing an array of
pharmaceuticals (2,4-dinitrophenol, etc.) have provided proof-of-concept data highlighting the utility of RMR
stimulation to reverse obesity, all existing pharmaceuticals that stimulate RMR exhibit unsafe pharmacokinetics
and are therefore banned for human use. Development of next-generation therapeutic strategies to combat the
obesity epidemic requires increased understanding of the biological controllers of RMR. The hypothalamus,
and more specifically the arcuate nucleus (ARC), is critically involved in the integrative control of RMR, and we
have recently documented a role for the angiotensin II type 1A (AT1A) receptor, localized to agouti-related
peptide (AgRP) neurons of the ARC, in the control of RMR by a diverse array of stimulators including leptin,
high fat diet, and the brain renin-angiotensin system (RAS). The objective of the current proposal is to
understand the second-messenger signaling cascade within AgRP neurons which is activated by AT1A, and to
clarify the neurocircuitry and neurotransmitters which mediate RMR control by the ARC RAS. Based on
exciting new unpublished data, we hypothesize that AT1A on AgRP neurons rather uniquely activates a G-
alpha-i-2 (GNAI2) cascade, which is sensitive to modulation by regulator of G-protein signaling-2 (RGS2).
Further, we hypothesize that this cascade mediates control of AgRP neurotransmission and therefore the
activation of melanocortin-mediated signaling through its type-4 receptor (MC4R). Finally, new data support the
novel concept that RGS2 also modulates MC4R second-messenger signaling, and is itself regulated by MC4R
signaling, which results in an autoregulatory cascade within MC4R neurons that may underlie cardiometabolic
sensitization as explored across projects in the current program.

## Key facts

- **NIH application ID:** 9977820
- **Project number:** 5P01HL084207-13
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Justin L Grobe
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $391,276
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977820

## Citation

> US National Institutes of Health, RePORTER application 9977820, Hypothalamic signaling mechanisms linking angiotensin and melanocortin pathways for metabolic control (5P01HL084207-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9977820. Licensed CC0.

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