# Neural Mechanisms of Nausea, Vomiting, and Energy Dysregulation

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $613,967

## Abstract

Project Summary
Nausea and vomiting promote mammalian survival. Paradoxically, emetic “side effects” are ubiquitously
reported for FDA-approved pharmacotherapeutics for obesity, diabetes, and cancer pharmacotherapies and
present alongside polymorbidities that contribute to detrimental life-threatening outcomes, such as poor
nutrition, quality of life, and patient prognosis. Here, we address two broad unmet clinical needs: 1) All existing
FDA-approved glucagon-like peptide-1 (GLP-1)-based therapeutics for the treatment of diabetes and obesity
elicit nausea and vomiting in a significant percentage of patients. 2) Despite existing antiemetic treatments
available, virtually all patients undergoing chemotherapy continue to exhibit profound debilitating symptoms,
such as severe nausea, vomiting, and cachexia. We use modern behavioral and neurogenetic approaches, and
appropriate, comparative, preclinical animal models that are critical to produce novel, effective, long-term
controls of nausea and vomiting to advance modern metabolic health care. Intestinally derived GIP regulates
postprandial glucose through direct action on GIP receptors (GIPR) expressed on pancreatic beta cells. GIP
analog efficacy as a monotreatment of diabetes and obesity is at best limited and controversial, however, the
expression of CNS GIPRs in regions implicated in nausea/emesis have spawned investigation of central actions
of GIP ligands as potential adjunct therapeutics to reduce unwanted adverse events. Specifically, our data
support that GIPR and GLP-1R dual agonism provide body weight loss, hypophagia, and glucoregulatory control
without nausea and emesis, compared to GLP-1R agonism alone, through activation of the GIP system. The area
postrema (AP) and nucleus tractus solitarius (NTS) of the dorsal vagal complex (DVC) play a critical role in
ingestive behavior, emesis, and nausea. Widely used emetogenic chemotherapeutics (e.g., cisplatin) and all FDA-
approved GLP-1-based ligands activate AP/NTS neurons. Our collective works suggest hindbrain GIPRs block
nausea and vomiting induced by GLP-1R and cisplatin chemotherapy in several animal species, suggesting
translational broad-spectrum antiemetic potential for GIPR agonists. We have identified cellular phenotypes of
AP/NTS GIPR- and GLP-1R- expressing cells, as well as shown the attenuation in AP/NTS neuron activity, and
preliminary data). Additionally, we have discovered a molecularly distinct GABA-ergic neuronal DVC population
that is modulated by chemotherapy but rescued by GIPR agonism. We hypothesize that there exists an antiemetic
system characterized by inhibitory (i.e., GABA-ergic) neurons expressing GIP receptors (GIPR). Here, we will:
Aim I: Examine behavioral, anatomical, and transcriptomic mechanisms by which GIPR-GABA+ AP/NTS
neurons exhibit antiemetic action. Aim II: Examine GIP antiemetic action in conjunction with established
antiemetics using a multi-species approach. Our data in multiple species all indica...

## Key facts

- **NIH application ID:** 10878874
- **Project number:** 5R01DK112812-07
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Bart C DE JONGHE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $613,967
- **Award type:** 5
- **Project period:** 2017-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878874

## Citation

> US National Institutes of Health, RePORTER application 10878874, Neural Mechanisms of Nausea, Vomiting, and Energy Dysregulation (5R01DK112812-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10878874. Licensed CC0.

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