# Hypothalamic MC4Rs and Antipsychotic Drug-Induced Metabolic Syndrome

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $466,210

## Abstract

PROJECT SUMMARY
 Antipsychotic drug (APD)-induced metabolic syndrome is a pressing clinical problem affecting millions of
patients. However, the difficulty in modeling their metabolic effects in laboratory animals has significantly
hindered relevant mechanistic studies.
 To this end, we have developed new mouse models that recapitulate human metabolic syndrome caused
by two commonly prescribed APDs (olanzapine and risperidone). Metabolic analyses revealed that drug-induced
hyperphagia is the driving force behind weight gain in both models. Using bulk RNA sequencing, we investigated
how APDs altered gene expression in the hypothalamus—a brain region that is critical for appetite control. Our
analyses revealed that the melanocortin 4 receptor (Mc4r) was among those that were directly regulated by APD
treatment. Furthermore, we found that the obesogenic effect of olanzapine and risperidone depends on Mc4r in
Sim1 neurons. Moreover, we found that APDs reduced hypothalamic Mc4r mRNAs before the weight gain.
Remarkably, whole-cell electrophysiology experiments demonstrated for the first time that olanzapine and
risperidone acutely inhibited Mc4r-expressing neurons in the paraventricular nucleus of the hypothalamus.
Furthermore, this inhibition was mediated by a postsynaptic potassium conductance. Collectively, these findings
provided the first experimental evidence linking deficits in hypothalamic MC4R signaling to APD-induced
metabolic syndrome.
 In the current project, we propose a multi-discipline approach to investigate the mechanisms underlying
1) how olanzapine and risperidone interact with MC4Rs and perturb their functions; 2) how they inhibit the activity
of Mc4r neurons; 3) how both drugs alter the transcriptional and chromatin landscapes in hypothalamic neurons
at the single-cell level. These studies have important clinical implications based on the suggestions that MC4R
can be a novel therapeutic target for APD-induced weight gain, and that they may guide the development of
next-generation antipsychotic medications with fewer metabolic side effects.

## Key facts

- **NIH application ID:** 10798286
- **Project number:** 5R01DK114036-07
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Chen Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $466,210
- **Award type:** 5
- **Project period:** 2017-07-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798286

## Citation

> US National Institutes of Health, RePORTER application 10798286, Hypothalamic MC4Rs and Antipsychotic Drug-Induced Metabolic Syndrome (5R01DK114036-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10798286. Licensed CC0.

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