# Hypothalamic Serotonin Receptors and Olanzapine-induced Metabolic Syndrome

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $405,000

## Abstract

PROJECT SUMMARY
 Second-generation antipsychotics (SGAs) such as olanzapine and clozapine are essential medications
for millions of schizophrenia patients worldwide. Moreover, the last decade has witnessed an exponential
increase of their uses for other neuropsychiatric conditions including bipolar disorder, major depressive
disorder, and autism. Despite their broad efficacy and low risks for extrapyramidal symptoms, most SGAs have
been linked to substantial drug-induced metabolic syndrome that is characterized by excessive weight gain,
dyslipidemia, and type-2 diabetes. Obesity and diabetes often develop shortly after SGA treatment. Moreover,
the risk for metabolic syndrome is significantly higher in female subjects. The rapid disease onset as well as
the gender difference strongly suggest a distinct etiology underlying SGA-induced metabolic syndrome.
Unfortunately, while tremendous resources and efforts have been spent combating obesity and diabetes in the
general population, little progress has been made toward understanding or treating drug-induced metabolic
disturbances.
 Genome-wide association studies in human patients have implicated a role for brain serotonin (5-HT)
receptors in SGA-induced metabolic syndrome. However, previous efforts to discern their roles have been
hindered by the difficulty to replicate SGA-induced metabolic syndrome in mice. Using a modified olanzapine
diet, we are able to reliably reproduce excessive weight gain and diabetes in C57BL/6 mice. The success in
modeling olanzapine-induced metabolic syndrome in mice provides us an opportunity to precisely characterize
metabolic alterations in olanzapine-treated mice. Furthermore, it allows us to apply sophisticated mouse
genetic tools to unraveling candidate genes and pathways that mediate olanzapine’s metabolic effects. Here,
we will carry out a series of in vivo analyses in transgenic mice to interrogate the contribution of individual
serotonin receptors to olanzapine-induced metabolic syndrome. We hypothesize that olanzapine acts through
serotonin 2c receptor (Htr2c) and serotonin 1b receptor (Htr1b) in distinct populations of hypothalamic neurons
to impair energy and glucose metabolism. This hypothesis is evidence-based, including exciting, solid
preliminary data that is presented here for the first time in which we show that olanzapine’s effect on food
intake and weight gain is blunted in mice lacking Htr2c or Htr1b. Experiments will include targeting Htr2c
specifically in hypothalamic POMC neurons and Htr1b in hypothalamic AgRP neurons to determine whether
Htr2c and Htr1b act on these sites to mediate the untoward metabolic effects of olanzapine. We will also test
the therapeutic potential of specific agonist for Htr2c in olanzapine-fed mice. Therefore, positive results from
these studies will provide necessary evidence and rationale for the clinical use of specific 5-HT receptor
agonists to treat SGA-induced metabolic syndrome in millions of patients.

## Key facts

- **NIH application ID:** 9959431
- **Project number:** 5R01DK114036-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Chen Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9959431

## Citation

> US National Institutes of Health, RePORTER application 9959431, Hypothalamic Serotonin Receptors and Olanzapine-induced Metabolic Syndrome (5R01DK114036-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9959431. Licensed CC0.

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