# Human hypothalamic neuronal epigenomics and risk for obesity

> **NIH NIH R01** · TEXAS A&M UNIVERSITY-SAN ANTONIO · 2021 · $389,421

## Abstract

ABSTRACT
Translating information on genetic risk for body weight regulation into molecular mechanisms can
have a significant impact on intervention and therapies. We are seeking to identify genetic variation
and their molecular mechanisms that influences obesity through direct effects on the hypothalamus as it
is the brain hub that regulates energy homeostasis and there is now considerable evidence for genetic
influence to impact this brain region. However, the majority of genetic loci associated with this common,
chronic disorder in the general population are located in noncoding regions of the genome, suggesting
their influence on energy homeostasis is manifested through changes to the regulome. Thus, pinpointing
the causal human variants and connecting them to their downstream targets in brain presents
challenges of tissue access for study because much epigenetic control is species-, tissue- and context-
specific. To overcome the barrier of limited human tissue access, we have developed a robust protocol
for generating human induced pluripotent stem cell (iPSC)- derived neuronal cultures that recapitulate
many of the features of hypothalamic neurons from the arcuate nucleus, including by benchmarking
this in vitro model to in vivo events that are pivotal in hypothalamic development. We are using this
human model and state of the art high throughput assays to map the currently uncharted regulatory
landscape of the human hypothalamic neurons across 3 stages in development (early, mid, and late)
and under experimental obesogenic conditions. We have published an integrated pipeline to chart the
regulatory landscapes of obesity-associated loci within two cell types central to obesity etiology. Next,
in order to precisely pinpoint the functional variants in BMI GWAS loci that have influence on body weight
regulation through hypothalamic epigenomic regulation, we will identify those that influence chromatin
accessibility and/or target gene expression by assay in 30 iPSC-derived hypothalamic-like cellular models
generated from subjects of the San Antonio Mexican American Family Studies. GWAS variants with
both properties have high potential to be causal and manifest effects on body mass index through
changes in chromatin structure. Causal determination will be made for a set of these variants using
genome editing techniques such as CRISPR/Cas9 to generate isogenic human neuronal cell lines that
differ by genotype only at the single locus. Changes in exon-specific target gene expression and
chromatin status will be assessed temporally and under each obesogenic condition. Discovery of
epigenetic mechanisms connected to genetic liability will translate the genetic risk information and identify
potential underlying factors behind both heritable and diet-induced obesity susceptibility.

## Key facts

- **NIH application ID:** 10836243
- **Project number:** 7R01DK114661-05
- **Recipient organization:** TEXAS A&M UNIVERSITY-SAN ANTONIO
- **Principal Investigator:** DONNA M LEHMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $389,421
- **Award type:** 7
- **Project period:** 2023-05-03 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10836243

## Citation

> US National Institutes of Health, RePORTER application 10836243, Human hypothalamic neuronal epigenomics and risk for obesity (7R01DK114661-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10836243. Licensed CC0.

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