# Investigating the role of the FAIM2 locus in predisposition to childhood obesity

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2022 · $46,752

## Abstract

ABSTRACT
 Childhood obesity is a complex, polygenic disease affecting over 13 million children in the United States
and reaching epidemic proportions around the world. An individual’s lifestyle and genetic predisposition may
cause an imbalance between food intake and energy expenditure, resulting in excess adipose tissue.
Heritability estimates that range from 40-85% indicate a strong genetic component. Current behavioral and
pharmacological treatments have only modest results, highlighting the importance of investigating the genetic
etiology of childhood obesity for the development of new treatment strategies. Many of the top signals from
genome-wide association studies (GWAS) of obesity reside near already well-established genes, such as
MC4R and BDNF. Through my lab’s international leadership of GWAS of childhood obesity, it has become
clear that the genetic signature of obesity in children is very similar to adults, although there is a significant
exception. The FAIM2 locus is much more pronounced in the pediatric setting and thus has been largely
overlooked to date. Our fine-mapping efforts at the FAIM2 locus have identified rs7132908 as the likely causal
non-coding variant in this genomic region. rs7132908 resides in the 3’ untranslated region of FAIM2 and is in a
region annotated as a candidate cis-regulatory element. Using a human stem cell-derived hypothalamic neuron
model, we have observed a physical contact between the rs7132908 region and the FAIM2 promoter utilizing
high-resolution genome-wide promoter-focused Capture-C, indeed implicating FAIM2 as the effector gene at
this locus. This cell model is biologically relevant as neural populations of the hypothalamic arcuate nucleus
have been implicated in childhood obesity by tissue enrichment analysis, gene set enrichment analysis and
rodent studies. FAIM2 encodes the transmembrane protein ‘Fas apoptotic inhibitory molecule 2’ and its
expression is largely restricted to neurons of the central nervous system. A transcriptome-wide association
study identified a significant association between FAIM2 expression in brain tissue and childhood body mass
index. Faim2 gene expression in the arcuate nucleus responds to nutritional status, increasing after restricted
food intake or food deprivation. This suggests that FAIM2 may function downstream of metabolic hormones.
The goal of my project is to characterize the cis-regulatory activity of rs7132908 and the function of FAIM2 in
hypothalamic arcuate nucleus neurons as they relate to the pathogenesis of obesity. I hypothesize that FAIM2
expression is regulated by rs7132908 and that FAIM2 functions in the neuronal response to metabolic
hormones. In my first aim, I will characterize the effect of the rs7132908 risk allele on FAIM2 expression in vitro
and in vivo. In my second aim, I will investigate the consequences of FAIM2 dysregulation in arcuate nucleus
neurons responding to metabolic hormones. Taken together, these findings will provide a first...

## Key facts

- **NIH application ID:** 10385126
- **Project number:** 1F31HD105404-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Sheridan Hope Littleton
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10385126

## Citation

> US National Institutes of Health, RePORTER application 10385126, Investigating the role of the FAIM2 locus in predisposition to childhood obesity (1F31HD105404-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10385126. Licensed CC0.

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