# Impact of the obesity-risk CREBRF p.Arg457Gln variant on energy expenditure, intake, and substrate utilization in Samoans

> **NIH NIH R01** · BROWN UNIVERSITY · 2021 · $748,828

## Abstract

PROJECT SUMMARY
There is a fundamental gap in our understanding of the reasons behind the high prevalence of obesity in
Samoa, which is among the highest observed across the globe. Over 80% of Samoan adults are overweight or
obese, with severe obesity reaching an alarming 33% in women in American Samoa. In a genome-wide
association study we recently identified a novel missense variant (p.Arg457Gln, minor allele frequency 0.259)
in CREB3 Regulatory Factor (CREBRF) that is highly associated with BMI, with an effect size greater than any
known common BMI risk variant. The overall goal of this research project is to gain insight into the metabolic
differences responsible for the excess weight gain associated with the CREBRF variant. Based on our
observations that overexpression of the missense variant promotes lipid storage and reduces energy substrate
oxidation (decreased mitochondrial respiration) in an adipocyte model, our hypothesis is that a lower resting
metabolic rate (RMR) is involved. Supporting a relationship between low mitochondrial respiration and low
RMR, we recently observed that lower skeletal muscle mitochondrial respiration is associated with lower RMR
in African American women (AAW). In addition, we recently demonstrated lower intervention induced weight
loss in AAW compared to Caucasian women due to a lower RMR, leading to lower energy requirements.
Based on these observations, and the fact that the majority of genes known to contribute to human obesity do
so primarily by influencing the central control of energy intake and/or expenditure, we propose to determine the
role that energy expenditure (EE) and energy intake (EI) play in the increased obesity risk in the Samoan
population associated with the CREBRF missense variant. Based on our long-term experience working with
obesity and health risks in the Samoan population, combined with our extensive experience assessing energy
and substrate metabolism, our research team is ideally positioned to conduct these studies.
We propose a longitudinal study to define the impact of the variant on energy balance in human subjects with
zero, one, or two copies of the risk allele to address the following three specific aims: 1) to determine the
components of EE and substrate metabolism [RMR; TEF, thermic effect of food; total EE; RQ, substrate
utilization; and PA, physical activity] using gold standard methods that include doubly-labeled water (DLW),
indirect calorimetry, and objective activity monitoring; 2) to determine EI using the gold standard method of
DLW intake balance technique; and 3) to determine the relationship between energy metabolism and weight
gain by comparing the above energy metabolism parameters and weight gain over 24-36 months. In the
applicants opinion the proposed studies will provide novel, and significant insight into the metabolic differences
responsible for the excess weight gain in those with the CREBRF variant, which in turn plays a significant role
in the extrem...

## Key facts

- **NIH application ID:** 10089476
- **Project number:** 5R01HL140570-04
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** James P DeLany
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $748,828
- **Award type:** 5
- **Project period:** 2018-02-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10089476

## Citation

> US National Institutes of Health, RePORTER application 10089476, Impact of the obesity-risk CREBRF p.Arg457Gln variant on energy expenditure, intake, and substrate utilization in Samoans (5R01HL140570-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10089476. Licensed CC0.

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