# Resilience to obesity in carriers of monogenic obesity mutations - a study on the underlying mechanisms

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $739,547

## Abstract

Obesity is a major risk factor for chronic disease. Besides our obesogenic lifestyle, people’s innate
physiology/metabolism, encoded by their genomes, is another major factor that determines why some people
gain weight more easily than others. Genetic studies in animal models and humans, have shown that the brain
is a key player in body weight regulation. In particular genes that constitute the leptin-melanocortin pathway have
been repeatedly implicated in obesity; i.e. mutations in LEP, LEPR, POMC, MC4R, PCSK1 and SH2B1 have
been frequently reported to cause early-onset severe obesity, likely through influencing appetite, hunger, satiety,
reward, etc. In addition, common variants near the same genes have been identified in GWAS for obesity/BMI.
 In a recent, large-scale exome-wide study, we showed that a nonsense mutation (Tyr35Ter) in MC4R was
associated with a ~15lbs higher body weight in carriers. MC4R Tyr35Ter was identified >20 years ago as a high-
impact monogenic mutation that causes severe early-onset obesity. In-depth functional analyses showed that
35Ter results in a complete loss of function of MC4R. Yet, of the 66 mutation carriers in the UK Biobank
(N~500,000), nine (14%) were of normal weight and had never been overweight, beating their genetic odds.
 This observation sparked our interest in investigating all mutations in genes of the leptin-melanocortin
pathway, reported to cause obesity. By in-depth comparison of normal weight carriers with obese carriers, we
aim the reveal compensatory mechanisms (genetic, non-genetic) that prevent weight gain, not yet targeted for
prevention and treatment. However, mutations reported so far as the “cause” of obesity have been identified in
small-scale case-biased populations, and their penetrance and effect on obesity at a population-level has never
been estimated. As mutations are rare, determining their impact with rigor requires extremely large populations.
 With access to sequencing data from >220,000 individuals and genotype data from ~500,000 individuals
(Mount Sinai BioMe Biobank, TOPMed Program, UK Biobank), we are uniquely positioned to (Aim 1) determine
the impact of mutations in established monogenic obesity genes (LEP, LEPR, POMC, MC4R, PCSK1, SH2B1)
through estimating their penetrance and assess their effect on obesity. Aim 2: To determine the characteristics
that protect normal weight carriers of high-impact mutations from gaining weight, using phenotype/genotype data
already available in BioMe, TOPMed, and UK Biobank. Aim 3A: To gain deeper insight in the underlying
mechanisms by performing extremely deep-phenotyping in 60 participants recalled from the BioMe Biobank to
assess energy intake, energy expenditure, lifestyle and other behaviors. Aim 3B: To investigate participants’
iPSC-derived hypothalamic neurons for signaling characteristics and allele-specific expression.
 While traditionally, obesity research focuses on obese individuals and on the mechanisms that cause weight
g...

## Key facts

- **NIH application ID:** 9997415
- **Project number:** 1R01DK124097-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Ruth JF Loos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $739,547
- **Award type:** 1
- **Project period:** 2020-05-21 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997415

## Citation

> US National Institutes of Health, RePORTER application 9997415, Resilience to obesity in carriers of monogenic obesity mutations - a study on the underlying mechanisms (1R01DK124097-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9997415. Licensed CC0.

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