---
title: One in 7,000 People Carry a Rare Gene Fault Linked to Less Belly Fat and More Muscle
description: A Nature study of more than a million people found rare FNIP1 variants linked to less belly fat, more muscle and around 60% lower cardiometabolic risk.
author: Dr Marina Nani (Editor-in-Chief)
date: 2026-08-05T17:33:39.836Z
updated: 2026-08-05T17:33:39.845Z
canonical: https://richhealthmagazine.com/article/fnip1-gene-variants-belly-fat-muscle-metabolic-disease
image: https://cdn.nanimediahouse.com/fnip1-gene-variants-metabolism-107368.webp
categories: Longevity & Science
content_type: News
region: Global
publication: Rich Health Magazine
schema_type: Article
---

A rare genetic fault leaves the people who carry it with less fat around the belly, more muscle and around 60% lower odds of [heart disease](https://richhealthmagazine.com/article/congenital-heart-defects-adult-genomics-cohort), type 2 diabetes and other metabolic illness, according to [a study of more than a million people](https://www.nature.com/articles/s41586-026-10864-2) published today in Nature. The fault sits in a gene called FNIP1, and the researchers say it points to a possible drug target for the people who do not have it.

The variants turn up in about one in 7,000 of the people sequenced. Those with one disabled copy of FNIP1 also had [lower blood sugar](https://richhealthmagazine.com/article/sickle-cell-trait-a1c-lab-method) and less fat stored in the liver than the rest of the group.

## The Search Started With One Blood Ratio, Not a Disease

The researchers ran exome sequencing on 1,032,116 people across 11 cohorts in the Americas, Europe and Asia. Instead of starting from a disease, they started from a single blood measurement: the ratio of triglycerides to HDL cholesterol, known as the TG:HDL ratio, which the paper ties to a range of cardiometabolic risk factors and diseases.

> "The higher this ratio is, the higher the risk of metabolic disease."
> — Luca Lotta, human geneticist at the Regeneron Genetics Center and co-author of the study

Screening rare protein-coding variants against that ratio turned up 59 genes, most of them active in the liver and in fat tissue, where they help govern how the body balances and stores energy. Twenty-three of them, close to four in ten, already encode targets of approved or clinical-stage drugs.

FNIP1 stood out. Ultra-rare variants that truncate the protein it encodes, carried by about 0.01% of people, tracked with a lower TG:HDL ratio and a more favourable distribution of body fat. The gene normally suppresses energy expenditure and mitochondrial metabolism, and plays a part in how cells sense and respond to certain nutrients.

## Tests in Cells and Mice Backed Up the Genetic Signal

To check whether the gene was driving the effect, the researchers silenced FNIP1 in human liver cells grown in a dish. The cells switched on genes involved in breaking down fat.

They then silenced the same pathway in mice eating a high-fat diet, either FNIP1 together with its close relative FNIP2, or a related gene called FLCN. Those mice gained less weight, stored less fat in their livers and handled insulin better than untreated mice on the same diet.

## The Result Points to a Drug Target for the Rest of Us

Cardiometabolic diseases, the group that includes coronary artery disease, obesity, type 2 diabetes and metabolic dysfunction-associated steatotic liver disease, are collectively the leading cause of death worldwide, the paper says. They “are the number one cause of death in the world, and they have a strong genetic basis”, said Luca Lotta, a human geneticist at the Regeneron Genetics Center in Tarrytown, New York, and a co-author of the study.

For the great majority of people who do not carry an FNIP1 variant, the authors present the discovery as a lead rather than a treatment: a target for drugs that could one day reproduce some of the protection the rare carriers already have. The paper describes its own finding as implicating the FNIP1 pathway in human energy metabolism and identifying inhibition of that pathway as a potential therapeutic strategy, work so far confined to cells in a dish and mice on a controlled diet.

## FAQ

**Q: What does the FNIP1 gene do?**
FNIP1 normally suppresses energy expenditure and mitochondrial metabolism and plays a part in how cells sense and respond to certain nutrients. The rare variants linked to better metabolic health disable one of the body's two working copies of the gene.

**Q: What is the TG:HDL ratio?**
It is the ratio of triglycerides to HDL cholesterol in the blood, a marker of the body's energy state that the study ties to cardiometabolic risk. The researchers used it as the starting point for their genetic search rather than any single disease.

**Q: What counts as cardiometabolic disease?**
The paper groups coronary artery disease, obesity, type 2 diabetes and metabolic dysfunction-associated steatotic liver disease under that heading, and says they are together the world's leading cause of death.

**Q: How rare are these FNIP1 variants?**
About one in 7,000 of the more than one million people sequenced carried one of the variants, which have an allele frequency of roughly 0.01%.