Some people appear to maintain a healthy body weight and metabolic profile more easily than others, even when their diets and lifestyles are similar. New research suggests that rare genetic variants may play an important role in this natural protection against obesity and metabolic disease.
In a large study involving genetic data from more than 1 million people across North America, Europe and Asia, researchers identified 59 genes associated with the way the body stores and uses energy. The findings, published in Nature, point to a particularly important role for the FNIP1 gene, which helps regulate cellular energy expenditure.
The researchers used exome sequencing, a technique that focuses on the roughly 1% of DNA that contains instructions for making proteins. They searched for rare genetic variants and examined how these variants were associated with the ratio of triglycerides to HDL cholesterol, a blood marker linked to metabolic and cardiovascular health.
A rare mutation with major metabolic benefitsAbout one in 7,000 people carries a naturally occurring variant that disables one copy of the FNIP1 gene.
The study found that carriers of this variant had a notably healthier metabolic profile than people without it. They tended to have:
lower body weight and body-fat levels;
less harmful fat accumulation in the liver;
a healthier distribution of body fat;
lower levels of triglycerides and LDL cholesterol;
better blood sugar levels; and
about a 60% lower likelihood of cardiometabolic disease.
FNIP1 appears to function partly as a brake on energy expenditure, helping prevent cells from using excessive amounts of energy. When one copy of the gene is switched off, this regulatory system appears to change in ways that promote healthier energy metabolism.
A blood test that reflects overall metabolic healthThe researchers analyzed genetic and health data from 1,032,116 people across 11 study groups spanning three continents.
They focused on the triglyceride-to-HDL cholesterol ratio, or TG:HDL, and found that it was strongly associated with several measures of metabolic health.
A higher TG:HDL ratio was linked to greater amounts of body fat, fat accumulation around internal organs, insulin resistance and elevated blood pressure.
The analysis identified 59 independent genes that influence energy balance, fat storage and metabolism. Most of these genes are active in the liver and adipose tissue, which play central roles in regulating metabolism.
Interestingly, 23 of the identified genes already have drugs targeting them, either through approved treatments or ongoing clinical trials.
Experiments in human cells and miceTo investigate whether FNIP1 itself was responsible for the observed metabolic benefits, the researchers switched off the gene in human liver cells.
The cells responded by activating genes involved in fat breakdown and the removal of cellular waste, suggesting that loss of FNIP1 directly affects metabolic pathways.
The researchers then tested the mechanism in mice. Animals in which the FNIP1 pathway was disabled in the liver were protected from weight gain and fatty liver even when they were fed a high-fat, high-sugar diet for up to 30 weeks.
The findings suggest that FNIP1 plays an important role in regulating how the body uses and stores energy.
The researchers believe that targeting this pathway could eventually lead to new treatments for obesity, diabetes and cardiovascular disease. However, further research will be needed to determine whether safely modifying FNIP1 in humans could produce the same benefits.
The study was published in Nature.
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