Some people seem able to stay relatively lean even when their diet is far from perfect.
Lifestyle still matters greatly, but scientists have long known that genes can influence how easily the body gains weight, stores fat, and uses energy.
A huge international study has now identified rare genetic changes that may help explain why some people are naturally protected from obesity and other metabolic problems.
The research examined genetic and health information from more than 1 million people in North America, Europe, and Asia.
Scientists found 59 genes connected with an important marker of metabolic health. One gene, called FNIP1, stood out because rare changes that reduce its activity were linked to unusually favorable health patterns.
Metabolism is the collection of processes the body uses to turn food into energy and to store energy for later use. When this system becomes unhealthy, excess fat can build up in the body and liver, blood sugar can rise, and cells can become less responsive to insulin. These changes can increase the risk of obesity, type 2 diabetes, and heart disease.
Genes are only one part of this picture. Diet, exercise, sleep, age, medicines, and many other factors also affect weight and metabolic health. However, studying people who carry rare protective genetic changes can reveal biological pathways that might eventually become targets for new medicines.
The researchers analyzed 1,032,116 people from 11 study groups. Instead of reading every part of the genome, they focused on the exome, the small portion of DNA that contains instructions for making proteins. Protein-changing variants can sometimes have large effects on how the body works.
The team compared these genetic differences with the ratio of triglycerides to HDL cholesterol in the blood. Triglycerides are fats that the body can use or store for energy, while HDL is often called “good” cholesterol because it helps carry cholesterol away from tissues. A high triglyceride-to-HDL ratio is often seen alongside other signs of poor metabolic health.
In the study, a higher ratio was associated with more body fat, greater fat buildup around internal organs, insulin resistance, and higher blood pressure. By searching for rare genetic variants connected with this measurement, the researchers identified 59 independent genes involved in the way the body handles energy and fat. Many of these genes were particularly active in the liver and fat tissue.
FNIP1 produced some of the most striking results. Normally, this gene helps control cellular energy use and can act somewhat like a brake that prevents cells from using too much energy. About one person in 7,000 carried a rare variant that effectively switched off one of their two copies of FNIP1.
These carriers tended to have lower triglycerides and lower levels of LDL, often called “bad” cholesterol. They also had lower body weight and body-fat levels, a healthier pattern of fat storage, lower blood sugar, and less fat in the liver. Their odds of cardiometabolic disease were reported to be about 60% lower than those of people without the protective variants.
The scientists then moved beyond population data to investigate whether FNIP1 itself could produce these effects. When they reduced FNIP1 activity in human liver cells in the laboratory, the cells increased the activity of genes involved in breaking down fat and removing damaged cellular material. This provided biological support for the patterns seen in people.
Animal experiments added another layer of evidence. Researchers disrupted the FNIP1 pathway in the livers of mice and fed the animals a diet high in fat and sugar for as long as 30 weeks. The mice were strongly protected against weight gain and the accumulation of fat in the liver despite eating the unhealthy diet.
The findings are important because obesity, diabetes, fatty liver disease, and cardiovascular disease are closely connected and affect enormous numbers of people worldwide. If scientists can safely reproduce some of the protective effects seen in FNIP1 variant carriers, they may eventually be able to develop treatments that improve several metabolic problems at once. The study also found that 23 of the 59 identified genes are already targeted by approved medicines or drugs being tested.
The research was published in Nature in 2026. Its enormous sample size is a major strength because rare genetic variants are difficult to study unless researchers have information from very large numbers of people. Combining human genetics with laboratory cell experiments and mouse studies also gives the FNIP1 finding more support than an association alone would provide.
However, the study does not show that people can ignore diet or exercise if they happen to have favorable genes. The protective FNIP1 variants are rare, and genetic associations do not automatically tell researchers whether blocking the same pathway with a drug will be safe. A gene can have different roles in different tissues, so long-term effects of reducing FNIP1 activity would need careful study.
Overall, the research provides a promising biological clue rather than a ready-made obesity treatment. FNIP1 appears to influence how the body uses energy and stores fat, and naturally occurring human mutations offer evidence that reducing its activity may improve metabolic health.
The next challenge is determining whether scientists can turn that discovery into a treatment without interfering with other important functions of the gene.
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Source: Nature.
