An international team of researchers has identified rare mutations in the FNIP1 gene that may protect the body against type 2 diabetes, cardiovascular disease, and other cardiometabolic conditions. An analysis of data from more than one million people across three continents showed that carriers of these genetic variants had approximately a 60 percent lower likelihood of developing such diseases.

Scientists identified FNIP1 while studying genetic variants associated with the ratio of triglycerides to high-density lipoprotein cholesterol, or TG. The higher this ratio, the greater the risk of metabolic disorders.

FNIP1 mutations occur in approximately one in every 7,000 people, and in the study population, such variants were identified in only 155 individuals.

The FNIP1 gene encodes a protein that interacts with folliculin. Together, they participate in regulating cellular energy expenditure, mitochondrial function, and the processes involved in recycling cellular components.

Researchers suggest that when FNIP1 function is partially reduced, a kind of “brake” on energy metabolism becomes weaker, causing the body to use energy more actively instead of storing it. Experiments using human liver cells supported this hypothesis. When FNIP1 activity was suppressed, genes associated with fat burning became activated.

In mice, modifying the same metabolic pathway while feeding them a diet high in fat and fructose prevented excessive fat accumulation, improved insulin sensitivity, and reduced the amount of fat and liver damage.

Carriers of the mutations also showed a more favorable distribution of body fat. Researchers emphasize that where fat is stored is important for health: visceral fat, which accumulates around internal organs and in the abdominal region, is associated with a higher risk of disease, whereas subcutaneous fat around the hips and buttocks is considered less harmful.

During the analysis, scientists identified another 58 genes associated with similar metabolic characteristics. Most variants had similar effects in men and women, but mutations in the PDE3B gene were more strongly associated with a favorable TG ratio in women. This gene has previously been linked to differences in body-fat distribution.

Researchers note that the effects of disrupting FNIP1 partially resemble those of GLP-1 drugs, which are used to treat obesity and type 2 diabetes. However, the mechanisms are different: GLP-1 drugs primarily act through hormonal signals, whereas FNIP1 appears to be directly involved in regulating cellular energy expenditure and storage.

The findings make FNIP1 a potential target for future medicines. However, the researchers emphasize that it is not yet known whether safely suppressing this gene with drugs could reproduce the protective effect of naturally occurring mutations. Completely disrupting the corresponding biological pathway could have serious consequences.

Researchers suggest that the rarity of these mutations may have an evolutionary explanation. For most of human history, the ability to efficiently store energy and calories may have increased the chances of survival. In modern conditions, when high-calorie food is abundant, the same mechanism may contribute to the development of metabolic diseases.

The study demonstrates how research into rare naturally occurring mutations can help reveal biological mechanisms that influence human health and identify potential targets for treating metabolic diseases.