Rare FNIP1 Mutation Mirrors Effects of GLP-1 Drugs

Scientists sequenced the coding DNA of more than a million individuals across three continents and identified a loss-of-function mutation in the FNIP1 gene that markedly accelerates calorie burning. The mutation, present in roughly one in 7,000 people, “nix[es]” the gene’s normal role of slowing cellular energy expenditure, leading to faster fat utilization and lower storage, according to the study published in *Nature*.

Scientific American

FNIP1 partners with the protein folliculin to conserve energy when food is abundant. When the gene is silenced, the body’s metabolic machinery shifts toward increased fat oxidation. In mouse models fed a high-fat, high-sugar diet, liver-specific shutdown of the FNIP1 pathway curtailed weight gain, cleared hepatic fat, improved insulin sensitivity, and prevented diet-induced fibrosis over a 30-week period.

Scientific American

The research cohort included about 150 carriers of the mutation. Compared with non-carriers, these individuals exhibited lower blood lipids, reduced liver fat, lower blood glucose, higher muscle proportion, and an estimated ~60 % lower odds of cardiometabolic diseases such as obesity and diabetes. However, the study notes that people inheriting two broken copies of FNIP1 are prone to heart disease and immune deficiency, indicating that complete systemic inhibition could be harmful.

Scientific American

Luca Lotta, a geneticist at Regeneron Pharmaceuticals and co-senior author, emphasizes that the mutation’s rarity reflects evolutionary lag in a modern, calorie-rich environment. He suggests that targeting FNIP1 only in the liver might preserve metabolic benefits while avoiding systemic risks, though any therapeutic approach remains many years away. Svati Shah, director of the Center for Precision Health at Duke University, points out that naturally occurring loss-of-function variants have historically guided drug development in other disease areas.

Scientific American

• “Nowadays, we are living in a very calorie-rich environment, and historically there’s no precedent for this” — Luca Lotta, a geneticist at Regeneron Pharmaceuticals and the study’s co-senior author

Scientific American

• “Individuals with loss-of-function genetic variants can naturally mimic effects of pharmacologic inhibitors, and such studies have led to important therapeutic advances in other diseases,” — Svati Shah, director of the Center for Precision Health at Duke University

Scientific American

• “If you were to therapeutically inhibit the gene everywhere in the body at 100 percent, that could have a negative impact on health,” — Luca Lotta, a geneticist at Regeneron Pharmaceuticals and the study’s co-senior author

Scientific American