About 1 in every 7,000 people carries a genetic variant that appears to give the body a remarkably different metabolic setting. These individuals have lower liver fat, healthier blood sugar, and a distinct pattern of body fat compared with most people. They didn’t follow a special diet or take a medication. They were born with a rare change in a gene that researchers are now investigating as a potential key to healthier metabolism.
The gene is called FNIP1, and the finding emerged from one of the largest genomic studies of its kind. Researchers performed exome sequencing on 1,032,116 people from America, Europe, and Asia, looking for associations between rare protein-coding variants and the ratio of triglyceride to high-density lipoprotein cholesterol (TG:HDL), an energy-state biomarker linked to a range of cardiometabolic risk factors and diseases. The TG:HDL ratio is calculated from a standard blood panel and can provide insight into how the body is handling fats and energy.
The researchers found that rare protein-truncating variants in FNIP1 were associated with a more favorable metabolic profile, including lower liver fat and healthier measures of blood sugar and body fat. The finding was not the result of researchers targeting FNIP1 specifically. Instead, the gene emerged from a large-scale search across the exome, the protein-coding portion of the human genome, as one of the rare genetic changes associated with a distinctive metabolic pattern.
Luca Lotta, VP and Head of Cardiovascular, Metabolic, and Skeletal Genetics at the Regeneron Genetics Center, was the corresponding author of the study published in Nature. His team’s findings raise the possibility that FNIP1 plays a previously underappreciated role in how the body regulates fat storage and energy metabolism.
A genetic variant fat metabolism researchers almost missed
The specific FNIP1 mutations are rare: roughly 1 in every 7,000 people carries a variant. Only 155 of the people studied had these “protein-truncating” mutations. In genomic research, that’s a vanishingly small group. Normally, sample sizes that small produce noise, not findings. But the metabolic differences were so large that they cleared statistical significance with room to spare.
Carriers of these variants had lower liver fat, lower glycaemia, favorable fat distribution, and around 60% lower odds of cardiometabolic disease. They also showed lower BMI, higher lean body-mass percentage, and lower atherogenic blood lipids. Altered energy metabolism is a shared driver across cardiometabolic diseases, which are the leading cause of death globally. Cardiometabolic diseases include coronary artery disease, obesity, type 2 diabetes, and metabolic-dysfunction-associated steatotic liver disease. A 60% reduction in risk across that entire cluster of conditions, from a single partially broken gene, is not a small finding.
The FNIP1 gene codes for folliculin-interacting protein 1, which normally works with another protein, folliculin, to suppress cellular energy expenditure and allow the body to store energy. The pathway helps regulate mitochondria – the cellular structures that produce energy – as well as the machinery involved in breaking down and recycling cellular components.
When FNIP1 is partially disabled, causing a dysfunctional protein, that brake appears to be released, and the body burns through energy. The people carrying these rare mutations aren’t just slightly less efficient at storing fat. Their entire energy metabolism appears to be running at a higher gear.
What happens inside the body when this gene breaks down
FNIP1 knockdown in primary human hepatocytes induced lipid breakdown and lysosomal gene expression, while combined hepatic knockdown of Fnip1 with its paralogue Fnip2 or knockdown of its interactor Flcn protected against weight gain, reduced liver fat, and enhanced insulin sensitivity in mice fed a high-fat diet. Over 30 weeks, it also prevented the fibrosis and liver damage the diet would otherwise cause. The liver results are especially significant because fatty liver disease is one of the fastest-growing contributors to metabolic illness globally, and current treatment options remain limited.
The authors noted important uncertainties, including species-specific functional differences between mouse and human versions of the gene, and the need for further experimental evaluation of the efficacy and safety of pathway modulation in humans. Liver safety also remains a consideration, given previous mouse evidence linking broader disruption of the related folliculin pathway to liver injury, although the present study observed favorable liver outcomes following liver-targeted pathway inhibition. A drug that activates fat-burning in the liver could theoretically stress the very organ it’s trying to help, if the dosing or targeting isn’t precise.
The lab findings provided a plausible mechanism. “These individuals consume, store and utilize energy more than individuals without those mutations, and that’s the protective factor,” explains Luca Lotta, MD, PhD, VP and Head of Cardiovascular, Metabolic, and Skeletal Genetics at the Regeneron Genetics Center and the study’s co-senior author. The carriers aren’t healthy because they eat differently or exercise more. Their cells are running a different metabolic program by default.
Fat location, not just fat amount
These FNIP1 variants don’t just reduce overall body fat — they appear to change where fat is deposited in the first place.
Visceral fat stored around the organs and in the midsection is more harmful to cardiometabolic health than fat stored subcutaneously in the hips and thighs. Visceral fat drives inflammation, disrupts insulin signaling, and floods the liver with fatty acids. In the study population, FNIP1 loss-of-function variants were associated with a lower visceral-to-gluteofemoral fat volume ratio, lower body fat percentage, and lower atherogenic blood lipids. That distinction may explain a significant portion of the 60% risk reduction, beyond what lower total fat mass alone would account for.
Rare variants in the PDE3B gene had a stronger association with a favorable TG:HDL ratio in women than in men, which is particularly notable because PDE3B is already implicated in fat distribution regulation. The researchers aren’t yet sure why women respond more strongly to PDE3B variants. The finding reinforces that fat metabolism genetics are not one-size-fits-all, and that sex-specific biology may play a larger role in cardiometabolic risk than standard risk calculators currently account for.
A drug target hidden in plain sight
The study identified 59 independent genes enriched for liver- and adipose-expressed master regulators of energy balance, storage, and metabolism, and 23 (39%) of those genes encode approved or clinical-stage drug targets. FNIP1 is among the genes being weighed as a potential therapeutic avenue.
GLP-1 drugs, the class of medications that includes semaglutide (sold as Ozempic and Wegovy), have transformed the treatment of obesity and type 2 diabetes in recent years. GLP-1 drugs act mainly through hormonal signaling, while FNIP1 influences machinery for burning or storing energy at the cellular level. Broadly, the FNIP1 pathway is mechanistically distinct from existing therapeutic approaches, and its therapeutic relevance is strongly supported by our human genetic findings.
Several hurdles remain in bringing these findings to the clinic, including research into the safety and efficacy of intentionally altering the FNIP1 pathway in individuals with normal versions of the gene. A key question that remains to be addressed is whether the FNIP1 pathway can be modulated safely in humans. The people naturally carrying these mutations lost one functional copy of the gene gradually, from birth, in a system that had time to adapt. Pharmacologically switching off that same pathway in adults might produce different and unpredictable effects.
FNIP1 protein-truncating variants are rare. This is why such a large study was needed to detect the signal at all, and why researchers from America, Europe, and Asia had to pool their sequencing data to find just 155 carriers with enough statistical power to analyze.
Why evolution didn’t spread this mutation
The mutation is so rare, Lotta says, because evolution can’t keep up with our changing world. “Nowadays, we are living in a very calorie-rich environment, and historically there’s no precedent for this,” Lotta says. The mutations that cut FNIP1 function are ancient. They didn’t suddenly appear in the last 10,000 years of agricultural surplus. They were always present at very low frequency, probably neutral or mildly beneficial in some contexts, but never widespread enough to become common. In a food-abundant modern world, they’ve become something closer to an unintentional metabolic advantage – the rare individuals who carry them may be accidentally well-suited to the caloric environment that’s making everyone else sick.
By analyzing diverse populations, the study identified a protective variant that spans ancestries and lifestyles, suggesting that targeting FNIP1 could potentially benefit people around the world.
What this means for you
Most people reading this don’t carry the FNIP1 mutation. That’s a near-mathematical certainty given how rare it is. But the research carries practical implications that go beyond whether your genome happens to contain a broken copy of one gene.
For the vast majority of people who lack those variants, the findings reveal a possible target for drugs that could one day reproduce some of the variants’ apparent protection against cardiometabolic diseases – a basket of interconnected conditions that includes stroke, diabetes, heart attack, and some forms of liver disease. A drug targeting FNIP1 is likely many years from clinical use, and significant safety questions remain to be resolved.
The study’s findings on fat distribution are also notable: where fat is stored matters for cardiometabolic risk, and the FNIP1 variants appear to shift fat away from visceral depots and toward less harmful subcutaneous storage. That distinction- fat location, not just fat amount – is a finding that researchers say may account for a meaningful share of the protection these rare variants confer.
Disclaimer: This information is not intended to be a substitute for professional medical advice, diagnosis, or treatment and is for information only. Always seek the advice of your physician or another qualified health provider with any questions about your medical condition and/or current medication. Do not disregard professional medical advice or delay seeking advice or treatment because of something you have read here.
AI Disclaimer: This article was created with the assistance of AI tools and reviewed by a human editor.
