A fat-storage gene that works outside the brain showed up in 11% of 154 hard-to-treat anorexia patients

Seventeen of 154 patients with hard-to-treat anorexia nervosa, about 11%, carried rare variants predicted to damage a gene called PLIN4, compared with about 3% of a healthy reference population. The gene is active mostly in body fat and muscle rather than the brain, where researchers have long looked for anorexia’s genetic roots. A team at Michigan State University reported the result in Frontiers in Psychiatry.

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The finding is a statistical association in a deliberately selected group of patients. It does not show that PLIN4 variants cause anorexia, and it says nothing about most people with the illness, because the 154 were chosen for a strong family history, multiple unsuccessful courses of treatment, or unusual clinical features.

A fat-storage gene in a disease studied through the brain

PLIN4 belongs to a family of genes involved in how cells hold fat. According to the Michigan State release on EurekAlert, it is mostly active in body fat and muscle, and it regulates how cells store fat. Anorexia research has traditionally concentrated on neural circuits for appetite, reward and fear, so a risk gene that does its work elsewhere sits awkwardly with the prevailing picture.

A.J. Robison, a Michigan State physiologist who advised the study, said the result “flies in the face of the dogma that the genes that contribute to this disease are expressed in the brain.” Michael Lutter, a longtime Robison collaborator who formerly worked at the University of Iowa and now treats eating disorders in clinical practice, went further in describing it: “The idea of an anorexic gene not in the brain is completely novel.”

The 154-patient cohort and the comparison with 3%

The patients, all of whom agreed to sequencing of the protein-coding portions of their DNA, were drawn from people with severe illness and often multigenerational family histories. The team compared how often rare, potentially damaging PLIN4 variants appeared in them against a public reference database of the general population, gnomAD, as Neuroscience News reported from the paper. That works out to 17 carriers in 154, or 11.0%, against 3.2% in the reference, an odds ratio of about 3.9.

PLIN4 was one of 32 candidate genes identified from family pedigrees, and it was the only one to remain significant after statistical correction for testing many genes at once. That matters because a single flagged gene among dozens can easily be chance, and surviving the correction is what gives the result weight. The reference group is a large public genome database, not a matched set of healthy volunteers.

Six disruptive variants and the families behind them

The more suggestive detail concerns severity. Six patients carried variants predicted to knock out the gene’s function, and in four of those six families a close relative with an eating disorder carried the same change. Family clustering of that kind fits an inherited contribution to risk, although a handful of families cannot settle the question, and the burden of those loss-of-function variants alone did not reach significance after correction.

The full paper, “Increased frequency of rare damaging variants in PLIN4 in patients with anorexia nervosa”, lists Lutter as lead author, with Robison among the co-authors. The patients were of European ancestry, which limits how far the numbers can be carried to other populations.

What replication and fat biology would have to show

Robison said the next work should look for other genetic differences that affect fat storage and examine patients’ body fat for abnormalities. One idea in the paper is that altered lipid storage could change satiety or leptin signaling, but the study did not test that mechanism; it remains a hypothesis. The release is explicit that the cohort was specialized and that findings must be replicated in a larger, independent group before anyone knows how widely they apply.

The context makes the stakes clear. The release notes that no medication is approved by the Food and Drug Administration specifically for anorexia, with treatment resting mainly on nutritional rehabilitation and psychotherapy, and that eating disorders ranked among the two lowest-funded categories in an analysis of National Institutes of Health spending from 2011 through 2023. Twin studies indicate that having a first-degree relative with anorexia raises a person’s risk five to ten times above that of the general population.

Lutter likened the hunt for rare, high-impact variants to the way BRCA1 and BRCA2 reshaped thinking about inherited breast cancer risk, while stressing that anorexia is polygenic, with many variants each adding a small share. Robison offered a sober counterweight, saying that discovering genes that underlie the disease “isn’t going to fix the disease,” though knowing the biology can reveal pathways and treatment targets worth pursuing.

For now, an 11% carrier rate in a hand-picked group is a lead, and its value will be decided by whether larger and more varied cohorts find the same variants again, and by whether lab work can show what PLIN4 changes in the body.

This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.

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