Fat-storage gene PLIN4 identified as potential anorexia risk factor

Anorexia nervosa kills more reliably than almost any other psychiatric illness. For decades, researchers have assumed the disease lives in the brain—in the psychology, the behavior, the distorted thinking that drives someone to starve. A team at Michigan State University just found something that doesn't fit that story at all.

They discovered that patients with anorexia were nearly four times as likely as healthy people to carry rare, damaging variants of PLIN4, a gene that has almost nothing to do with the brain. PLIN4 works primarily in fat tissue and muscle, where it controls how cells store energy. The finding, published in Frontiers in Psychiatry, suggests that for some people, anorexia may not be purely a disorder of the mind—it may involve how the body itself handles fat and metabolism.

The research grew from a focused study of 154 patients with particularly severe or treatment-resistant anorexia. Seventeen of them—about 11 percent—carried rare variants of PLIN4 predicted to damage the gene's function. In the general healthy population, only about 3 percent carry such variants. Six anorexia patients had especially disruptive versions, and in four of those families, a close relative with an eating disorder carried the identical genetic change. "The idea of an anorexic gene not in the brain is completely novel," said Michael Lutter, who led the research and now treats eating disorder patients clinically.

The finding challenges what A.J. Robison, an MSU physiology professor who advised the study, calls the prevailing dogma. "The bias is that anorexia is a purely psychiatric disorder or even hysteria in women who just want to be thin," he said. "This new finding flies in the face of the idea that the genes contributing to this disease are expressed in the brain." That bias may run deeper than science. Anorexia strikes women ten times more often than men, and Robison suggests the disease has been dismissed partly because of how people view women and vanity. The evidence tells a different story: someone with a first-degree relative who has anorexia is five to ten times more likely to develop it themselves, suggesting powerful genetic underpinnings.

Yet anorexia remains one of the least studied and least funded psychiatric conditions. A recent analysis of National Institutes of Health funding from 2011 to 2023 found eating disorders among the two lowest-funded categories. Treatment options have barely evolved—patients receive nutritional rehabilitation to restore weight and psychotherapy to address behaviors and thoughts. There are no FDA-approved medications specifically for anorexia. Lutter compares his search for anorexia genes to the hunt for BRCA1 and BRCA2, the breast cancer genes. Those variants are rare but drastically increase risk. Anorexia is different: it's polygenic, meaning many different genetic variants likely contribute to susceptibility. "The best way to think about what I do is, I look for the BRCA1 and BRCA2 of anorexia," he said.

The researchers are careful to note that their study involved a specialized group of patients with particularly difficult cases. The finding must be replicated in a larger, independent population before anyone knows how broadly it applies. But if PLIN4 proves significant, it opens a new direction entirely. Genes don't work in isolation—they're part of larger biological pathways. If researchers can map those pathways, they can hunt for drug targets. "Discovering genes that underlie this disease isn't going to fix the disease," Robison said. "But what it can do is teach us what's causing the disease in lots of people, and we can use that information to design new treatments." Next, the team will search for other genetic differences affecting fat storage and anorexia risk, and they'll examine patients' body fat itself for abnormalities that might reveal more about how the disease works. For now, the field has a new place to look—not in the brain, but in the body's most basic machinery for storing and using energy.