Anorexia risk may begin outside the brain, new study suggests

A gene primarily active in fat and muscles could make a person more susceptible to anorexia nervosa, a deadly eating disorder with one of the highest mortality rates of any psychiatric disease.

For years, scientists have known genetics play a role in anorexia, but the biological pathways that make some people more susceptible remained a mystery. Now, a Michigan State University–supported study has identified a surprising new candidate.

The research team found that patients with anorexia were nearly four times as likely as a reference population to carry rare, potentially damaging variants of PLIN4, a gene mostly active in fat and muscle rather than the brain. The gene regulates how cells store fat, raising the possibility that altered fat metabolism could contribute to anorexia in some patients.

This finding, published in Frontiers in Psychiatry, opens a new area for research and new opportunities for developing treatments.

While much anorexia research has focused on the brain and behavior, PLIN4 points researchers toward another potential piece of the disease: how the body stores and uses energy.

“The prevailing bias is that anorexia is a purely psychiatric disorder or even hysteria in women who just want to be thin,” said A.J. Robison, an MSU Research Foundation Distinguished Professor of physiology who advised the study. “This new finding flies in the face of the dogma that the genes that contribute to this disease are expressed in the brain, and that’s really new and exciting.”

Robison worked with his longtime collaborator Michael Lutter, a former University of Iowa researcher who now has a clinical practice treating patients with eating disorders. The study focused on 154 patients with strong family history, multiple courses of unsuccessful treatment or unusual clinical features who agreed to undergo sequencing of the protein-coding regions of their DNA.

Seventeen — about 11% — carried rare variants predicted to damage a gene called PLIN4, compared to about 3% in a healthy reference population. Six anorexia patients carried especially disruptive variants that could keep the gene from functioning normally, and in four of those families, a close relative with an eating disorder carried the same genetic change.

“Probably the single most remarkable thing about this study is that this gene is mostly expressed in body fat and in muscle,” Lutter said. “The idea of an anorexic gene not in the brain is completely novel.”

The researchers caution that the study involved a specialized group of patients, and the finding must be replicated in a larger, independent population before scientists know how broadly it applies.

Understudied and underfunded

For the most part, anorexia treatment hasn’t evolved much past nutritional rehabilitation to restore body weight and psychotherapy to address eating behaviors and psychological symptoms. There are no Food and Drug Administration–approved medications specifically for anorexia.

One potential reason for the lack of treatment options is that anorexia and other eating disorders have historically been understudied and underfunded compared with many other psychiatric disorders. A recent analysis of National Institutes of Health funding from 2011–2023 found that eating disorders were among the two lowest-funded categories.

“There’s a misperception that anorexia is a result of vanity,” Robison said. “This idea may stem to some degree from misogyny. This is a disease that occurs tenfold higher in women than in men. That can lead to people having thoughts about the disease that stem from their own biases against women.”

Lutter has devoted much of his career to finding genes linked to anorexia. Decades of twin studies, such as the Michigan Twins Project, indicate someone with a first degree relative who has anorexia is five to 10 times more likely to develop it than the general population.

But researchers are still working to identify the many genetic variants that contribute to a person’s susceptibility to the disease.

Lutter compared the search to researchers finding Breast Cancer Genes 1 and 2, or BRCA1 and BRCA2. While the genetic variants are rare, they also drastically increase a person’s likelihood of developing breast or ovarian cancer. Unlike diseases caused by a single genetic mutation, however, anorexia is polygenic, meaning many different genetic variants may contribute to a person’s risk.

“The best way to think about what I do is, I look for the BRCA1 and BRCA2 of anorexia,” Lutter said. “Variants are in a small percentage of the population, but they dramatically increase your risk of having anorexia.”

A gene doesn’t operate on an island, Robison said. It’s part of a larger pathway with transcription factors that regulate it, as well as cellular functions upstream and downstream.

If researchers can find genes associated with anorexia, they can find biological pathways they belong to and look for targets for new treatments.

“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 look for genetic differences that could affect how fat is stored and how susceptible a person is to anorexia. They’ll also study patients’ body fat to look for abnormalities that could provide more clues about the disease.

It’s all part of Lutter’s goal that, one day, patients with anorexia will have better options for treatment — and better outcomes.