Not everyone who is obese is unhealthy. So say some researchers, who note that a small fraction of overweight people have normal blood sugar levels and blood pressure, and are thus “healthy obese.” Now, scientists have identified a single protein that seems to determine whether obesity is harmful or benign.

The protein is a new player in our understanding of how obesity leads to disease, says Alan Saltiel, a cell biologist at the University of Michigan, Ann Arbor, who was not involved in the study.

It is well known that obesity leads to a wide range of health problems, from diabetes to heart disease to cancer. So established is the link between extra pounds and illness that last year the American Medical Association voted to classify obesity itself as a disease. Although some researchers have suggested that a small number of obese people are healthy, that idea remains controversial. Instead, the emerging consensus is that healthy obesity is a transient phase, says Ravi Retnakaran, an endocrinologist at the Leadership Sinai Centre for Diabetes in Toronto, Canada. Sooner or later, he says, these outliers will develop metabolic syndrome, a condition in which glucose, cholesterol, and lipid levels soar, causing diabetes and heart disease.

In fact, so-called healthy obese people may already have early signs of disease, which are too muted to show up on routine tests. In a study of more than 14,000 metabolically healthy Korean people last year, scientists found early plaque buildup in the arteries of obese subjects more often than they did in the lean ones.

To figure out when the transition from healthy to unhealthy obesity occurs, Harald Esterbauer, an obesity researcher at the Medical University of Vienna, and his colleagues took a closer look at a protein called heme oxygenase-1 (HO-1), which was thought to suppress inflammation—the critical bridge that links obesity to metabolic disease. When the pancreatic islets, small masses of cells in the pancreas that produce insulin, are exposed to high levels of nutrients—as is the case among people who eat a lot—they become inflamed. This leads to the death of some islet cells, in turn decreasing the secretion of insulin and causing type 2 diabetes.

To understand the role of HO-1, the researchers examined blood, fat, and liver tissue from a group of 44 obese people and six controls. All the obese subjects were apparently healthy: They had normal fasting glucose levels, no obvious inflammation, and took no medicine. However, there was one critical difference among them: Twenty-seven of the subjects showed early signs of insulin resistance, a precursor of diabetes. Insulin responses were normal in the remaining 17 obese subjects. When Esterbauer’s team biopsied the tissues from both groups, it found HO-1 levels to be nearly twice as high in the insulin-resistant group. The finding suggested that HO-1 was causing the insulin resistance.

To be doubly sure, the researchers removed the HO-1 gene from mice. When these knockout mice were fed a high-fat diet, they gained as much weight as normal mice did, but they managed to remain sensitive to insulin. In addition, the knockout mice also showed lower levels of inflammation.

The researchers also tried the converse experiment: genetically engineering mice to produce more HO-1. This time, they found that the mice grew insulin-resistant, even when on normal diets.

“We believe that HO-1 is a very early marker of metabolic disease,” says Esterbauer, whose team reports its findings today in Cell.

Esterbauer’s team also found that levels of the HO-1 protein were slightly higher in healthy obese subjects than in the lean controls. This supports the concept of transient healthy obesity that Retnakaran advocates: Compared with lean, healthy people, obese people are already at a slight disadvantage.

Knowing what causes metabolic syndrome may make it easier to treat and diagnose it. Blocking HO-1 in mice controls inflammation, so it could possibly do the same in humans. But before that, it is important to understand how HO-1 causes inflammation, Esterbauer says. “Based on this knowledge, we can then develop drugs that interfere with a specific function of HO-1.”