Dangerous obesity enzyme

More than two billion people in the world are overweight or obese. But not all of them suffer from secondary diseases like diabetes or liver cancer. Why?

Dr. J. Andrew Pospisilik from the Max Plank Institute for Immunology and Epigenetics and Harald Esterbauer from the Medical University of Vienna have discovered that obese people with low levels of a particular enzyme don't develop these illnesses. Pospisilik talked to DW about his research.

DW: Dr. Pospisilik, are you saying obesity is not unhealthy anymore?

J. Andrew Pospisilik: No, we specifically try to avoid this terminology. In obesity, you could stratify two classes: metabolically healthy and metabolically unhealthy. Obesity carries with it many secondary diseases. Many are metabolic, like insulin resistance, cardiovascular disease, stroke and ultimately liver cancer, for instance. But there are also for example, joint problems and breathing difficulties. Those seem to be separated from the metabolic side. They still occur in a category that we and others label "metabolically healthy obesity." So the term "healthy obesity" is a bit of a misnomer.

Could you explain what this enzyme you're talking about, called HO-1, is? What is its function in the human body?

Heme oxygenase-1, or HO-1, is responsible for the breakdown of heme, which is a major component of what makes our bloodcells red. It's also a stress-responsive enzyme. So in most tissues, you don't find it in normal conditions, only when there are inflammatory stresses around.

Tell us how this enzyme relates to health in obese people. What happens if the level of HO-1 in your body is too high?

What we found out is that at very low, basal levels, it seems to control the threshold of cellular function. We call these signaling pathways. In a liver cell, for instance, the pathway we looked at was insulin signaling. Insulin is the major hormone that takes up sugar from our blood into the tissues. If it doesn't work very well, we get diabetes.

HO-1, by regulating the energy metabolism in a cell, manages to set the threshold for insulin signaling and tune it up or down, so that it's either more sensitive or more resistant. It seems that the presence of HO-1, or increased levels of it, blunt some pathways like insulin signaling, which we want to be active, and turn on other, major inflammatory pathways. So people who have low levels of this enzyme are protected of insulin resistance and they're protected from excessive inflammation.

How can we influence the level of HO-1 in our bodies? Is it a question of diet, of taking certain medication, or is it hereditary?

I think it's pretty much everything you mentioned. Diet and exercise will definitely be beneficial, they reduce inflammation. We don't know enough to make a simple, generalized statement about the best way to lower HO-1 levels. Certainly lifestyle interventions are there. At the moment, medications for broad use don't exist.

HO-1 could play a role in a number of different illnesses. You talked about diabetes, but what are some other illnesses?

Basically any inflammatory process. But also the whole set of ageing-related diseases, including Parkinson's and Alzheimer's. These are also known to have increased HO-1 levels. So we presume HO-1 also has a negative influence there, but we don't know yet. There's still a lot of work to be done. HO-1 is also increased in multiple cancers.

How could the knowledge you gained about HO-1 be used to treat these illnesses?

We don't know yet the exact mechanism of how it causes the changes in cell signaling. And until we know that, we can't target it from a therapeutic standpoint. There's still one or two key biological questions, but these are questions that can be answered in a few years. These aren't questions that are decade-long challenges.

But our findings already facilitate a new molecular tool to single out people who are at high-risk to develop metabolic complications. For instance in Germany, more than 10 percent of people with Type 2 diabetes don't know it. They'd have to go to the doctor and get measurements done. This is a factor that could easily be used in screening: high HO-1 levels should be a big warning flag to do further measurements.

J. Andrew Pospisilik is a physiologist and group leader at the Max Plank Institute of Immunobiology and Epigenetics in Freiburg. The Canadian's area of expertise are metabolical diseases - illnesses related to obesity.

This interview was conducted by Carla Bleiker.