Walter J. Koch, PhD, Senior Investigator at Temple University talks about how the heart communicates with other parts of the body.
The name of the story, heart talks to fat, is intriguing. What does that mean?
KOCH: Well, in the context of what we’ve been studying, what that means is that the heart releases factors or substances that travel through the blood and communicate at a cellular level with fat cells. By manipulating certain enzymes in the heart, you can change these factors and change obesity when animals are fed a high fat diet.
Who is on the receiving end and how is the heart talking?
KOCH: Through the release of substances, it’s talking straight to the visceral white fat we have in our abdominal cavity. Our main type of fat. By manipulating this enzyme, called GRK2, only in heart muscle cells, we could change that communication and that communicative link. And, by turning that enzyme up and down, we get a reciprocal regulation of fat accumulation. When the enzyme was inhibited, animals got super fat. When that enzyme was higher, they were lean and didn’t gain weight, even by eating the same number of calories.
Can you walk us through that process?
KOCH: We have genetically engineered animals that have an inhibitor of this enzyme present only in cardiac and heart muscle cells. This inhibitor makes the heart beat stronger. We’re developing it as a therapy for heart failure. We didn’t expect when we fed these mice a high fat diet, where normal mice gain a certain amount of weight over two or three months, these mice with only their heart changed gained about three times as much weight. I initially thought it might be an artifact, but it’s real. We were able to take the study out of the animals into the laboratory at the cellular level and show that, yes, the heart is releasing something that’s talking to fat cells directly.
So, the high fat diet that was fed to the lab animals is a particular very bad diet?
KOCH: Yes. It’s a diet typically used by people to induce type 2 diabetes. It has high saturated fat. Over time, the animals will get obesity which causes insulin resistance leading to diabetes. We were interested in studying that at the level of the heart because there is cardiac dysfunction associated with type 2 diabetes. We found this weight gain and weight loss in the animals, then followed that story instead.
Was this something that you expected before this discovery happened?
KOCH: That’s a great question. We didn’t expect it at the level of this enzyme, so the heart does secrete other factors. We’ve known for decades the heart secretes natriuretic peptides, or small proteins that regulate blood volume and blood pressure. Other labs have shown similar effects between the heart and fat. This is just the tip of the iceberg. I think the heart can be considered an endocrine organ like the adrenal gland and pancreas. It’s secreting all kinds of substances that communicate with other organs. We’re following that lead for the heart to fat. But we also believe there’s a heart to brain connection that we’re getting into.
Is it a surprise to physicians that the heart speaks to other organs?
KOCH: I think to the level that it may occur is a surprise. The cardiac muscle cell is a very specialized cell. It serves a lot and is a great pump. We can’t live without it, but obviously it has more vital life-giving forces than just beating and pumping the blood.
You mentioned white fat is different than brown fat. Is it also speaking to that?
KOCH: We didn’t see much evidence of that. We looked because that would be a healthier fat and it generates heat. Mice have more brown fat than humans. But we didn’t see much changes in the brown fat, only the white fat.
Where are you in the process or timeline of this discovery?
KOCH: Right now, we have several candidate molecules including small metabolites that the heart is releasing. Whether these are the signals that are talking to fat cells, we’re working through them one by one in this manuscript and paper that we published a couple of months ago. We’ve worked through one which is a branch chain amino acid metabolite. It certainly has the properties that are consistent with what we found in the whole animal, but we must do more studies. We’re working actively on this in the lab.
Do you have any other ideas what the heart is communicating?
KOCH: We found more fat cells and bigger fat cells, so the factor is driving “adipogenesis”. The cells are proliferating more and they’re taking in more fat so they’re getting bigger. It’s something that’s increasing the number and size.
What do you hope to see happen from this finding because obesity is such a huge problem in this country?
KOCH: If we get lucky, we might find a factor that can regulate our fat mass. We’re also interested in obesity and heart failure. Some patients who have heart failure and who are obese could do better. Obviously, we know fat cells talk to the heart. It’s a two-way communication. We’re interested in how the failing heart may change these factors that we’re discovering and how that relates to a person’s obesity level.
So, who’s initiating the conversation, the chicken or the egg?
KOCH: That’s a good question. The two-way communication is. We don’t know enough about the chicken and egg. They’re independent, in a way, because the molecules that are secreted by fat, we know some of those. One is called adiponectin and it protects the heart. And, of course there’s leptin. So, the fat secretes many things and some of them do have specific cardiovascular effects.
What is your next step in this process?
KOCH: The next step that the fellow in the lab is working on is going through systematically one by one about 10 or 12 candidate molecules that we found by a large screen. Eventually, if we get to the right point in the data generation, we will treat animals with that substance and see if they gain or lose weight.
In situations like this, it appears that there could be maybe hundreds or thousands of variables. How do you dwindle that down to where you really need to be focused?
KOCH: It’s all trial and error and you must have patience. You can’t get too discouraged when some don’t pan out. Fortunately, we have several candidates which will keep us busy for a couple of years.
As a physician and a researcher, how did you view this when you found out?
KOCH: At first, I thought it was an artifact and told myself to repeat it because I didn’t believe it. But, that’s how science progresses. This was certainly a lucky find and one we didn’t expect.
Was it the grad students that started this whole thing rolling?
KOCH: It was a grad student’s PhD thesis. He wanted to study cardiac function in the face of type 2 diabetes. So, he had to induce diabetes. When he did, he found this obesity phenotype that we followed and that became his thesis. Nothing about diabetes or heart function.
What would you tell people watching this segment about obesity and its impact? Why is this study so important that you wanted to learn more about this?
KOCH: Obesity is an epidemic, not just in the United States, worldwide because of the social habits of eating the wrong things. As a heart researcher, I care about the effects of obesity on the heart. Heart disease remains the number one killer in the world. We must do a better job.
Where is the fat more dangerous? Is it around the middle of the heart or is it a different kind of fat that’s surrounding the organs?
KOCH: The visceral fat that’s around our organs is dangerous because it can stop certain functions of those organs, and there are actual cultural differences. What we’re seeing around the world in places like India and China is those populations are more brittle than say North Americans. They can only gain five or 10 pounds in their abdomen and they’ll get type 2 diabetes. Whereas in the United States, we can gain 50 to 100 pounds and not get diabetes. So, there is cultural and genetic differences in the susceptibility to weight gain.
END OF INTERVIEW
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If you would like more information, please contact:
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