By Scott Scanlon – Refresh Editor
The process of trying to learn more about a challenging human condition that could one day improve thousands – if not millions – of lives also can have its unpleasantries.
In Kathryn Medler’s case, that involves fattening up, and euthanizing, mice.
“The worst part of the job is having to euthanize the animals and we all take it very seriously and do it humanely,” said Medler, an associate professor of biological sciences at the University at Buffalo, and subject of this week’s “In the Field” story in WNY Refresh.
Medler hopes research she and others at UB are conducting will help scientists determine how taste buds impact obesity. If they are successful, this could be an important ingredient in efforts to improve treatments and medications that can take a big bite out of the growing obesity epidemic.
The Houston native has gone far afield academically in her pursuit. She grabbed her bachelor’s at Texas A&M, her master’s at San Diego State University and her PhD at Louisiana State University – all in biology – before landing at UB.
Which city has the best food?
“The Mexican food in Texas, I miss that dreadfully, and all of the food in Louisiana – fried crawfish and catfish, and everything’s in a creamy sauce – pralines. It’s better for my waistline I don’t live there anymore.”
In fact, she generally loves the weather in Western New York and she and her husband are raising a family here.
Meanwhile, her research continues in a small laboratory in Cooke Hall on the UB North Campus in Amherst.
During an interview last month in her office, she drove deeply enough into her research that I didn’t have enough room in the print edition for more details of her work. Below are excerpts from our discussion:
What are some of the things that drive obesity now?
The change in our lifestyles the last 25 years has contributed to it ... and the way we eat, the diet. The number of processed foods that are available now that are cheap and easy. Everybody’s working now. There’s no time to make a roast for dinner. You’ve got to get something to eat quick, because it’s 7 o’clock. But the food tastes good! Everybody knows that it’s bad for you. Forget about the heart attack and the diabetes. It’s just walking down the street, through the house. All of that is hard, but it’s harder to stop eating because we’re programed to eat. I mean, I eat when I’m not hungry, (so I’m observing, not judging)...
If we all ate just broccoli and kale, there wouldn’t be an obesity epidemic, but we’re not all going to do that. We’re not going to get rid of the food companies. ... There’s some realistic constraints of what you can do within that. For people who can’t stop, they need some medical intervention.
Lap band surgery is an option, but what if we can come up with something less invasive?
Why use mice?
You don’t want to use people because we want to look at the cells themselves. No one’s going to donate their taste buds to us. ... The nice thing about mice, in general, is that researchers have found a way that if we can selectively remove one protein, we can figure out that Protein A is dramatically reduced in the obese mouse in the diet, then we can go buy a (genetically modified) mouse that doesn’t have that gene and then we can do all these studies with that. We use a mouse because it’s a mammal and more closely related to humans than, say, a fish.
Talk about the science behind this research study. How do you work with the mice?
After they are weaned from their mother, we put half of them on a high-fat diet; it’s basically 60 percent fat. Then, the rest of them are normal and have balanced food. We left one group of mice to eat as much as they wanted and they very rapidly gained weight and were way heavier than their brothers and sisters on the low-fat diet. Then, when they’re 30 or 40 percent heavier than the other mice, we did some behavior tests, including a two-bottle preference test.
In this preference test, we put them in a cage by themselves and they’re given two different bottles: one that has water and one that has a taste solution in it. If it’s something that they like, sucrose, once they can taste that, they’re just going to drink that. They’re not going to drink the regular water. ... We can measure how much water did they drink and how much sucrose did they drink.
We know these obese animals that aren’t tasting sweet as well, because their normal litter mates might prefer the sucrose 80 or 90 percent of the time, whereas the fat mice only about 60 percent. So we infer from that maybe they don’t taste it as well, and so they don’t prefer it because they can’t detect how sweet it is.
Anyway you can confirm that?
We isolated the cells and loaded them with dye (the mice are killed during this process) and then we’ll put the sweeteners on the cells and we can test the cells and measure how the cell responds to the stimulus. We did a bunch of cells and found that about twice as many cells responded in the normal mice than responded in the obese mice.
The number of sensitive cells were significantly reduced in the obese mice and the characteristic responses were different. So we and many, many other labs now know that once you stimulate the cell, you get a certain type of response and that translates information being sent to the brain and those signals were being significantly affected by obesity. I can’t tell you yet how, but that’s the next thing were trying to understand, what’s different inside the cell. Once we do that, then we can start trying to figure out how to fix it.
How do you try to understand this?
In other labs, people have shown some of the impact of hormones that control your appetite – leptin and ghrelin, which work together. These are hormones that regulate whether you feel hungry or whether you feel full. We all have these hormones and your body fat secretes these hormones. People who are morbidly obese, with significantly more fat, have a disregulated level of these hormones. They’re just not normal anymore. What’s also been established is that there are receptors for those hormones in taste receptor cells. Our hypothesis is – though we have not proven this yet – is that when those hormones are disregulated they are not going to modulate the taste receptor cells like they normally would, and that can change how the cells are going to respond.
So when we do some future experiments, we can see – and that’s when the transgenic mice come in handy – we can knock out the receptor for lepin and then the cell’s not going to be able to respond to that anymore. Then we can start understanding how that signal pathway helps control what’s going on inside the cell.
How will you be able to remove the protein?
That’s the transgenic mice. It’s a complicated thing that (scientific mice breeders) do. They go in and remove it from the genome, so it’s no longer present for the cells to be able to turn it on and make it.
So you can make a mouse without a protein?
Yes, for me I can buy that mouse from a company that’s already done it. Mice don’t exist for all proteins, because if you don’t have particular proteins you’re not going to survive. But this hormone, when animals don’t have this protein, leptin, they become very obese and develop diabetes. It definitely seems like a relationship.
So is the leptin the ‘I’m full’ protein?
Would there be a way you could put more of this protein into a human being?
Yeah, it’s a hormone we normally have, so it wouldn’t be anything that could make you crazy sick or anything, but we first need to understand how it works before we start injecting people. There could be other implications.
There are people who study nothing but obesity that definitely are investigating and trying to understand. The problem is that injecting your body with something, if you give somebody too much of something, your cells will recognize that and will quit producing the receptors in their own. You just never know. People have to do a lot of experiments and studies to figure it out.
So first you’d better do that with mice?
Yes. That’s why these things take a long time. It’s so complicated. We could inject you with leptin but it might mess up your pancreas. There’s all these other things that have to be in balance.
So, are researchers using animals like this to save lives?
It’s not just to understand things. There’s a very strong human health relationship to it. I always tell people we design experiments to minimize the number of animals that we use. ... This is more of an enviable life than most of the animals who live you your backyard. We have veteranarian-approved, American Medical Association-approved techniques where we kill the animals with the minimal amount of discomfort. ... It’s not a great life living out in the dirt, because they’re probably going to be eaten or starve to death. The worst part of the job is having to euthanize the animals and we all take it very seriously and do it humanely.
The more we understand these (human eating) processes, the more we can make everybody healthier.
There’s so many cancers that people can survive today that they couldn’t have 50 years ago, unfortunately, not all of them yet. People have seen how medicine has progressed. That’s because we figured it out with animals first.
Is this a chicken and egg thing? Does this change take place and then a person gets obese, or does a person get obese and then this change takes place?
That is a very good question that we have not answered yet, and we are in the process of setting up those experiments. The only two differences between my fat mice and the normal mice – because they’re genetically identical – is this one’s on a high-fat diet and gets obese and this one’s on a normal diet and doesn’t. So there’s the diet and the obesity. So is the diet affecting the taste cells and the taste cells aren’t working because they’re on this diet and then they become obese and it feeds forward that way? Or do they have too much fat in their diet, they become obese, and because of the hormonal changes the taste cells go down? We don’t know that but we have a way we can design that experiment where we can keep the animals on a high-fat diet but if we give them this drug, they don’t get fat. And we’re going to be able to figure out is it the diet or did they have to become obese before the taste cells change?
Obesity studies in this context, are they relatively new?
Obesity as an epidemic has blown onto the scene in the last 20 years. There’s a huge change even when I was a kid. There were very few people and certainly you didn’t see people walking around at 5, 600 pounds, which you can see pretty regularly, unfortunately, now. We don’t understand very much about it because science doesn’t (always) move that rapidly.
What do the taste receptor cells do to the nerve cells?
The chemicals in your food will activate the receptor that’s on the taste receptor cell. If you have a sugar receptor on the cell and you’re eating sugar, it stimulates that cell and it sends the information. The taste cell sits out on your tongue and there’s a nerve that comes out and gets the message. It carries that information up to the brain and it goes to several spots in the brain for processing.
Are there parts in your brain that say, ‘Hey, I’m full’ or ‘I’m still hungry?’
Yes. There’s cells from your tongue and your stomach and small intestines that send information up to your brain that say, ‘You’re full,’ the ones from your gut that are saying, ‘We’re busy, we’re digesting, you don’t have to send us anymore.’ There’s information from your tongue that’s saying, ‘It’s sweet, it’s good.’ If it’s sour or bitter, it’s not good and you’re not going to eat it. We don’t really understand how the signals from the tongue go back to the brain to generate an appetite but they definitely make a significant contribution...
Your test cells on your tongue are an excitable cell, like most neurons in your body, but they’re actually in physical contact with your environment. All of the rest of your neurons are not. They’re encapsulated inside your body. They’re mostly in your brain with a bone wrapped around them to keep them safe. But in your tongue, it’s a changing environment, so they continuously turn over, so you’re always getting new taste cells. So if you have a cup of coffee and burn your taste cells in your 20s, you haven’t ruined your taste cells for life.
The turning over breaks down a bit as we age – and malnutrition becomes an issue (because food doesn’t taste as good).
The taste system is a very plastic system. It changes over time and it changes culturally. ... Our preferences for things kind of change depending on our environment and what we’re around, and what we’re used to eating. I’m not trying to set up myself as an expert on the food industry, but they’ve definitely added more concentrated sweeteners and a lot more salt in our food. ... Now, if you eat something without salt, it tastes horrible. I do the same thing. I want my sugar...
If we pulled someone out of a time machine from the ‘60s, and dropped them here, and showed them the size of a meal, or gave them a bag of potato chips or french fries, they would probably horrified with how salty or sweet some of that stuff is.
And food can dull our taste buds?
Right. They just don’t work that well. I don’t know what it says for us in Buffalo with our pizza and chicken wings.
It’s easy to tell somebody, ‘How can you eat two candy bars? One’s enough.’ I’m fine at one, but perception is an interesting thing. We both can eat the same thing, but how do we know we taste it the same way? So maybe it’s helpful to know, ‘If I’m obese, maybe I’m not tasting this as well.’
What does the lack of ability to sense sweetness mean? Do you have to eat more for the same payoff?
Yeah. People have done studies on obese people – some of them are conflicting – but obese people don’t taste sweet as well, but once they taste it, they like it more ... because they’re not tasting it as well, they’re not getting the same satisfaction and finish at the same rate as other people. That seems to be what our data is supporting.
How might this research help when it comes to this connection between taste, appetite and obesity?
Once we can understand the relationship between how obesity can affect taste, which can affect appetite, we can understand the relationship between those things. Once you see how it’s supposed to work, it’s easier to understand why it’s being disregulated by obesity and we can develop the most effective therapies to interrupt it. We can see that it’s connected, but we have to understand what’s happening inside the cells.
Do you have a ballpark of when someone might be able to bring a product or treatment to market?
No. Even when someone has a great candidate drug, they have to go through rounds of test with mice and then rabbits and then humans. It all depends on so many factors. If it works really well, someone can streamline things and get something to market within five years. But it hasn’t been identified yet. Obesity’s a really important health problem. A lot of attention has been focused on it and the amount of work is growing ... but we just don’t understand a lot of cellular mechanisms that have been controlling it yet.