Can Fat Mice Teach Us How Obesity Kills?

by Alicia P. Gregory
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mouseLisa Cassis has been studying fat since before it was “big.” Back when kids still played outside, and restaurant portions weren’t the size of your head. Before two-thirds of American adults were labeled overweight or obese. “Back in the ’80s scientists didn’t really care about fat. It was boring,” she says, drumming her fingers on the table.

And even after Cassis made a landmark discovery about fat cells in 1988, she says it was difficult to get funding for her research. “My scientific peers thought I’d made a mistake—surely fat couldn’t be doing anything,” Cassis says with a wry smile.

Her discovery, which she describes as a “pure accident,” happened while she was looking for a protein that makes angiotensin, a component of the renin-angiotensin system. This hormone system regulates blood pressure. “I was trying to find out if blood vessels could make this stuff themselves, so I was looking for the precursor protein, angiotensinogen.” But because she hadn’t thoroughly cleaned the bit of vessel she was examining under the microscope, she accidentally found heaps of angiotensinogen in the fatty tissue clinging to the vessel.

If a fat cell could make this protein, she reasoned, that meant it could make angiotensin and drive up blood pressure. And suddenly the “boring” fat cell was brimming with activity, and dangerous potential.

This discovery led Cassis, now chair of the University of Kentucky’s Graduate Center for Nutritional Sciences, to 25 years of research to answer new questions: why would a fat cell make angiotensinogen? Does it automatically make angiotensin? What regulates a fat cell’s ability to produce these things? And then, says Cassis, the ultimate question: is this the link between obesity and cardiovascular disease?

To find out if angiotensin is a mediator of obesity’s cardiovascular complications—hypertension (high blood pressure), atherosclerosis (hardening of arteries) and abdominal aortic aneurysms (ruptured bulges in the aorta that cause massive internal bleeding)—Cassis started feeding mice a high-fat, “Americanized” diet. She admits that mice aren’t a perfect model for human obesity: “There’s always a disconnect between species. Mice aren’t men or women.” But she’s convinced that fat mice can teach us how obesity kills and can reveal mechanisms by which we can stop it.

Big Fat Deal

It wasn’t Cassis’s dream to make mice fat. Chuckling at the thought, the West Virginia native says, “My parents didn’t go to college. They grew up during the Depression. They told my brothers and I that if they were going to send us to college, we were going into health care, because we’d always be able to make a living.

“I wasn’t really interested in health care; my favorite subject was English. But I looked around and settled on pharmacy—mostly because I wouldn’t have to touch people,” she laughs. “So I went to pharmacy school and liked it, but I didn’t know if I wanted to do that my whole life.” One of her professors asked Cassis if she’d ever considered research, and she ended up working in his lab on “a really boring project.” Her blue eyes roll, and then she admits, “It’s amazing I stayed in research.” But with that experience Cassis caught the discovery bug.

She earned her Ph.D. in pharmacology at West Virginia University, went to Germany for a year and a half on a prestigious Alexander von Humboldt postdoctoral fellowship, and spent three years as a postdoc at the University of Virginia with mentor Michael Peach, the biggest name in the renin-angiotensin game at the time.

In 1988, Cassis got her first faculty position in the UK College of Pharmacy. And that position brought success and marriage—her future husband, Rob Lodder, started in the college just three months after Cassis, and their professional collaboration led to a new medical device and research on a sugar substitute that may be a therapy for diabetics. (For more, see "Love, Patents and Sugar.")

It was in her first year at UK that Cassis made her discovery that a lot more is going on inside fat than meets the eye.

Fat, a.k.a. “adipose,” is connective tissue composed of adipocytes—fat cells. These cells have one big vacuole, a large compartment that stores lipid droplets. Lipids are naturally occurring molecules (like oils, waxes and cholesterol) that can dissolve into fat tissue. Adipose tissue stores energy in the form of fat, and it cushions and insulates the body.

The angiotensinogen Cassis first found was in a specialized type of fat called brown adipose tissue, the so-called good fat that generates heat. “But there are other types of fat that even I combat in my daily life,” she says begrudgingly, with a downward glance at her mid-section. White adipose tissue—to blame for the telltale “spare tire”—harbors vast stores of angiotensinogen. Cassis adds, “I looked in virtually every fat deposit in rats I could find, and the protein was everywhere.”

This is the finding she presented at a conference in 1988, and one that skeptics questioned until years later when, she says, “a number of high-powered scientists found fat was pumping out all kinds of things.” At least 50 known substances are made by fat cells. Scientists labeled these substances adipokines, and Cassis’s protein angiotensinogen became one of them. “Many adipokines regulate inflammation. Angiotensin promotes inflammation in blood vessels, and that’s important because inflammation underlies a lot of diseases.”

Cassis points out that where fat ends up is critical to the development of disease. “If fat is deposited subcutaneously—under the skin—many studies have shown it’s not as dangerous as when it’s deposited viscerally—in the abdomen around the organs. When we make mice obese, the biggest changes to the renin-angiotensin system are in the abdomen. The mouse’s fat tissue makes more of the precursor protein and more angiotensin specifically in the belly.” She says other scientists are transplanting fat from the abdomen to other parts of the body to see if fat retains its bad effects, but for now nobody knows why abdominal fat is so life-threatening.

“We do know there is a connection between obesity and type 2 diabetes, and there are well-established connections between both of these conditions and cardiovascular disease.”

In fact, in 1998 the World Health Organization defined an entirely new disorder—Metabolic Syndrome—to draw attention to these connections. The American Heart Association estimates that more than 50 million Americans have Metabolic Syndrome. Risk factors include excessive abdominal fat, low HDL and high LDL cholesterol, elevated blood pressure, and insulin resistance.

“Obesity seems to be the common denominator in diabetes and cardiovascular disease. What we don’t know is exactly how those connections are mapped out on the cellular, biochemical level. If we knew those mechanisms, we’d be able to develop new treatments. That’s why I’ve used mouse genetics to manipulate the renin-angiotensin system specifically in fat cells,” Cassis says, gesturing toward her lab space on the fifth floor of the Wethington Building. The roar of a helicopter, taking off from the roof of the UK Hospital next door, is a temporary distraction from her description of how she makes mice fat.

“We feed them commercially available diets high in saturated fat. We have a 45 percent fat diet and 60 percent fat diet.” Cassis notes that “the 45 percent fat diet is more analogous to what most Americans are eating. We feed the mice this diet and they become very obese little butterballs. They get all the different parts of the Metabolic Syndrome and some develop atherosclerosis.”

A Systematic Approach

“I want to learn how obesity kills, so that’s the angle I take in looking at the renin-angiotensin system. People have been studying this system since the late 1800s, and, believe it or not, just this year we published a paper on a new component: ACE 2.”

But, Cassis says, “Let’s start with the basics. This is a hormonal system. It has proteins and enzymes that come together to make a peptide family called angiotensins.” (Peptides are short molecules formed from the linking of amino acids, the building blocks of life.)

The system starts with the protein. “Angiotensinogen: my daughter loves that word,” Cassis says, overemphasizing each syllable in a squeaky kid voice. She adds that her daughter Laura, now 14, can’t wait to spend a summer working in a UK lab like her 17-year-old brother Andy. Both of Cassis’s children are interested in science. Her son will probably follow in his father’s engineering footsteps, while her daughter has expressed an interest in health care. “I’m not pushing them in this direction. To me, the important thing is that you like what you do, because if you’re spending all this time at it and you’re miserable, that’s no way to live.”

Clearly, for Cassis, studying angiotensinogen has been the right choice. “This big protein is fascinating. In humans it’s 452 amino acids long,” she explains. “Forgive me, but it makes you wonder why God would create this huge protein and in the 100 years people have been studying it the only thing they’ve found it does is give rise to this puny eight amino acid peptide. Such biological inefficiency!”

Angiotensinogen is made predominantly by the liver, “but we found it is also made in fat cells. It’s basically spit out from the cells into the bloodstream. There it encounters the enzyme renin, secreted by the kidneys, that converts this big ol’ protein by clipping off 10 amino acids at one end to make angiotensin I.” Cassis explains that the only purpose for angiotensin I is to lead to angiotensin II.

“As angiotensin I floats by in the blood, a second enzyme, angiotensin-converting enzyme (ACE), clips it to eight amino acids to create angiotensin II. This is the biologically active peptide that causes blood vessels to constrict and drives up blood pressure.” She adds that angiotensin II has a very short half-life: about 12 seconds. “It’s not around long, but it does a lot in a very short time.”
           

Two ACEs in the Hole

Scientists had figured out that overproduction of angiotensin II was dangerous, but what component of the system was the first target for therapeutic drugs? ACE.

First discovered in the mid-1950s, ACE could produce angiotensin II, a way to raise blood pressure, as well as break down bradykinin, a peptide that lowers blood pressure. Cassis explains, “Drug companies went after it because you get two for the price of one. You take out this enzyme and you have two mechanisms to control blood pressure. It was the most-studied component of the system. They knew a whole lot about its chemical structure, so they knew how to keep it from doing its job.”

Developed in the ’70s, ACE inhibitors are widely used today to treat high blood pressure and congestive heart failure. And Cassis says her research confirms that these drugs should be the number-one choice of physicians—“anything that controls the overproduction of angiotensin II in the obese, at-risk population is going to benefit cardiovascular health.”

Just last year Cassis began working on a new enzyme produced by fat cells, ACE 2. “It has a similar structure to ACE, but what this enzyme does is break down angiotensin II—it converts it to a different form of angiotensin.” She explains, “We found that this enzyme doesn’t work well in fat cells from obese mice. Why? It’s being shed from the cell, so it can’t control the local concentrations of angiotensin II. And, as it turns out, it gets cast off to a greater extent when the mice are obese. Interestingly, the same enzyme that sheds ACE 2 also sheds tumor necrosis factor, which is linked to insulin resistance and diabetes.”

Cassis hopes these kinds of findings will lead to novel ways to regulate the renin-angiotensin system in fat tissue. And now she’s looking at fatty acids as a prime regulator. “The diets we feed mice are enriched with fatty acids. We’re looking at the effects of specific types—the bad, saturated fatty acids versus the Omega 3, heart-healthy fatty acids.” Cassis’s goal is to answer the question: Could diet modification alone regulate this overactive system and save lives?

The Trash Collector Controls Angiotensin

“Drug companies looked at ACE first, because renin differs from species to species and this makes it hard to develop a drug that effectively inhibits the enzyme,” Cassis explains. “Basic scientists like me discovered pretty early on that if we developed a drug that targeted renin in a rodent, it didn’t work in humans. It was simply harder to figure out.” But eventually the drug company Novartis did and, because of a chance encounter in a hotel lobby, Cassis and her main UK collaborator Alan Daugherty were chosen to test this renin inhibitor.

Daugherty, the Gill Foundation Chair in Preventive Cardiology, has spent almost all of his 12 years at UK working with Cassis. Born in Liverpool, England, Daugherty earned his Ph.D. and D.Sc. (an even higher tier of research doctorate) in pharmacology at the University of Bath and then spent 15 years at the Washington University School of Medicine in St. Louis. He now serves as senior associate dean for research in the UK College of Medicine. This past spring Daugherty, director of the UK Cardiovascular Research Center, was named American Heart Association Scientist Advocate of the Year for his work in promoting the importance of cardiovascular research.

Daugherty is emphatic as he says atherosclerosis is something everyone should care about: “all men and women in their 40s and 50s have a degree of atherosclerosis. With the population bubble coming up—the baby boomers in their 60s—studying this disease is more important than ever.”

Cassis and Daugherty are perhaps most widely known for accidentally creating a mouse model of aortic abdominal aneurysms (AAA), a disease that predominantly affects males over 55. “In 2000 Lisa and I were doing studies in which we infused angiotensin into this specific strain of mice. And we began to notice these big bulges in their abdomens.” The bulges turned out to be AAA. When Daugherty and Cassis published their finding, the scientific community adopted their animal model as a way to study the mechanisms of the disease, and their work has been cited in medical journals close to 300 times. (For more on AAA, see www.research.uky.edu/odyssey/winter07/research_profs.html.)

Of their professional collaboration, Daugherty laughs and says, “We’re quite often described as scientific brother and sister. We have some discussions that are not so cordial at times. Lisa and I feel fairly secure with each other to express our opinions. That’s what you need in science: a colleague who will tell you exactly what they think because there’s not much point beating around the bush, frankly. I would have never gotten into angiotensin without her.”

Daugherty points out that high blood pressure on its own increases a person’s risk for atherosclerosis, so utilizing a drug to control the renin-angiotensin system has a lot of potential to curb this disease. “The way we started working with Novartis was one of those strange, small-world experiences,” he says.

Cassis explains, “I was at a conference, and I was standing in line to get my hotel room. This man in front of me said something funny, so I laughed. He turned around and we started talking. He worked for Novartis and told me they were making this compound, aliskiren, a renin inhibitor, to treat patients with high blood pressure. So I told him about our work with mice models of atherosclerosis.”

“It turns out I’d known this guy, David Feldman, for 20 years!” Daugherty says, explaining that he met him when Feldman worked at the Cleveland Clinic but hadn’t seen him in years. “We started to discuss whether we could do studies with their drug.” Now, Daugherty is the principal investigator, and Cassis co-investigator, on two contracts with Novartis. Last year the UK team published findings that Novartis’s renin inhibitor successfully reduced the size of atherosclerotic lesions in mice. And these findings led to a worldwide clinical trial. “Novartis is recruiting 700 people. They’ll have two groups: one will take 300 milligrams of this new renin inhibitor, and the other will take a placebo. Each group will undergo something called an intravascular ultrasound to look at the size of their lesions. Two years later, they’ll come back for another ultrasound to see if the inhibitor has altered the lesion size.”

Daugherty explains that atherosclerosis is a chronic inflammatory response in the walls of arteries due to accumulation of macrophages (“the professional trash collectors of the body”) and cholesterol-carrying proteins. Macrophages are born from monocytes, white blood cells that speed to the site of inflammation and change into macrophages to elicit an immune response. “Macrophages are our first line of defense,” he states. “They attack and ingest foreign substances in an indiscriminate way.”

Cassis says, “In studying Novartis’s compound, we took renin away from bone marrow-derived cells in mice that develop atherosclerosis in response to a high-fat diet. And we found that even though the rest of the renin-angiotensin system was present in the mouse, taking away renin from these cells effectively reduced atherosclerosis.”

Daugherty mentions that other scientists had suspected renin could be made in other places than the kidneys, but nobody thought enough of it was produced to be of any importance. “We were the first to show that targeting renin in bone marrow-derived cells, such as macrophages, can dramatically reduce atherosclerosis.”

Cassis adds, “We think macrophages are little synthetic factories that make angiotensin, and they deliver it to wherever they go. If they travel to a forming atherosclerotic lesion, they take it with them. If they go to fat cells, they take it there.”

But Daugherty quickly points out, “Macrophages are a very diverse cell type, so our next question is: ‘Why are some macrophages generating angiotensin and probably causing disease while others are inert?’”
“We’ve just found the tip of the iceberg,” says Cassis.

COBRE: A Training Tool to Tackle Obesity

For Cassis, making new discoveries in the laboratory wasn’t enough. She wanted to promote the importance of obesity in cardiovascular disease, and she found two big ways to do it. In 2003 she became the director of the Graduate Center for Nutritional Sciences (a center started by faculty because nutritional sciences training was scattered across campus), and in 2008, after three grueling rounds of competition for NIH funding, she became principal investigator of the UK COBRE in Obesity and Cardiovascular Disease. Center of Biomedical Research Excellence (COBRE) grants are focused on training junior research faculty to compete successfully for NIH funding.

“In 2003-2004, when I went to professional meetings, there was just a void,” Cassis says. “There were researchers studying why people become obese, but there were very few scientists with cardiovascular expertise asking, ‘Why do people who are obese die from cardiovascular disease?’” Cassis’s voice underlines the word “die.”

“So Fred DeBeer [chair of internal medicine] and I championed the idea here on campus that we should have a center dedicated to obesity and cardiovascular disease, and we submitted our proposal to the NIH COBRE program.” Because of the highly competitive nature of COBREs, it took UK three tries to secure the $10.5 million, five-year grant. But even without the money, Cassis’s brainchild thrived—five of the junior scientists on the proposal had already “graduated” (secured grants) by the time UK received the COBRE funds in fall 2008.

“We have a whole new batch of junior investigators—Jianhua Shao and Shuxia Wang in nutritional sciences, and Eric Eckhardt, Zhenyu Li and Victoria King in internal medicine—doing very novel research, all using our diet-induced mouse model of obesity. Because they’re all using the same mechanism to induce obesity, and all of our mice end up diabetic, they can crosstalk.” She explains that Dr. Shao, who’s looking at adiponectin, an anti-inflammatory substance produced by fat cells, can share his findings with Dr. King, who’s studying serum amyloid A, a substance involved in chronic low-grade inflammation. “By sharing their findings, our researchers can get at the complexity of how fat cells change with obesity.”

The COBRE team is bolstered by a new initiative to fight diabetes. Last fall Patricia Barnstable Brown and her family pledged funding to develop the Barnstable Brown Kentucky Diabetes and Obesity Center at UK. Funds will come specifically from the internationally known Barnstable Brown Gala in Louisville, whose proceeds allow the family’s foundation to support diabetes research, education and patient care in Kentucky.

“Kentucky needs few things more urgently,” says Michael Karpf, UK executive vice president for health affairs. “This gift will catapult UK into national prominence as a diabetes center and help address the health needs of Kentucky.”

According to the CDC, Kentucky has the fourth-highest rate of death from heart disease among the 50 states. The state comes in at No. 7 for the prevalence of both obesity and diabetes, and it ranks high in other primary risk factors for cardiovascular disease, such as hypertension and inactivity, according to the most recent Robert Wood Johnson Foundation statistics.

“These stats show just how important it is that we tackle these problems at UK,” Cassis emphasizes. The university recently recruited Philip Kern to lead this center, which will serve as a nexus for faculty efforts in diabetes and obesity care, and research. “Dr. Kern is a physician-scientist with an internationally known research program in type 2 diabetes,” Cassis says, introducing the man now in the office next to hers. “Working with him, we’ll be able to take the mechanisms I identify in mice—say Omega 3 as a regulator for the renin-angiotensin system—and apply them in the clinic to humans. Dr. Kern will help basic scientists studying obesity and diabetes bridge the gap between mice and men.”

Love, Patents and Sugar

Rob Lodder, who earned his Ph.D. in analytical chemistry from Indiana University in 1988, came to the University of Kentucky just three months after Lisa Cassis, and they began working together. Why? “Because she had rats,” Lodder deadpans. “I needed rats with atherosclerotic plaques.”

The calling card of atherosclerosis is plaque. “The theory with ‘vulnerable plaques’—the ones most likely to rupture and kill you—is that they have a large lipid pool that can leak, and a thin fibrous cap that can tear.” Lodder puts it simply: “When the contents ooze out, a large clot forms and you fall over dead from a heart attack or stroke. But if the plaque has a small lipid pool and is covered with a lot of collagen, then maybe it will never cause a problem.”

In 1988 Lodder was trying to do something no one had done before: use near-infrared spectroscopy—a technique that uses laser light to measure the absorption of light by different molecules—to peek inside human arteries. He wrote an algorithm that could digitally reconstruct a blood vessel wall, with the ultimate goal of predicting where a heart attack was going to occur up to a year before it happened.

“We took some of Lisa’s mice, removed the artery, suspended it by its ends in a solution, and pumped a solution containing excessive LDL cholesterol through it,” Lodder explains. “We think atherosclerosis can develop at the site of a previously existing injury, so we were causing that injury, then using the spectrometer to see how the artery tried to repair the damage using the cholesterol.”

His technique looked so promising that in 1988 Lodder and three other UK faculty members formed a start-up company, InfraReDx. His relationship with Cassis, which began as a convenient way to get rats, became something more, and this project essentially secured their future: “In 1990 I entered the paper based on this research in the IBM Supercomputing competition. I won first prize—$25,000—in the life sciences division. We took the money, got married and made a down payment on a house.”

In 1995, Lodder’s infrared spectrometer was patented, and InfraReDx took the technology, developed a commercial catheter and secured FDA approval. In May 2008 the new catheter was used in the first patient. Lodder, who’s only a shareholder in the company now, says, “The catheters are relatively inexpensive—around $1,000. You use it once and throw it away. The clinical studies still under way are showing that approximately one in five patients, assigned to a therapy based on conventional catheterization, is assigned to the wrong one.” He explains that once physicians see the data from his infrared catheter, they better know what length of stent (a tiny mesh “scaffold”) to use and where to place it inside the artery to maximize blood flow. “Based on this alone, we think Medicare will approve our device this year.”

Lodder, who holds joint appointments as a professor in pharmacy, engineering and chemistry, says his interests have always veered toward the sci-fi. In fact, he serves as editor in chief of the journal Contact in Context, a scientific forum for research in astrobiology and the search for intelligent life in the universe. And as far as TV preferences in their household: “Lisa hates when I watch sci-fi at home. She always switches to Law & Order.”

In fact, his sci-fi bent led him to work with Spherix. Lodder serves as president of this scientific research company that is developing a sweetener, Naturlose™ (D-tagatose USP), as a therapy for Metabolic Syndrome. “Spherix went public back in the ’60s. Their big claim to fame was the Mars Viking Mission,” he says, adding that the company’s founder, Gilbert Levin, examined a large number of sugars because of the Viking project.

“Viking took three life-detection tests to Mars. One of those was Gil’s labeled-release experiment.” Lodder describes how the test worked: “Viking would take some Martian soil, add radioactive sugars (like tagatose), some water, and mix them up. Viking would heat it up so the water didn’t freeze and then wait. If there were any microbes or spores, they would “hatch” and release radioactive carbon dioxide gas that they made from the sugar.

“And it worked. The test resulted in carbon dioxide, but then the other two life-detection tests showed zip.” So everyone assumed something was wrong with Levin’s test. “It took NASA 20 years to figure out that there was something wrong with the other two tests!” In fact, Lodder says his friend Levin has always maintained that had the probe dug 5 or 6 more centimeters into the Martian dirt, they would have hit the ice scientists now know is there.

“Viking was why I got involved with Spherix. I began working on a proposed Mars mission with them in 2004. But when tagatose started looking like a therapy for disease—when it looked like we could really do something with it—I was the only one on the board of directors with pharmaceutical experience, so I switched over to tagatose.”

Tagatose is a natural sweetener. It’s very similar in texture to table sugar and is 92 percent as sweet, but has only 38 percent of the calories. “If you heat up milk on the stove, you’ll make tagatose,” Lodder says. Spherix had been trying for a number of years to market tagatose as a replacement for artificial sweeteners, but they just couldn’t produce it cheaply enough to compete.

However, Lodder says, during food-safety testing, Spherix scientists discovered tagatose had hidden potential as a therapy for diabetes. “Things that aren’t economical as foods can be economical as drugs. Tagatose has the same number of atoms as fructose, only rearranged. Because of the way it’s arranged, your body doesn’t really recognize it, and 75 percent of the tagatose you eat passes through unchanged.” You don’t metabolize it, so you don’t gain calories. “The sugar goes down the same pathways, hitting the same enzymes, as glucose and fructose. So if you’re diabetic, glucose and fructose end up being stored in the liver until the tagatose is gone. It has an effect like insulin, even though it’s not.”

But this wasn’t what Lodder, Cassis and her graduate student Sara Police were looking for; they had set out to find out if tagatose promoted atherosclerosis. In 2007, the FDA issued a warning that the diabetes drug Avandia had the potential of significantly increasing the risk of heart attack and heart-related deaths. The FDA is making roughly 50 companies go back and retest their diabetes drugs for cardiovascular effects because of the Avandia scare.

Cassis says, “Rob wanted to test tagatose in mice models of obesity and atherosclerosis, so we did a series of studies comparing diets containing sucrose to diets enriched in tagatose. The sucrose diet made the mice very obese, and they had all the symptoms of Metabolic Syndrome, including much worse atherosclerosis. The tagatose diet did next to nothing.”

The UK team’s findings, published in the journal Obesity in 2008, revealed tagatose lowered “bad” LDL cholesterol, which meant less atherosclerosis, stabilized plaques, and lowered blood sugar levels. Recent preliminary results from a phase 2 human trial also show that tagatose lowered glycosylated hemoglobin, triglycerides and LDL. (The glycosylated hemoglobin percentage corresponds to the average glucose level over the previous two to three months, unlike routine diabetic blood-sugar measurements, which reflect food intake over the previous 12 hours.) And in some human trials tagatose has even caused weight loss. “A treatment for diabetes that causes weight loss and improves atherosclerosis? I think we’re going to make some money,” Lodder muses.

He’s so sold on tagatose, he’s been making sweets. “We went to a conference last week, made peanut brittle out of tagatose, and passed it out to people. When we told them it was made from our drug, of course they asked ‘Can you do that?’ Yes.” In 2001 tagatose was classified as a Generally Recognized as Safe product by the FDA. Today tagatose is used in some diet sodas, light ice creams and hard candies, and the University of Kentucky and Spherix are in the process of patenting tagatose as a therapy for Metabolic Syndrome.
Lodder asserts, “Nobody had any ill effects. Compare that to some other diabetes drugs. You can have a heart attack or you can have peanut brittle.”

mouse on scale

Using fat mice, Lisa Cassis is learning how obesity kills and finding mechanisms to stop it. Click the photo above to hear her explain why she's spent 25 years studying obesity and cardiovascular disease.


 

Lisa Cassis in her lab

The chair of the UK Graduate Center for Nutritional Sciences, Lisa Cassis leads a team of 10 who are studying the mechanisms of the renin-angiotensin system in fat cells. Pictured with Cassis is her nephew Paul Cassis (center), from Charleston, West Virginia, who came to work in her lab for a month last summer, and Sean Thatcher, a postdoc with a Ph.D. in physiology from Marshall University, who has worked with Cassis for two years.

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renin

Renin is an enzyme, secreted by the kidneys, that converts the protein angiotensinogen to angiotensin I.

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angiotensin II

“As angiotensin I floats by in the blood, a second enzyme, angiotensin-converting enzyme (ACE), clips it to eight amino acids to create angiotensin II. This is the biologically active peptide that causes blood vessels to constrict and drives up blood pressure.”—Lisa Cassis

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Alan Daugherty

Of his professional collaboration with Lisa Cassis, Alan Daugherty says, “We’re quite often described as scientific brother and sister. We have some discussions that are not so cordial at times. Lisa and I feel fairly secure with each other to express our opinions. That’s what you need in science: a colleague who will tell you exactly what they think because there’s not much point beating around the bush, frankly.”

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artery illustration

Atherosclerosis is a chronic inflammatory response in the walls of arteries due to deposited macrophages (white blood cells) that contain lipids (cholesterol and fatty acids). These deposits, a.k.a. plaque (the yellow buildup), narrow the artery, raising blood pressure. Robert Lodder explains: “The theory with ‘vulnerable plaques’—the ones most likely to rupture and kill you—is that they have a large lipid pool that can leak, and a thin fibrous cap that can tear. When the contents ooze out, a large clot forms and you fall over dead from a heart attack or stroke.”

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Lisa Cassis and Rob Lodder

Fat mice brought Lisa Cassis and Rob Lodder together shortly after they both became assistant professors in the UK College of Pharmacy in 1988. The professional collaboration of this husband and wife team led to a new medical device that allows doctors to peek inside arteries and identify dangerous plaques before a heart attack happens, and research on a sugar substitute that may be a therapy for diabetes.

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