There’s no doubt about it, people all over the world are getting fatter. Could a virus be to blame, asks Bob Holmes?
WHAT IF YOU COULD CATCH OBESITY as easily as you can catch a cold? Just one unlucky sneeze in a crowded railway carriage or lift, and that’s it. Bang! Never mind that you’ve been a string bean all your life. Never mind that you’ve always taken plenty of exercise and watched what you eat. Pick up the wrong virus, and you’re almost certain to get fat.
It sounds preposterous, but remember that only a few years ago the idea that a bacterium could give you ulcers or heart disease sounded crazy. Those theories are now well accepted—and the “obesity virus” could be the next one to become respectable. Traces of the virus show up in enough overweight people to suggest that the “epidemic of obesity” in today’s world may be more than a mere metaphor. But don’t sidle away from that extra-large person on the train just yet. Your greatest risk of catching obesity might come from someone you least expect.
BOMBAY, INDIA, 1988--Nikhil Dhurandhar’s life was turning out just as he’d always imagined. Like his father before him, Dhurandhar was a doctor specializing in obesity. His practice was thriving and he saw a thousand patients a year. Until, one day, a casual remark changed his life forever.
A family friend, veterinary pathologist Sharad Ajinkya, mentioned that he’d been studying a viral epidemic that was sweeping through poultry flocks, killing hundreds of thousands of chickens. And oddly enough, when he examined the dead birds he’d been surprised by the large amount of body fat they were carrying. Dhurandhar was amazed. How could birds ill enough to die of a virus be overweight? “There should be little or no fat,” said Dhurandhar. “They should be wasting away.”
The two men decided to investigate. They injected the virus, known as SMAM-1, into some chickens in the lab. Six weeks later the infected ones had almost 50 per cent more fat in their body cavity than chickens that had not been exposed to the virus. Oddly enough, the fatter group also had less cholesterol and triglycerides in their blood. This was surprising because fat animals usually have high levels of these two molecules, which transport fat round the body in the bloodstream. Intrigued, Dhurandhar took blood samples from 52 of his obese patients and tested them for SMAM-1 antibodies. He found them in 10 of the 52, and those 10 were heavier than the other patients. They also had lower cholesterol levels—the same unusual signature he had found in the chickens. “When I got that, I thought this was something which was very important to pursue,” says Dhurandhar.
But he knew, too, that he didn’t have the lab space or funding to study this at his clinics in India. He started writing and phoning obesity researchers in the US, and soon realized that no one was going to take a chance on an unknown Indian scientist with an offbeat idea. He hoped there’d be a better chance of convincing someone if he went there. “So I closed my clinics—I had three at that time—got permission from my wife and my son, and we all came to the States,” he recalls. “It was a big, big leap of faith.”
THE WORLD has become dramatically fatter in the past few decades. Since 1980, obesity rates have risen more than 30 per cent in the US. Today, fully 23 per cent of adult Americans and about 20 per cent of adult Britons are obese, as defined by a body mass index (weight in kilograms divided by the square of height in meters) over 30, which works out to 97 kilograms for a person 1.8 meters tall (see Graphs). The problem is even worse in countries like Samoa, where more than half the adults are obese.
This sudden billowing of fat in rich and poor countries alike puzzles obesity experts. The usual suspects—notably poor diet and inadequate exercise—haven’t worsened as rapidly as obesity has burgeoned, which has left experts with the feeling that they must be overlooking some important factor. “The fat content of the diet is too high and the level of physical activity has declined, but still we feel we cannot explain all of this obesity problem,” says Arne Astrup of the University of Copenhagen.
What if the problem was, quite literally, an epidemic—a pathogen sweeping through the population, leaving obesity in its wake? The idea had always intrigued Richard Atkinson, an obesity researcher at the University of Wisconsin in Madison.
Atkinson was aware that three other viruses—including canine distemper virus and Borna disease virus—had been shown to cause obesity in animals, usually by destroying the part of the brain that regulates appetite. In his lectures, he’d often joked about the possibility that fat could be contagious in humans, too. “I’d say, well, it’s possible you get on an elevator, somebody sneezes on you, and you catch obesity. It got a good laugh,” says Atkinson. But he’d never seriously tried to follow up on the idea.
MEANWHILE, Dhurandhar’s big gamble had not paid off. He had landed a job as a researcher at North Dakota State University in Fargo. But as he neared the end of his second bitterly cold winter, he still had found no one willing to support his work on the chicken virus. Discouraged, he decided he’d pack up and move back to Bombay. But just before he gave up, one of his letters ended up on Atkinson’s desk. A few months later Dhurandhar moved to Madison to take a research position in Atkinson’s new lab.
The collaboration almost ended before it ever began. “The plan was that we would import SMAM-1 and start working on it,” recalls Dhurandhar. “Of course, you need permission from the US Department of Agriculture to import a virus. We applied for a permit, and they very promptly refused it.” Not all that surprising since the virus would devastate chicken flocks if it got out and maybe even make people fat.
Unable to do the research they had planned, the researchers decided to try their experiments with a different virus. Since SMAM-1 belonged to a group of viruses called adenoviruses, they scanned a list of the 50 or so commercially available human adenoviruses, which cause colds, diarrhea and conjunctivitis. They decided to start with one called Ad-36, mostly because it was different enough from other adenoviruses to make antibodies formed against it easy to recognize. Scientists knew almost nothing about Ad-36 except that it had originally been isolated from a German girl with diarrhea.
It turned out to be a lucky choice. After just three weeks, chickens inoculated with Ad-36 had two-thirds more abdominal fat than chickens without the infection—and once again, they had unusually low cholesterol. The new virus they had picked out of a catalogue, in other words, had exactly the same effect as their banned Indian virus. “We should have bought a lottery ticket on that day,” says Dhurandhar, who suspects that their good fortune must mean that at least a few other viruses have similar effects.
When the researchers gave Ad-36 to mice, the effect was the same: two-thirds more abdominal fat than controls, and lower cholesterol levels. In a pilot experiment with marmosets, three animals infected with the virus put on three times as much weight over a six-month span as monkeys not exposed to the virus, Dhurandhar and Atkinson reported in May at the European Obesity Congress in Antwerp. And, as with the chickens and mice, their cholesterol went down. The monkey experiment should go a long way towards convincing sceptics that the animal experiments are relevant to people, says Atkinson. “People can dismiss chickens, and they have. They can dismiss mice, and they have. It’s a lot harder to dismiss monkeys,” he says.
But even if Ad-36 can make chickens, mice and monkeys pile on the fat, could it really do the same thing to people? To find out, Dhurandhar and Atkinson collected blood samples from 313 obese people and 92 lean ones in Wisconsin, Florida and New York. They found antibodies to Ad-36 in just four of the lean people but in 100--that’s 32 per cent—of the fat ones. Once again, the obese people exposed to Ad-36 had unusually low cholesterol levels. What those numbers suggest is frightening: should you be unlucky enough to get the virus, you’re overwhelmingly likely to end up fat. “That’s pretty scary,” says John Foreyt, an obesity researcher at Baylor College of Medicine in Houston, Texas. Could it be that fat people are just more likely to get the virus than skinny folks? After all, obesity often leads to a depressed immune system. To test this, Dhurandhar and Atkinson also looked for antibodies to three other adenoviruses—Ad-2, Ad-31 and Ad-37. All three turned up equally often in lean and obese people, and none was associated with the telltale signature of lower cholesterol.
And Dhurandhar keeps accumulating more evidence. Recently, he looked for antibodies in blood samples drawn from 86 pairs of identical or fraternal twins. In the 26 pairs where one twin had antibodies to Ad-36 and the other didn’t, the one who had been exposed to Ad-36 proved to be significantly heavier, with a body mass index 1.5 points higher, on average. Once again, there was no such pattern with the other three adenoviruses.
Even with this growing weight of evidence, though, Dhurandhar and Atkinson have had trouble convincing their colleagues to accept their theory. “We’ve had people laugh at us,” says Atkinson. “One of the most frustrating things I’ve ever done in my life is trying to get this stuff published. We’re getting nit-picked to death.”
That’s not too surprising, says Frank Greenway, an obesity expert at the Pennington Biomedical Research Center in Baton Rouge, Louisiana. “I think that’s typical in the scientific community,” he says. “People aren’t comfortable with taking quantum leaps. The guy who decided that Helicobacter pylori was responsible for ulcers had a terrible time.”
But their persistence may finally be paying off. Dhurandhar and Atkinson’s first peer-reviewed paper, on their animal experiments, appeared this month in the International Journal of Obesity (vol 24, p 989). And none of the obesity experts contacted by New Scientist thinks the idea that a virus might cause some cases of obesity ridiculous, though most still say the idea is “not proven” in humans. “I think we can say for the moment that this virus induces obesity in some animals, but that this is not yet found to be true in humans,” says Luc Van Gaal of the University of Antwerp. Even Dhurandhar agrees. “Everybody wants me to say this virus causes obesity in humans for sure. I’m not prepared to do that yet,” he says.
Truly convincing proof in people may be hard to come by, though. “In the theoretically ideal world, you’d take a bunch of people and infect half of them and see what happens,” says Greenway. “That’s clearly unethical, so the next best thing is to understand the mechanism.” Once scientists know what molecular triggers the virus trips to make animals fat, they can look to see if the same triggers are active in humans.
Dhurandhar is beginning to see the first hints of how the virus might make people fat. In test-tube experiments, he added Ad-36 to cultures of immature fat cells of mice. The infected cells were three times as likely as uninfected ones to mature into fully fledged fat cells, he found. Sure enough, he also found that Ad-36-infected animals have more fat cells in their bodies. Once formed, these still-slender fat cells begin doing their job, sending out the hormonal signals to gather and store fat. Which means that you’re more likely to put on weight.
This summer, Dhurandhar—who moved last autumn to take up a professorship at Wayne State University in Detroit—is beginning a new set of experiments to try to understand how the virus lowers cholesterol even as it increases obesity. He’s now testing to see whether hamsters—the lab animal of choice for cholesterol researchers—respond to Ad-36 in the same way as chickens, mice and monkeys. If researchers can figure out how the virus lowers cholesterol, they will know whether this reduction benefits the individual or not. “Where does it go? If it’s going into arterial walls, that’s not good,” says Dhurandhar. On the other hand, if the liver breaks it down and excretes it—or if the liver simply produces less—scientists may eventually be able to treat high cholesterol with drugs that mimic the virus’s action.
IF DHURANDHAR and Atkinson’s work eventually proves that the Ad-36 virus is responsible for some proportion of the obese people we see today, what happens then? To begin with, Dhurandhar has seen some hints that obese people with antibodies to the virus may respond better to anti-obesity drugs. Perhaps, he guesses, such people lack any genetic predisposition to obesity—they simply had the bad luck to catch the virus, so their obesity is easier to reverse. And antiviral drugs or, eventually, a vaccine might prevent the disease altogether in such people. Dhurandhar is already working with a company—which he won’t name—to develop an antiviral drug which is effective against Ad-36. Governments should also begin screening blood donors for the virus, suggests Dhurandhar. His experiments show that the virus remains infectious in human blood even after long storage, meaning that someone could become infected after a blood transfusion. If obesity does prove to be infectious, the researchers hope this knowledge may help erase some of the stigma that surrounds fat people. “Obese people suffer huge discrimination, and it’s because of this moralistic Judaeo-Christian ethic that you must be greedy, you must not have any self-discipline, and so therefore you must be a bad person,” says Atkinson. “If people understood that there but for the grace of God go they—because somebody didn’t sneeze on them in an elevator—they might have a bit more compassion.”
But might obese people just be trading one stigma for another? After all, most human adenoviruses are highly contagious. And Ad-36 clearly spreads easily in animals. For example, Dhurandhar can detect viral DNA in the blood of previously uninfected chickens just 12 hours after housing them in the same room as chickens carrying the virus. And birds that catch the virus in this way get fatter, just like ones that Dhurandhar inoculates directly with the virus. “They caught obesity just from being in the same room,” says Dhurandhar. So what does this mean for people who must share buses, offices and theatres with potential carriers? Should people play it safe and shun fat people even more than they do already?
Dhurandhar thinks not. “The virus is highly infectious, for sure,” he says. But so far he has only found antibodies to the virus in obese people, not the live virus itself. “The million-dollar question is, does the person carry the virus intact for many years or not, and are obese people carrying the virus more than lean people?” The marmosets, for example, stopped releasing live virus in their faeces after 60 days. If that’s typical, people who have become fat because of the virus are likely to be long past the infectious stage, even though their blood still carries antibodies as evidence of their past infection.
As Atkinson says: “A fat person who’s gotten fat because of this virus isn’t going to hurt you. It’s that skinny guy with a cold who’s sneezing on you. Watch that guy. Discriminate against him.”
From New Scientist magazine, 05 August 2000.
© Copyright New Scientist, RBI Limited 2001
Five different animal viruses have been reported to cause obesity in animals. Out of these five viruses, we have identified the obesity promoting effect of two, an avian adenovirus named SMAM-1 and a human adenovirus named Ad-36. (There are about 50 different types of human adenoviruses that are available with American Type Culture Collection (ATCC) and are usually implicated in respiratory tract infections, eye infections and gastrointestinal tract infections). Obesity induced by viruses is a novel finding and Ad-36 is the first human virus implicated in causing obesity. Several animal experiments conducted in our labs have demonstrated that Ad-36 infected animals increase total body fat and abdominal fat but surprisingly, drop their serum cholesterol and triglycerides (fat in the blood) compared to the uninfected control animals. Ad-36 is a human virus and these findings raise the possibility of some human obesity being of viral origin. Naturally, for ethical reasons we can not do the conclusive study of infecting humans with the virus and we will have to depend on circumstantial evidence to determine the role of Ad-36 in human obesity. Based on the above-mentioned findings, we are conducting research in three major directions described below.
ANIMAL EXPERIMENTS
Our experiments are aimed at characterizing Ad-36 induced obesity using animal models. We have observed that Ad-36 induced obesity is highly communicable and can easily be passed on to other animals. Animals receiving transfusion of blood drawn from Ad-36 infected animals developed significant obesity. The National Institutes of Health has funded us to study the obesity promoting effect of other human adenoviruses. We are also interested in finding the mechanism responsible for obesity promoting and cholesterol and triglycerides lowering effect of Ad-36. From our experiments it appears that Ad-36 spreads quickly in the blood, and to the fat tissue but not to the skeletal muscle. Viral DNA is present in fat tissue of infected animals even 16 weeks after the viral inoculation. These observations have lead to experiments using fat cells.
EXPERIMENTS WITH FAT CELLS
We are using fat cell cultures to investigate
the mechanism of Ad-36 induced obesity. Our experiments have shown that
Ad-36 increases fat cell size and number in Ad-36 infected animals. In
tissue culture, Ad-36 appears to increase differentiation of adipoblasts
to adipocytes, i.e., Ad-36 encourages cells that are pre-fat cells to become
fat cells. Adipoblasts (pre-fat cells) exposed to Ad-36 have 3 times as
many adipocytes (fat cells) compared to the adipoblasts not exposed to
Ad-36. These are very exciting data and we are currently pursuing various
effects caused by Ad-36 in fat cells at a biochemical, molecular and genetic
level.
HUMAN EXPERIMENTS
Ad-36 is not only the first human virus implicated
in obesity, it is the first human virus associated with human obesity.
We have screened several hundred humans for the presence of antibodies
to Ad-36. We find that the presence of antibodies to Ad-36 is strongly
associated with obesity in humans. About 30% of the obese individuals and
only 5% of the lean individuals tested had Ad-36 antibodies. Moreover,
obese antibody positive individuals had significantly lower serum cholesterol
and triglycerides compared to that of the obese antibody negative group
(similar to the animals infected with Ad-36). We are currently investigating
different population groups from various countries for the prevalence of
antibodies to Ad-36.
LONG-TERM GOALS
The long-term goal of this research is to find
the mechanism of action of Ad-36 in increasing obesity and lowering serum
cholesterol and triglycerides. Also, we continue our efforts to develop
better assays to test people for the presence of Ad-36 virus and antibodies.
An obvious long-term goal is to develop a vaccine to prevent Ad-36 induced
obesity.
CLINICAL TREATMENT OF OBESITY
I am interested in finding out effective treatment
of obesity as well as the health effects of various obesity treatments
in a clinical setting. This work is being conducted at the recently founded
Rochester Center for Obesity Research (RCOR) in collaboration with Crittenton
Hospital, Rochester, MI, and Wayne State University, Detroit, MI. A large
and generous donation from an anonymous donor created RCOR, which is located
in Rochester Hills, MI, and has combined its resources with that of the
Crittenton Weight Management Center. The mission of RCOR is to advance
the knowledge in the field of obesity and extend the information in the
community through various outreach programs and activities. RCOR will be
involved in various clinical research protocols in the area of obesity
management. My aim is to conduct lab based research in obesity
at Wayne State University and clinical research in weight management at
the RCOR.
Viruses can induce progressive neurologic disorders associated with diverse pathological manifestations, and therefore, viral infection of the brain can impair differentiated neural functions, depending on the initial viral tropism. We have previously reported that canine distemper virus (CDV) targets certain mouse brain structures, including the hypothalamus, early and selectively. Infected mice exhibit acute encephalitis, with late disease, characterized by motor impairment or obesity syndrome, appearing in some of the surviving mice several months after the initial viral replication. In the present study, we show viral persistence in the hypothalami of obese mice, as demonstrated by low, but still significant, levels of CDV nucleoprotein transcripts, associated with a dramatic decrease in F gene mRNAs. Given the pivotal role of the hypothalamus in obesity (eating behavior, energy consumption, and neuroendocrine function) and that of leptin, the adipose tissue-derived satiety factor acting through hypothalamic receptors, we analyzed the leptin networks in both obese and nonobese mice. The discrepancy found between the chronic and dramatic increase in blood leptin levels and the occurrence of obesity may be due to leptin resistance in the brain. In fact, expression of the long leptin receptor isoform, representing the functional leptin receptor, was specifically downregulated in the hypothalami of obese mice, explaining their inability to generate an adequate response to leptin in the brain. Intriguingly, during the acute phase of infection, its expression was increased in CDV-targeted structures in all infected mice and remained high in obese mice in all CDV-targeted structures, except for the hypothalamus. The biphasic change in hypothalamic leptin receptor expression seen during the progression of CDV-induced obesity provides a new paradigm for understanding mechanisms of neuroendocrinological, virus-induced abnormalities.
http://www.cnn.com/2000/HEALTH/07/28/fat.virus.ap/
In four experiments, the Wisconsin researchers inoculated chickens and mice with adenovirus-36, a member of a viral family that includes about 50 strains. Most adenoviruses cause colds, diarrhea or pinkeye.
After several months, animals infected with adenovirus-36 weighed only 7 percent more on average than those without the virus, but their bodies contained more than twice as much fat. "This is the first human virus that has been shown to cause obesity in animals," said Nikhil Dhurandhar, one of the study's authors. It is also the first virus the researchers looked at, raising the possibility that other human viruses may also cause obesity. Dhurandhar and his colleagues picked adenovirus-36 simply because little is known about it and the strain is relatively easy to work with. Their study is being published in the August issue of the International Journal of Obesity.
"It raises a host of very interesting questions," said John Foreyt, an obesity expert at Baylor College of Medicine. "If it really does play a role I think it's a real breakthrough."
The latest results do not indicate that all obesity is caused by viruses, Foreyt said. But they strongly suggest that infection plays an important role. "There's just so much more we need to do on this before we can say anything definitive," said Richard Atkinson, a University of Wisconsin professor and author of the study.
Unpublished studies in humans show that 20 to 30 percent of overweight people are infected with adenovirus-36, compared to about 5 percent of the lean population. Experts are not completely surprised by the Wisconsin group's results. In the last few years, they have found signs that many chronic health conditions are caused by infections. Three different microbes are thought to contribute to clogged arteries. Long thought to be a product of high stress and a poor diet, ulcers are now known to be caused by the bacterium Helicobacter pylori.
In addition, several animal viruses are already known to cause obesity in both animals and humans. But adenovirus-36 is the first human virus known to cause an increase in fat. Researchers do not know yet how adenovirus-36 causes obesity. Infected animals did not eat more than uninfected ones, suggesting that the virus decreases energy expenditure rather than increasing appetite. "I feel that it increases the number of fat cells, which encourages them to store more fat," said Dhurandhar, who recently joined Wayne State University in Detroit.
The animal obesity viruses appear to work differently from adenovirus-36, by damaging the part of the brain that controls appetite. The Wisconsin researchers saw no brain damage in chickens and mice infected with adenovirus-36. Aside from a day or two of cold-like symptoms, Atkinson said, the virus produced no observable effects besides obesity. Paradoxically, animals infected with the virus also had decreased levels of cholesterol and triglycerides in their blood. Generally, obesity is associated with high cholesterol and triglyceride levels.
Far more research is needed before any practical
benefits can be reaped from this research, Atkinson said. It is still too
early to know whether it may be possible to develop an effective vaccine
against obesity or otherwise counteract the effects of the virus.
Copyright 2000 The Associated Press. All rights
reserved.
A preliminary study of 199 people has shown that as many as 15 percent of obese people may carry antibodies to the virus, indirect evidence that they once were exposed to the virus itself. None of the lean volunteers tested had the antibodies. Dr. Nikhil Dhurandhar described the findings Mon., April 7, at the Experimental Biology annual meeting in New Orleans. An assistant research scientist in the UW Medical School department of medicine, Dhurandhar conducted the research with UW Medical School Professor of Medicine and Nutritional Sciences Dr. Richard Atkinson.
Between 80 and 90 million Americans are obese, defined as having a body-mass index of 27 or above. Body mass index is calculated by dividing a person's weight in kilograms by the square of height in meters. A viral connection to obesity in humans has never been seriously considered before, the researchers noted.
Dhurandhar first found that one type of adenovirus that infects birds and is found only in his native India could induce obesity when it was injected into chickens. Human adenoviruses form a large family of some 50 viruses. Transmitted through the air, they can cause upper respiratory infections, cold symptoms, gastrointestinal problems and eye inflammation in humans. Dhurandhar and Atkinson next injected laboratory animals with a form of adenovirus known to affect humans, Ad-36, which resulted in obesity.
"A paradoxical characteristic of the virus is that in animals it appears to produce low levels of cholesterol and triglycerides along with the obesity," said Dhurandhar, noting that obesity is usually accompanied by elevated levels of these substances. In the current study, Dhurandhar tested 154 obese and 45 lean human volunteers for the presence of antibodies to Ad-36. He found about 15 percent of the obese volunteers had antibodies to Ad-36 while the lean volunteers showed none. The antibody-positive obese people had significantly lower cholesterol and triglycerides levels than the antibody-negative obese people, a pattern similar to that seen in animals infected with Ad-36. But the two groups did not differ on any of 29 other measures the researchers compared, including age or family history of obesity. In males the presence of antibodies was associated with a significantly better response to treatment with obesity drugs, said Dhurandhar.
"There has been an alarming worldwide increase in the prevalence of obesity in the past 30 years," said Atkinson, noting that its revalence in the United States rose 30 percent between 1980 and 1990, affecting more than 33 percent of the population. "This increase is the type of pattern that might occur with a new infectious disease, as has been seen with the AIDS virus. A great deal of further research is necessary to determine if the global epidemic of obesity may be due in part to infection with Ad-36. "The research was funded in part by the UW Beers-Murphy Clinical Nutrition Center.
http://www.news.wisc.edu/thisweek/Research/Med/Y97/obesityvirus.html
RESEARCH -- Health sciences
Virus May Be Linked to Obesity (posted
4/8/97)
A virus that can cause obesity in animals may be linked to some cases of obesity in humans, researchers at the University of Wisconsin Medical School have found.
A preliminary study of 199 people has shown that as many as 15 percent of obese people may carry antibodies to the virus, indirect evidence that they once were exposed to the virus itself. None of the lean volunteers tested had the antibodies. Dr. Nikhil Dhurandhar described the findings Mon., April 7, at the Experimental Biology annual meeting in New Orleans. An assistant research scientist in the UW Medical School department of medicine, Dhurandhar conducted the research with UW Medical School Professor of Medicine and Nutritional Sciences Dr. Richard Atkinson.
Between 80 and 90 million Americans are obese, defined as having a body-mass index of 27 or above. Body mass index is calculated by dividing a person's weight in kilograms by the square of height in meters. A viral connection to obesity in humans has never been seriously considered before, the researchers noted.
Dhurandhar first found that one type of adenovirus that infects birds and is found only in his native India could induce obesity when it was injected into chickens.
Human adenoviruses form a large family of some 50 viruses. Transmitted through the air, they can cause upper respiratory infections, cold symptoms, gastrointestinal problems and eye inflammation in humans.
Dhurandhar and Atkinson next injected laboratory animals with a form of adenovirus known to affect humans, Ad-36, which resulted in obesity.
"A paradoxical characteristic of the virus is that in animals it appears to produce low levels of cholesterol and triglycerides along with the obesity," said Dhurandhar, noting that obesity is usually accompanied by elevated levels of these substances. In the current study, Dhurandhar tested 154 obese and 45 lean human volunteers for the presence of antibodies to Ad-36. He found about 15 percent of the obese volunteers had antibodies to Ad-36 while the lean volunteers showed none. The antibody-positive obese people had significantly lower cholesterol and triglycerides levels than the antibody-negative obese people, a pattern similar to that seen in animals infected with Ad-36. But the two groups did not differ on any of 29 other measures the researchers compared, including age or family history of obesity.
In males the presence of antibodies was associated with a significantly better response to treatment with obesity drugs, said Dhurandhar.
"There has been an alarming worldwide increase in the prevalence of obesity in the past 30 years," said Atkinson, noting that its prevalence in the United States rose 30 percent between 1980 and 1990, affecting more than 33 percent of the population. "This increase is the type of pattern that might occur with a new infectious disease, as has been seen with the AIDS virus. A great deal of further research is necessary to determine if the global epidemic of obesity may be due in part to infection with Ad-36."
The research was funded in part by the UW Beers-Murphy
Clinical Nutrition Center.
CONTACT: Dian Land, 608-263-9893
WHAT CAUSES OBESITY
Overview
Human obesity is a complex disorder. Medical
experts suggest that it is unlikely that one single factor causes obesity
and scientific and medical literature indicate that obesity can result
from neurological, endocrinological, genetic, metabolic, biochemical, physiological,
or nutritional defects or from non-biological influences such as physical
activity, psychosocial/behavioural psychology, or environmental conditions. The body’s weight regulation mechanism is perhaps
the key to understanding how obesity is caused. Although much has been
discovered to widen our understanding of fat metabolism and feeding behaviour,
we still do not fully understand what causes obesity. It is from research
areas into nutrition, genetics, metabolism, biochemistry, physiology and
psychology that we can gain better knowledge about obesity.
Normal Body Weight Regulation
Normal body weight is controlled by the interplay
between internal physiological processes (such as the neuroendocrine control
of appetite, metabolic and biochemical aspects of energy intake and expenditure)
and molecular genetics (including the molecular mechanisms of adipose tissue
production and regulation within the body) and external and environmental
factors (such as eating behaviour, composition of foods, and physical activity).
An excess in body weight develops when any one or more of the processes
associated with these interactions, or the interactions themselves, are
attenuated or exacerbated, resulting in increased energy intake and decreased
energy expenditure.
Ageing and Gender
Ageing has been shown to play a part in the processes
leading to obesity. As a general rule, the body’s metabolic rate slows
down as one ages. Thus, if a person at 50 years of age was compared to
when they were 25 years of age taking into account that the diet and physical
activities were constant for both, there is a greater chance that the person
at 50 years of age will have gained weight over time.
Gender also enters into the obesity equation:
men have a higher resting metabolic rate (RMR) than women and so require
more calories to maintain their body weight. When women become postmenopausal,
their metabolic rate decreases significantly, which is why they are prone
to weight gain after the menopause.
Molecular Genetics
Over the years, animal studies have identified
gene defects that can lead to obesity; however, human obesity is more complex
than animal obesity and only small populations of genetically determined
conditions have resulted in excess weight and fatness. These conditions
include Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen’s syndrome,
and Carpenter’s syndrome, to name but a few and but these account for only
a small proportion of the obese population. Mutations in the following
genes have been linked to obesity: Db, Fat, Tub, Agouti, Mg, PTB-1B, and
Beta-3 adrenoceptor gene. Geneticists have recently updated the human obesity
gene map and they have documented 12 single gene mutations in seven genes.
Together with other markers (eg b3-adrenergic receptor, lipoprotein lipase,
dopamine receptor-D2, glucocorticoid receptor, and apolipoprotein B, D,
and E genes) that have been associated or linked with human obesity (their
numbers increasing very rapidly and now approaching 200), suggests that
genetics play a significant role in the obesity.
Neurophysiological Aspects of Eating
Eating involves many physiological and psychological
factors and interactions. Normal food intake is regulated by the lateral
hypothalamus of the brain (also known as the appetite centre) an area which
motivates the individual to actively search for food and eat. The ventromedial
portion of the hypothalamus - a satiety centre - acts to inhibit appetite
when adequate food intake has been reached. Higher brain centres such as
the amygdala and some cortical areas of the limbic system also play important
roles in the control of feeding. These are specifically involved in the
modulation of eating patterns.
A complex signalling network between neurotransmitters, neuroanatomical structures, hormones, and peptide receptors controls food regulation and energy balance. It includes the coordination of signals to the brain of taste perception and memory at times of feeding, signals of fat mass at a tissue level, and signals from the gastrointestinal tract related to the presence of food and the digestive process. Abnormal body weight regulation, where a neurophysiological cause is suspected, is thought to occur when these central mechanisms that control food intake and energy balance are defective or damaged.
Neurological and Endocrinological Causes of
Obesity
Obesity and excessive weight gain can be caused
by a number of conditions that result from endocrinological and neurological
abnormalities. These include:
Hypothyroidism
Disorders of corticosteroid metabolism, e.g Cushing’s syndrome.
Sex hormone disorders, e.g hypogonadism; ovariectomy
Other hormone disorders, eg Insulinoma; growth hormone deficiency
Polycystic ovarian syndrome
Hypothalamic tumour
Brain damage to hypothalamic region
Brain infection
Brain trauma
Congenital abnormalities eg Prader-Willi syndrome
Metabolic Aspects of Obesity
Metabolic factors have been identified from cross-sectional
studies of obese and lean individuals. These factors include a low resting
metabolic rate; a low level of physical activity; substrate oxidation rates;
and thermogenic activity levels.
Resting Metabolic Rate
The National Institutes of Health (NIH) in the
USA has studied a population of Pima Indians in Phoenix, Arizona, since
1992 to investigate risk factors associated with the development of diabetes
and obesity. Researchers found that Indians with a low resting metabolic
rate were approximately eight times more at risk of gaining 10 kg of body
weight compared with those with a high resting metabolic rate.
Resting metabolic rate generally represents 60% of daily energy expenditure and depends largely on fat-free body mass, which is more metabolically active than fat tissue. Obese people therefore have higher resting metabolic rate than lean people because of the increased body size including fat-free mass. Researchers have however found fat-free mass and resting metabolic rate to be comparable for both obese and nonobese individuals after adjustment for body composition suggesting that there is variability in resting metabolic rate among individuals.
It as assumed, therefore, that a low resting metabolic rate is associated with weight gain and several longitudinal studies have addressed this possibility with conflicting results.
Physical Activity
A strong link exists between physical activity
and weight gain. In a large population survey of over 12000 Finnish adults,
overweight was found to be much higher in sedentary women (21%) and men
(14%) compared with physically active women (8%) and men (7%). Obesity
experts in the UK have suggested that a modern inactive lifestyle plays
an important role in the increasing prevalence of obesity. Support for
the role of physical inactivity in the development of obesity comes from
a study where normal weight post obese women who reported being ‘nonexercisers’
gained more than twice as much weight over 4 years of follow-up than those
who exercised regularly.
Substrate Oxidation
Studies have shown that a high respiratory quotient
- a metabolic index reflecting fat oxidation - can predict weight gain.
The Baltimore Longitudinal Study showed that a higher resting respiratory
quotient correlated with greater weight gain but this was only found in
lean subjects. Further studies, however, have shown that a low respiratory
quotient did not predict weight loss and that resting fat oxidation rates
were the same for obese and non obese women. These data suggest that the
effects of fat oxidation on obesity are unclear and warrant further investigation.
Thermogenic effects
Thermogenesis is the process whereby through
the process of fat oxidation, heat is produced. However, it accounts for
only a fraction of total energy expenditure but a defect in the process
is thought by some scientists to account for the development of obesity.
A number of studies suggest that a postprandial increase in energy expenditure
is possibly due to a decreased sympathetic nervous sytstem (SNS) activity.
The SNS is a major physiological regulator of body homeostasis - it regulates
the cardiovascular system and blood pressure but also has an important
role in regulating body temperature, digestive secretions, respiratory
function and pupillary dilation. The SNS also has effects on the pancreas
and adipose tissue. Animal studies have shown that low SNS activity predisposes
to obesity via thermogenesis but large inconsistencies are found in the
literature when SNS activity is compared in lean and obese humans. However,
a logitudinal analysis shows that low SNS activity is associated with body
weight gain and central adiposity.
Biochemical Aspects of Obesity
Weight regulation is controlled and regulated
by many biochemicals or peptides, which include:
(1) neurotransmitters in the brain that act on
the appetite centre;
(2) hormones that affect food intake and regulation;
(3) signal transporter proteins and receptors
involved in the metabolic pathway of weight regulation; and
(4) enzymes involved in the metabolism of nutrients.
Scientists suggest that there are probably hundreds
or even thousands of other gene products and molecules that have not yet
been discovered, which contribute to the onset of obesity. Arguably, defects
in any one or more of these peptides might interfere with the normal intake
of food and body weight regulation and these peptide molecules have to-date
been the focus of pharmacological antiobesity treatments.
Peptides
Peptides commonly associated with food intake
and regulation are listed below:
Functional role: Peptides found to increase food
intake
Peptides found to decrease food intake
Enzyme Protein tyrosine phosphatase-1B
Glucocorticoids Cortisol Cortisone
Hormones: Leptin Insulin
Neurotransmitters Noradrenaline Serotonin
Opioid Dopamine
Growth hormone releasing hormone Cholecystokinin
Galanin Corticotrophin-releasing hormone
Neuropeptide Y Neurotensin
Melanocyte concentrating hormone Bombesin
Amylin
Adrenomedullin
Glucagon
Glucagon-like peptide-1
Comparative animal studies have shown that the most potent neuropeptides that might play a critical role in influencing energy balance include neuropeptide Y (NPY), corticotrophin-releasing hormone (CRH), glucagon-like peptide 1 (GLP-1), insulin, and leptin. Many other neuropeptides and hormone signalling molecules and receptors are also implicated in the normal regulation of food intake and maintenance of body weight and go beyond the scope of this section.
Peptides commonly linked to obesity
Carboxypeptidase E
Corticotrophin-releasing Hormone
Glucagon-like Peptide-1
Insulin
Leptin
Neuropeptide Y
Protein Tyrosine Phosphatase-1B
Uncoupling Proteins
Neuropeptide Y
This peptide is found in high concentrations in the hypothalamic region of the brain and induces feeding by interacting with a receptor subtype that binds NPY. Injections of NPY into the brains of rats reduces energy expenditure by inhibiting the sympathetic nerves that innervate and stimulate brown adipose tissue (BAT), causing hyperphagia. NPY is the only neurotransmitter that when given as a repeated dose will increase body fat and induce true obesity, an effect also observed in satiated or overfed animals.
Carboxypeptidase E
Carboxypeptidase E (CPE) is an enzyme that may be involved in the final stages of processing insulin, pro-opiomelanocortin (POMC), and other hormones. There is one obese person who has been identified to carry a mutation in the gene for prohormone convertase-1 (PC-1), an enzyme that catalyzes a reaction preceding that catalyzed by CPE. These findings indicate that correct processing of certain, as yet unknown, proteins and hormones can be essential for mice and humans to maintain a lean body composition.
Corticotrophin-releasing hormone
Corticotrophin-releasing hormone inhibits feeding and increases metabolic rate when injected into the brains of animals. CRH stops obesity through stimulation of sympathetic nerve-mediated mechanisms and inhibition of vagus nerve-mediated mechanisms.
Glucagon-like Peptide-1
Glucagon-like peptide-1 (GLP-1) is produced in the small intestine and stimulates insulin secretion and inhibits gastrointestinal secretion and motility. Its function is to signal nutritional abundance and enhances deposition of nutrients. Its role in obesity was demonstrated when brain injections of GLP-1 inhibited feeding in rats.
Insulin
Insulin - produced by the pancreas - is a hormone that promotes the conversion of glucose to fat and storage of fat in adipose tissue. Obese individuals tend to be hyperinsulinaemic - it is thought that overeating increases insulin secretion. Insulin injections to the brain have the opposite effect on fat deposition to peripheral insulin injections. When administered centrally in the brain it inhibits feeding, stimulates brown adipose tissue thermogenesis and causes weight loss. It is thought that insulin affects food intake by reducing NPY expression in the hypothalamus.
Protein Tyrosine Phosphatase-1B
Protein tyrosine phosphatase-1B (PTP-1B) is an active enzyme in the regulation of insulin. Recently, it was linked to obesity and insulin insensitivity. It was shown that mutated PTP-1B gene mice were resistant to weight gain and remained insulin sensitive, whereas normal mice rapidly gained weight and became insulin resistant when both groups were fed a high-fat diet. Researchers suggest that because fat metabolism has been affected in the knockout animals, PTP-1B could become the basis of a new antiobesity therapy.
Leptin
Leptin is secreted by adipocytes or fat cells and is the gene product of the ob gene. Discovered in 1994, leptin deficiency and leptin resistance has been found to lead to severe obesity in mice, suggesting that it might be crucial to the normal control of food intake and body weight. However, to-date only a few cases of congenital leptin deficiency associated with severe early-onset obesity have been found. Paradoxically, most obese patients present with hyperleptinaemia, but this has been interpreted as evidence of leptin resistance, suggesting a reduced sensitivity to leptin's physiological effects.
The theories for high concentrations of leptin in obese individuals include: (1) a compensatory response to the absence of functional receptors as well as reduced leptin bioactivity or signalling; (2) supraphysiological leptin concentrations do not trigger maximal effects due to saturation of receptors; or (3) that functional leptin receptors themselves are lacking. Additionally, there is some evidence that transport of leptin receptor isoforms may be abnormal in obesity or that there might be a decreased capacity of leptin transport in cerebrospinal fluid.
Uncoupling Proteins
Uncoupling proteins are found on the membrane of cell mitochondria and have recently been linked to obesity. The uncoupling protein-1 (UCP1) is an inner mitochondrial membrane protein found in brown adipocytes and is responsible for producing heat instead of ATP. UCP1 was originally thought to be exclusively found in BAT, but is now found to be a member of a family of uncoupling proteins expressed in humans, animals and even plants. Other UCPs have been found - UCP2 and UCP3 - which are also expressed in humans and animals. In genetically obese rodents activity of brown adipose tissue is reduced and the level of UCP1 mRNA and/or UCP1 is lowered.
Researchers suggest that uncoupling proteins might play a role in energy balance and weight gain in humans and mutations in their genes could be predictors of obesity or diabetes.
Nutrition
Dietary Fat
Intake of excessive dietary fat has been implicated as a major cause of obesity for decades. This, however, represents only one piece of the puzzle. Fat provides more energy than carbohydrate or protein if these nutrients were compared weight for weight; fat may contribute to obesity independently of its role in energy balance and it can influence food intake, energy metabolism, and substrate oxidation. High-fat foods are also preferentially selected by individuals because of their high palatability and it has a weak satiety effect.
A study in 1997 compared fat intake of normal weight, moderately obese and severely obese subjects and found that subjects in the moderately and severely obese groups consumed significantly more fat and cholesterol and less carbohydrate than did normal weight subjects. Obese individuals also had higher intakes of saturated, monosaturated and polyunsaturated fat compared with normal weight subjects. Another study has reported that a positive association was found between dietary fat and adiposity after adjusting for age, total energy intake, physical activity level, and smoking status.
There has been a recent debate and difference of opinion about whether the percentage of dietary fat plays an important role in the rising prevalence of overweight and in its treatment once it has developed. Experts reviewed the results of 28 clinical trials that studied the effects of a reduction in the amount of energy from dietary fat. It was shown that a reduction of 10% in the proportion of energy from fat was associated with a reduction in weight of 16g/d and concluded that dietary fat plays a role in the development of obesity. The data, however, were criticised for being nonexperimental, short term, and nonrepresentative of world population. Regardless of these issues, scientists generally agree that a high-fat diet may promote obesity independently of its calorie contribution.
Viral Infection and Obesity
An interesting theory suggests that obesity is caused by a viral infection. Five different viruses have been shown to cause obesity in animals. AD-36, one of the viruses isolated in human is an adenovirus - from a family of viruses commonly associated with upper respiratory tract infections, which may cause enteritis and conjunctivitis. A recent study showed that serum samples obtained from obese subjects had a 30% prevalence of the human AD-36 virus compared with 5% for nonobese subjects. Researchers concluded that there is a strong association to show that human adenovirus causes obesity although the exact mechanism remains unknown at present.
Physical Activity
It has been shown that physically active individuals are less likely to gain weight and more likely to produce lean mass. They also have increased metabolic benefits with respect to blood lipid composition. Physical activity may also affect the distribution of body fat. An inverse relationship has been shown between levels of physical activity and indirect measures of body fat distribution, for example, waist-to-hip ratio. Some studies have shown that active men and women have lower waist-to-hip ratios than their sedentary counterparts.
Individuals who are physically inactive might also be predisposed to not engaging in physical activities because of muscle fibre types and metabolic characteristics - obesity-prone rats and obese people have an increased proportion of fast-twitch muscle fibres, which have decreased oxidative capacity and oxidize less lipid during steady-state exercise. Also, differences in the muscle oxidative capacity may influence the perceived level of fatigue and, hence, the capacity or tendency to be physically active.
In 1999, a randomised trial of the effects of lifestyle activity versus structured aerobic exercise in obese women found that after a 16-week period while on a low-fat diet, those in the aerobic exercise group lost on average 8.3 kg compared with 7.9 kg for the lifestyle activity group. In addition, improvements were found in systolic blood pressure and serum lipid and lipoprotein levels. The results confirmed that sedentary overweight individuals can reduce weight by adopting gradual and moderate intensity physical activity which contributes to enhanced weight management and improved cardiovascular risk profiles.
Other studies have shown that exercise enhances body image, boosts self-esteem, and improves mood.
Physical activity may facilitate weight maintenance and weight loss through direct energy expenditure and improved physical fitness. Regular exercise may help to equate fat intake with fat oxidation rates thereby reducing excess fat mass. This effect is very visible in professional athletes where the prevalence of obesity is close to zero.
Psychosocial Aspects
Psychology is an important aspect of human eating behaviour. Taste preferences and memories are uniquely involved in macronutrient selection, satiety, and feeding frequency; and activity-related behaviours are governed by attitudes to health and fitness.
The obesity epidemic is regarded by some to be caused by modern day lifestyle influences such as the 'comfort' eating of high-fat foods during times of emotional stress; the ingestion of high fat, high carbohydrate foods at regular family gatherings; and the 'silent' consumption of high-fat high-carbohydrate foods during long periods of inactivity (eg sedentary jobs, watching TV).
Overeating may be exacerbated by psychological distress - including poor mood, depression, and low self-esteem - and obesity may result from difficult life events such as abuse, addiction, or marital or family dysfunction.
Appetite Control
Research on obese individuals suggests that they are unable to control their appetite adequately. Studies show that following a covert energy preload, obese subjects had a reduced capacity to accurately compensate for the energy content of the preload at a subsequent meal compared with lean subjects resulting in overeating and increased energy intake.
Taste Perception
Studies suggest that the perception of tastes might influence the amount and type of food consumed. Fat in the diet has been shown to exhibit weak satiating properties and individuals readily overeat in response to high-fat foods. It has been shown that obese women expressed a preference for fat tastes, whereas anorectic, low BMI women expressed a preference for sugar rich foods.
External Cues
It has been shown that obese individuals are more sensitive to external cues such as the time of day, sight or smell of food. Interestingly, obese people eat more than normal weight people when food tastes good but eat less than normal weight individuals when it tastes bad. An increased responsiveness to food cues suggests that obese individuals may be more susceptible to overindulging during meal times. A study showed that obese diners were more influenced by the description or display of a dessert than nonobese diners.
Eating Disorders
A variety of psychological disorders have been associated with obesity and include anorexia nervosa and bulimia. Binge eating develops when individuals consume large amounts of food with the subjective sensation of loss of control. Social scientists have linked binge eating to the onset of obesity whereas others have linked it to emotional distress. There is also evidence of a higher level of personality disorders and depression among binge eaters.
Stress
Some evidence exists to show that emotional stress might play a role in the onset of obesity. Stress has been associated with overconsumption of high-fat foods and another theory suggests that obesity can be caused by stress through neuroendocrine pathways.
Environmental and Sociocultural Factors
Examples of the effects of the environment on obesity come from studies on the Naura people in Micronesia, and Polynesians in Western Samoa. These populations have experienced dramatic changes in diet and lifestyle over recent years and obesity prevalence has increased to over 60%. Familial studies have also shown that different environmental circumstances can alter average weight by as much as 25kg. For example, migrant Africans living in the Caribbean/US showed a significant increase in the prevalence of obesity compared with their native countries of Nigeria or Cameroon.
Studies of physical activity and body mass index from a variety of cultures have reported a sevenfold increased risk of overweight; and within developed countries there is a relationship between low levels of physical activity and an increased risk of becoming obese.
A strong class gradient has also been linked to the origins of obesity. Socioeconomic studies in the UK show that the prevalence of obesity among women ranges from 10.7% in high social classes compared with 25% in the lower social classes. It is thought that this effect might also be due to the types and quantities of food consumed, education about food and physical activity, and affordability of food.
Gender, ethnicity, familial hierarchies, and social and moral pressures are also associated with obesity but their true part in the onset of obesity is far from clear.
Copyright 2000
www.Understanding-obesity.com
University of Pennsylvania researchers say they have discovered a hormone that may be the long-sought link between obesity and Type II diabetes.
They say the hormone, which they have named resistin (for "resistance to insulin"), is produced by fat cells.
However, another expert says, while the finding is important, it may not fully explain the connection between obesity and diabetes.
Normally, the body turns food into a kind of sugar, called glucose, for fuel, and the hormone called insulin helps glucose enter our cells. In people with Type II diabetes, either their bodies don't make enough insulin or they are resistant to the hormone.
Type II diabetes accounts for 90 percent to 95 percent of the 15.7 million cases of diabetes in the United States. Meal planning, weight loss, exercise and blood sugar checks usually can keep this form of diabetes under control. Still, diabetes is the seventh leading killer in the country, contributing to nearly 200,000 deaths each year. Insulin can help, but the disease has no cure.
Obesity is a risk factor for Type II diabetes, but doctors haven't had a clear idea as to why. The latest study, published in the Jan. 18 issue of Nature, suggests that resistin may be a molecular link between fat cells and insulin resistance.
Senior investigator Dr. Mitchell Lazar, director of the Penn Diabetes Center, had been researching a fat cell receptor that appears to be the target for a class of antidiabetes drugs called thiazolidinediones (TZDs), which help insulin work more effectively.
Lazar and his team treated fat cells in a tissue culture and looked for genes that "turned off" after the cells were treated with TZDs. That led them to resistin. "Not only was it reduced by these antidiabetes drugs, but it was also increased in a number of models of obesity," says Lazar.
Condition improves without hormone His team studied mice that became obese by eating a diet of roughly 50 percent fat, which Lazar compares to eating fast foods. "What we found is resistin levels are very high under those conditions," he says.
To confirm that resistin was contributing to diabetes, and not just a marker of obesity, Lazar found that animals given the hormone could not handle glucose as well. When animals with high levels of resistin were injected with an antibody to neutralize the hormone, he says "their diabetes … improved."
"All those things together lead us to conclude that resistin really is a potential link between obesity and diabetes," says Lazar.
Creating insulin resistance by injecting resistin, and improving the resistance with an antibody takes the link "beyond being circumstantial," says Dr.Jeffrey Flier, a professor of medicine at Beth Israel Deaconess Medical Center in Boston, "The main thing the patient needs to keep in mind is that somehow, having more fat, especially in certain locations like the abdominal area, causes the complication of insulin resistance," says Flier. Beyond diabetes, insulin resistance also is linked to high blood pressure and coronary artery disease.
"Therefore, anything that can make the obesity go away … or, more directly, inhibit a specific molecule that makes obesity dangerous [would be helpful]. That's what resistin could be," says Flier.
Still, he says, "It would be very optimistic to say that this would be the main mechanism for insulin resistance." Currently, other mechanisms that trigger insulin resistance are being studied, and he says researchers still need to find out how important resistin is. Also, he says resistin's effect on cellular function must be determined.
Lazar says a compound to inhibit resistin could be found in one to two years, and, depending on how it performs during clinical trials, new therapies could be ready in roughly two to five years. But he says if resistin has other, as yet unknown functions, an inhibitor may have side effects. This area is currently under investigation.
SOURCES: Interviews with Mitchell A. Lazar, M.D., Ph.D., professor, Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine and Genetics, and director, Penn Diabetes Center, University of Pennsylvania, Philadelphia; Jeffrey S. Flier, M.D., professor of medicine, Beth Israel Deaconess Medical Center, Boston; January 18, 2001 Nature HealthSCOUT Date Published: Jan 18 2001 11:02:38 Date Reviewed: Jan 18 2001 11:04:55 NOTE: The above links will open a new browser window to an external site. You will be leaving drkoop.com. External sites are not part of, or recommended by, drkoop.com. drkoop.com has no control over the content and availability of these sites.
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January 2001
Insulin resistance, a disorder in which target tissues—muscle, fat, and liver cells—fail to use insulin effectively, accompanies and usually precedes type 2 diabetes. Eighty percent of people with type 2 diabetes are overweight, but the mechanism by which obesity sets the stage for insulin resistance and diabetes has long puzzled scientists.
A research team led by Dr. Mitchell Lazar, director of the Penn Diabetes Center at the University of Pennsylvania School of Medicine, discovered resistin while studying the thiazolidinediones (TZDs), a group of insulin-sensitizing drugs that includes the oral diabetes medications pioglitazone (ActosTM) and rosiglitazone (AvandiaTM). The researchers knew that the TZDs activate a nuclear receptor in fat cells called PPARgamma, which belongs to a family of receptors that regulate gene expression in response to hormones, vitamins, and some drugs. The researchers discovered resistin by screening fat cells for a gene that was inhibited by TZDs.
“It seemed likely that the TZDs were acting on PPARgamma to regulate a gene,” says Dr. Lazar. “We reasoned that this gene might encode a previously undiscovered fat cell hormone that impaired the actions of insulin on peripheral tissues. If the gene were overactive in obesity, it could explain the association between diabetes and obesity. And, if TZDs reduced the expression of this gene, we’d have an explanation for some of the benefit of the TZDs in diabetes.”
Resistin circulates in the blood of normal mice, falling after a fast and rising after feeding, and it dramatically rises in mouse models with genetic as well as diet-induced obesity. When the researchers administered resistin to normal mice, the animals developed impaired insulin action and glucose intolerance, precursors to type 2 diabetes. Treatment with the TZD rosiglitazone, however, decreased blood levels of resistin. Alternatively, administration of an agent that blocked resistin’s effects in mice with diet-induced obesity improved both insulin action and blood glucose.
“I don’t think it’s an exaggeration to say this is a blockbuster paper with potentially major clinical impact,” said Dr. Allen Spiegel, director of the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), the part of the National Institutes of Health that funded the research. “In one fell swoop, Lazar and colleagues have discovered a novel hormone secreted by fat cells, possibly explained how TZDs act as antidiabetic agents, and provided a key link between obesity and type 2 diabetes.”
Not only do blood levels of resistin in mice correlate with insulin resistance and diabetes, Lazar’s work suggests that increased resistin levels are one of the causes of type 2 diabetes. “If this observation also turns out to be true in humans, measuring resistin levels could help diagnose people at risk for type 2 diabetes. If resistin is really causing insulin resistance, then lowering levels of the hormone or blocking its action could constitute a new treatment for type 2 diabetes,” says Dr. Lazar.
About 16 million people in the United States have diabetes, the most common cause of blindness, kidney failure, and amputations in adults. Type 2, which accounts for about 90 percent of diabetes in the United States, is most common in people who are overweight, inactive, over age 40, and have a family history of diabetes. The disease is also more common in minorities: African Americans, Hispanic/Latino Americans, American Indians, and some Asian Americans and Pacific Islanders are at particularly high risk for this form of diabetes. With the onset of insulin resistance, the pancreas compensates by producing more insulin, but gradually its capacity to secrete insulin in response to meals falters, and the timing of insulin secretion becomes abnormal. After diabetes develops, pancreatic production of insulin continues to decline. Many people can control their blood glucose by following a careful diet and exercise program, losing excess weight, and taking oral medication. However, the longer a person has type 2 diabetes, the more likely he or she will need insulin injections, either alone or combined with oral drugs.
About 10 percent, or 1.6 million of people with diabetes, have type 1, formerly known as juvenile onset diabetes or insulin-dependent diabetes. This form of diabetes, which usually occurs in children and adults under age 30, develops when the body’s immune system attacks the insulin-producing cells of the pancreas.
This research was funded by the NIDDK under grant 5R01-DK-49780-06. Claire Steppan was supported by an unrestricted postdoctoral grant from Pfizer, Inc. Ronadip Banerjee is an M.D./Ph.D. trainee in the NIH-sponsored Medical Scientist Training Program. Elizabeth Brown was supported by a medical student research fellowship from the American Diabetes Association.
Director: Dr. Allen Spiegel National Institute
of Diabetes and Digestive and Kidney Diseases (NIDDK) is part of the National
Institutes of Health, Bethesda, MD, USA. General inquiries may be
addressed to Office of Communications and Public Liaison, NIDDK, NIH, Building
31, room 9A04 Center Drive, MSC 2560, Bethesda, MD 20892-2560, USA
from PMID 12368411:
In our rhesus monkey study, the fact that all
of the 15 monkeys had Ad-36 antibodies at some time during the 90-mo period
suggests a covert epidemic of Ad-36 infection in the rhesus monkey colony
at WRPRC. The source of Ad-36 infection in monkeys is not yet known. However,
transmission from humans is a possibility. Although most adenoviruses are
species specific in their replication cycle, we have recovered infectious
Ad-36 virus from Ad-36–infected chickens (6 ,7 ) and have detected naturally
occurring antibodies to Ad-36 in chickens as well as rats (unpublished
data). The ability of Ad-36 to infect and replicate in widely disparate
vertebrate species is in itself unusual. Therefore, the presence of naturally
occurring antibodies in rhesus monkeys to a human adenovirus is not very
surprising.
Obes Res. 2004 May;12(5):770-7. Related Articles, Links
Vangipuram SD, Sheele J, Atkinson RL, Holland TC, Dhurandhar NV.
Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA.
OBJECTIVE: Adenovirus 36 (Ad-36) has been shown to increase adiposity in experimentally infected chickens, mice, and marmosets (nonhuman primates). Neutralizing antibodies to Ad-36 are associated with obesity in humans. The metabolic and molecular mechanisms responsible for Ad-36-induced adipogenesis are unknown. As a potential adipogenic mechanism, this study examined if Ad-36 enhanced differentiation of preadipocytes. RESEARCH METHODS AND PROCEDURES: To determine the suitability of 3T3-L1 cells (murine preadipocyte cell line) as a model, the first experiment determined if Ad-36 attaches and initiates replication in the cells. Next, effects of Ad-36 on the number of differentiated adipocytes, glycerol 3-phosphate dehydrogenase (GPDH) levels, and cellular lipid accumulation were determined. The last experiment determined the effect of Ad-36 on human primary preadipocyte differentiation. Ad-2, a known nonadipogenic human adenovirus, was used as a negative control in these experiments. RESULTS: Immunofluorescence studies showed adenoviral attachment to 3T3-L1 cells, and reverse transcriptase-polymerase chain reaction showed expression of the Ad-36 E1A gene in the infected cells. Ad-36, but not Ad-2, increased the number of differentiated adipocytes, GPDH enzyme levels, and the total cellular lipid content. Also, Ad-36, but not Ad-2, increased GPDH levels in human preadipocytes. DISCUSSION: Taken together, these experiments showed that Ad-36 enhanced differentiation of preadipocytes, which may be a contributory mechanism to its adipogenic effect in vivo. The lack of effect of Ad-2 on differentiation demonstrated that the observed findings were not a common characteristic of all adenoviruses. Future understanding of the molecular interactions of cellular and viral genes responsible for enhanced differentiation may reveal novel signaling pathways and controls of preadipocyte differentiation. Copyright 2004 NAASO
PMID: 15166297 [PubMed - indexed for MEDLINE]
J Nutr. 2002 Oct;132(10):3155-60. Related Articles, Links
Dhurandhar NV, Whigham LD, Abbott DH, Schultz-Darken NJ, Israel BA, Bradley SM, Kemnitz JW, Allison DB, Atkinson RL.
Department of Nutrition and Food Science and the Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA. ndhurand@sun.science.wayne.edu
Although obesity has multiple etiologies, an overlooked possibility is an infectious origin. We previously identified two viruses, SMAM-1, an avian adenovirus (Ad), and Ad-36, a human adenovirus, that produce a syndrome of visceral obesity, with paradoxically decreased serum cholesterol and triglycerides in chickens and mice. In the two studies presented in this paper, we used nonhuman primates to investigate the adiposity-promoting potential of Ad-36. In study 1, we observed spontaneously occurring Ad-36 antibodies in 15 male rhesus monkeys, and a significant longitudinal association of positive antibody status with weight gain and plasma cholesterol lowering during the 18 mo after viral antibody appearance. In study 2, which was a randomized controlled experiment, three male marmosets inoculated with Ad-36 had a threefold body weight gain, a greater fat gain and lower serum cholesterol relative to baseline (P <0.05) than three uninfected controls at 28 wk postinoculation. These studies illustrate that the adiposity-promoting effect of Ad-36 occurs in two nonhuman primate species and demonstrates the usefulness of nonhuman primates for further evaluation of Ad-36-induced adiposity.
PMID: 12368411 [PubMed - indexed for MEDLINE]
J Nutr. 2001 Oct;131(10):2794S-2797S. Related Articles, Links
Dhurandhar NV.
The Department of Nutrition and Food Science and the Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48202, USA. ndhurand@sun.science.wayne.edu
In the U.S., the prevalence of obesity increased by 30% from 1980 to 1990, and this increase appears to be continuing. Although obesity has multiple etiologies, an overlooked possibility is obesity of an infectious origin. Six pathogens are reported to cause obesity in animals. Canine distemper virus was the first virus reported to cause obesity in mice, followed by Rous-associated virus-7, an avian retrovirus, which has been shown to cause stunting, obesity and hyperlipidemia in chickens. Next, the obesity-promoting effect of Borna disease virus was demonstrated in rats. Scrapie agents were reported to induce obesity in mice and hamsters. The final two reports were of SMAM-1, an avian adenovirus, and Ad-36, a human adenovirus that caused obesity in animals. Additionally, an association with human obesity is the unique feature of SMAM-1 and Ad-36. Although the exact mechanism of pathogen-induced obesity is unclear, infection attributable to certain organisms should be included in the long list of potential etiological factors for obesity. In addition, the involvement of some pathogens in etiology of obesity suggests the possibility of a similar role for additional pathogens.
PMID: 11584109 [PubMed - indexed for MEDLINE]
Obes Res. 1997 Sep;5(5):464-9. Related Articles, Links
Dhurandhar NV, Kulkarni PR, Ajinkya SM, Sherikar AA, Atkinson RL.
Department of Medicine, University of Wisconsin, Madison 53706, USA.
We previously reported that chickens infected with the avian adenovirus SMAM-1 developed a unique syndrome characterized by excessive intra-abdominal fat deposition accompanied by paradoxically low serum cholesterol and triglyceride levels. There have been no previous reports of avian adenoviruses infecting humans. We screened the serum of 52 humans with obesity in Bombay, India, for antibodies against SMAM-1 virus using the agar gel precipitation test (AGPT) method. Bodyweights and serum cholesterol and triglyceride levels were compared in SMAM-1-positive (P-AGPT) and SMAM-1-negative (N-AGPT) groups. Ten subjects were positive for antibodies to SMAM-1, and 42 subjects did not have antibodies. The P-AGPT group had a significantly higher bodyweight (p < 0.02) and body mass index (p < 0.001) (95.1 +/- 2.1 kg and 35.3 +/- 1.5 kg/m2, respectively) compared with the N-AGPT group (80.1 +/- 0.6 kg and 30.7 +/- 0.6 kg/m2, respectively). Also, the P-AGPT group had significantly lower serum cholesterol (p < 0.02) and triglyceride (p < 0.001) values (4.65 mmol/L and 1.45 mmol/L, respectively) compared with the N-AGPT group (5.51 mmol/L and 2.44 mmol/L, respectively). Two subjects positive for SMAM-1 antibodies had antibodies against each others' serum, suggesting the presence of antigens in one or both. When these two serum samples were inoculated into chicken embryos, macroscopic lesions compatible with SMAM-1 infection developed. The inoculation of serum from N-AGPT subjects did not produce such lesions. The presence of increased obesity, antibodies to SMAM-1, reduced levels of blood lipids, and viremia that produces a typical infection in chicken embryos suggests that SMAM-1, or a serologically similar human virus, may be involved in the cause of obesity in some humans.
PMID: 9385623 [PubMed - indexed for MEDLINE]