THE mice in Maria Rupnick’s lab eat like pigs. They’ve always got their snouts in the trough. “If they’re awake they’re eating, and if they’re not eating they must be asleep,” says Rupnick, who works at Brigham and Women’s Hospital in Boston. Needless to say, all this scoffing has made them a little tubby – in fact they look like furry baseballs with legs.
The mice belong to a strain with a mutation that makes them constantly hungry, and they have been at the front line of medical research into obesity for decades. Despite scientists’ best efforts, however, there are still no chemical fixes for the epidemic of obesity sweeping the west. Drugs have been developed to boost metabolism, suppress the appetite, even block fat absorption in the gut – but none is an effective long-term solution. Existing diet drugs usually cause only a small loss in weight, and are not supposed to be taken for longer than a year because question marks hang over their safety for prolonged use.
With the help of her congenitally greedy mice, however, Rupnick has hit on a completely new approach to tackling fat. She has found a way to shrink adipose tissue by melting away its blood supply. Her inspiration has come from an apparently unrelated field of medicine – cancer research. One of its hottest topics at the moment is the development of “angiogenesis inhibitors”, drugs that block the growth of new blood vessels to supply tumours. Rupnick’s work suggests these agents are even more effective at shrinking fat than they are at throttling tumours. It could eventually lead to the development of more effective weight-loss drugs that patients could take safely for years. And in a neat twist, her latest findings point to a way of destabilising the blood vessels that supply tumours, making them just as susceptible to angiogenesis inhibitors as the capillaries feeding fat tissue.
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An effective way of treating obesity is long overdue. Increasingly unhealthy eating habits and inactive lifestyles have led to a growing epidemic of obesity – the biggest health problem facing developed countries. In England, the incidence of obesity has trebled in the last two decades, to around a fifth of all adults. Australia faces a similar problem, and things have got even worse in the US, where about a third of adults are now obese. Those surplus pounds of flesh exact a heavy price on health through heart disease, type 2 diabetes, joint problems and cancer.
Judah Folkman certainly wasn’t thinking about fat when he first developed his angiogenesis theory of cancer, more than 30 years ago. While working as a surgeon at the Children’s Hospital Boston, he came up with the controversial idea that to grow beyond a certain size, tumours must stimulate the formation of new blood vessels to provide them with nutrients and oxygen.
We now know there are numerous compounds whose natural role in the body is either to promote the growth of blood vessels or inhibit them. Much research has gone on around the world into drugs that can shrink a tumour’s blood supply, either using versions of natural angiogenesis inhibitors, or agents that block a tumour’s own angiogenesis promoters. The great thing about such molecules is that, unlike standard chemotherapy, they are non-toxic. The field has suffered a few setbacks over the years, but in February the first drug specifically developed to inhibit angiogenesis was approved: a medicine called Avastin, which has been licensed in the US. The molecule is a monoclonal antibody that blocks a tumour’s angiogenesis promoters.
When Rupnick joined Folkman’s team of angiogenesis researchers in 1989, she became interested in whether angiogenesis affects the growth of other tissues apart from tumours. As a cardiologist, she wanted to find out if blood vessel growth controls the way cardiac tissue repairs itself after a heart attack. Conventional thinking at the time had it that angiogenesis does not happen in healthy adult tissues, outside of pregnancy and menstruation. So Rupnick was at a loss for a way to investigate the process.
Then she had a brainwave – fat. She points out it is the only tissue that retains the capacity to grow or regress substantially throughout life. “That’s a normal part of its function. If you decide to eat 10 pizzas then you’re going to gain weight – regardless of how stable your weight has been for decades – because your adipose tissue will expand.” And as every surgeon who has sliced into it knows, fat has an excellent blood supply. In previous research, Rupnick used fat as a rich source of the endothelial cells that make up capillary walls. Perhaps, she wondered, fat’s ability to burgeon or shrink in times of feast and famine depends on changes in its blood supply.
The strain of mice she used to test her hypothesis are born to be obese. Called ob/ob mice, they make an inactive version of the appetite-suppressing hormone leptin, so they are always famished. Rupnick and her colleagues treated 8-week-old animals with angiogenesis inhibitors for three weeks, half-expecting they might not get any fatter and half-hoping they might shed a few grams. They were in for a surprise. “Not only did they not gain weight, they lost substantial amounts,” she says. “It was dramatic.”
Tests confirmed the mice were indeed shedding adipose tissue, not muscle. After three weeks some weighed less than half as much as controls, while remaining perfectly healthy. The drugs also worked on genetically normal mice that had gained weight on a high-fat diet (Proceedings of the National Academy of Sciences, vol 99, p 10730).
One of the most surprising findings was that they didn’t just inhibit new blood vessel growth in adipose tissue, they also made some established vessels regress. With tumours, there is only a narrow window of opportunity during which angiogenesis inhibitors work, and that is just after new capillaries have formed. At this point they are still immature and will regress if they encounter an inhibitor, says Rupnick. “But once the vessels are established, they’re not vulnerable.”
Rupnick’s findings suggest that at least some of the blood vessels in fat tissue never get properly established. They are more like the metal roads laid by armies to supply temporary camps, designed to be extended or dismantled within hours. This leaves them vulnerable to angiogenesis inhibitors. However, even in fat tissue it seems some of the vessels do mature as the animal ages, because older obese mice shed less weight on the drugs than younger animals.
Rupnick’s work has led to a new understanding of the interplay between the chemical signals that determine whether a tissue’s blood supply grows or regresses. It’s not just the balance of angiogenesis promoters and inhibitors that dictates whether blood vessels grow or retreat, Rupnick has found. The maturity of the vessels is also crucial. This raises the intriguing possibility that by either artificially rejuvenating or maturing blood vessels you could make them more or less susceptible to angiogenesis inhibitors.
In November last year, Rupnick described how she injected ob/ob and normal mice with angiopoietin-1, a growth factor already known to mature blood vessels. She found the mice had a reduced ability to gain weight compared with controls (Biochemical and Biophysical Research Communications, vol 311, p 563). It is still in the realms of theory, but using a drug to block maturation factors like this could make obese mice – and humans – more susceptible to angiogenesis inhibitors. Rupnick speculates that even people who have been overweight all their lives could benefit from taking a combination of an “immaturity promoter” and an angiogenesis inhibitor.
There is a clear need for effective obesity drugs that are safe to take for years – perhaps for a lifetime. As anyone who has struggled with their weight knows, losing pounds in the short term is relatively easy – the real challenge is keeping them off. In the past, says Rupnick, doctors have had little sympathy for patients who regained weight. But there’s a growing realisation that obesity is a lifelong medical condition, like diabetes or high blood pressure. “Just because we get someone’s blood pressure under control we don’t say, ‘OK, it’s up to you now’,” says Rupnick. But suitable drugs that can be taken for years are simply not available.
Only two existing weight loss therapies can be used safely for more than a couple of months at a time, and even they are not recommended for longer than a year. One, called orlistat, blocks fat digestion in the gut, but has several unfortunate side effects – including anal leakage of undigested fat. Sibutramine, which increases the feeling of fullness after eating, works by raising levels of the neurotransmitter serotonin in the brain. Like other psychoactive drugs, there is a theoretical risk of abuse, and the drug can also raise blood pressure – a bad side effect in this group of patients. These drugs certainly work, says Steve O’Rahilly, who researches the genetics of obesity at the University of Cambridge, “but there’s a limit to how much weight comes off, and there’s an inexorable tendency for it to come back after treatment stops.” Like Rupnick, he believes obese patients need drugs they can take long-term, as with any other chronic disease.
O’Rahilly has reservations about the wisdom of using a drug to directly reduce the size of fat stores. If the patient is still eating as much as ever and not exercising, what happens to those surplus calories? “Fat is the safest place to store excess calories,” he says. “If you restrict the size of fat depots, that excess has to go somewhere – such as the liver, muscles or pancreas, which are not designed for this purpose.” Rupnick counters that mice treated with angiogenesis inhibitors have a raised metabolic rate – they are somehow burning off the excess calories, not stashing them away elsewhere. And their appetites decline dramatically while they are losing weight.
Precision targeting
Another objection to angiogenesis inhibitors as an obesity treatment is that, theoretically, they could damage the immune system. Caroline Pond, an adipose tissue expert at the Open University in the UK, points out that the so-called minor fat depots associated with lymph nodes distributed around the body are essential for mounting a defence against infection. Angiogenesis inhibitors could deplete these as well as the major fat stores. The mice in Rupnick’s experiment may have seemed healthy, but any damage to their immunity would be masked in the sterile lab environment, she says.
Rupnick acknowledges that this could be a problem. Her team tried to monitor the effect of the drugs on the minor fat depots, but in mice these are so tiny it was hard to judge their size accurately. To be certain, studies with larger animals are needed.
Pond is concerned, too, about the possible effect on wound healing, which also requires new blood vessel growth. But Folkman points out that this has only proved to be a problem with some of the angiogenesis inhibitors tested as anti-cancer drugs, not all. Different agents seem to target blood vessel growth in particular tissues. For example, a natural angiogenesis inhibitor called endostatin blocks vessel growth in tumours but not in wound healing. A more potent inhibitor called TNP-470, on the other hand, does slow healing. “You can’t generalise,” he says. “It’s like the different activities of antibiotics – so too with angiogenesis drugs.”
So, in theory at least, you could target an angiogenesis inhibitor at the major fat stores, without harming the immune system or affecting wound healing. “Maria’s work is compelling proof that [blood vessels] control normal tissue as well as malignant tissue,” says Folkman. He cautions, however, that no one yet knows whether angiogenesis inhibitors would make people lose enough weight for them to be medically useful.
Those kinds of questions can only be answered by clinical trials. Rupnick’s team has taken out a patent on the technology and hopes a commercial partner can be found to develop the concept into a marketable drug. William Li, president of the Angiogenesis Foundation, a non-profit group based in Cambridge, Massachusetts, says the possibility of this drug class making the leap to obesity treatments is exciting. As well as the recently approved Avastin, some 50 angiogenesis drugs are in clinical trials worldwide. “It’s quite possible that efforts in the war against cancer will yield dividends in the war against fat,” he says.
And the benefits aren’t just one-way. Rupnick’s finding about the importance of blood vessel maturity could help in the use of angiogenesis inhibitors as anti-cancer agents too. Perhaps you could soften up a tumour’s blood supply to make it more vulnerable to inhibitors, she speculates. “Certain tumours may be failing to respond to inhibitors because their vessels are simply too mature,” she says.
Indeed, the link between fat, blood vessels and cancer may run even deeper. Obese people are known to have higher death rates from cancer, including liver, breast, colon, pancreas and kidney. Li wonders if this is because they have raised levels of angiogenesis promoters in their bodies. The work of Rupnick and others shows that fat is a greedy tissue, sending out signals to recruit more blood vessels to feed it, and evidence is emerging that the same signals could predispose people to certain tumours. A study published by Cancer Research UK last October showed a link between higher levels of oestrogen circulating in the blood of obese women and their risk of developing breast cancer (Journal of the National Cancer Institute, vol 95, p 1218). Fat cells produce oestrogen, which is a powerful angiogenesis promoter.
The irony, says Li, is that many of us already take angiogenesis inhibitors every day without even knowing it, and they could be protecting us from cancer and keeping us thin into the bargain. A long list of dietary factors strongly inhibit blood vessel growth, among them resveratrol in red wine, as well as genistein in soya, catechins in green tea and brassinin in Chinese cabbage. “Obesity is traditionally less of a problem in Asian countries where many of these foods are consumed,” he points out. Perhaps even ravenous ob/ob mice would stay thin on an unlimited diet of soy cheese, bok choi and green tea.
Rupnick isn’t planning research along those lines, but she does hope her findings will lead to better drug treatments for obesity. “The consequences are devastating in terms of heart disease, diabetes, stroke, cancer,” she says. “If our research can translate into a treatment for a condition that has reached epidemic proportions in the developing world, that will be a worthwhile contribution.”
