Treatment of obese monkeys with experimental drug
Researchers have found that obese monkeys lost an average about 11% of their body weight after four weeks of treatment with an experimental drug that selectively destroys the blood supply of fat tissue. This may have implications for the treatment of obesity in humans.
Norman Swan: Let’s stay with fat cells but focus on weight loss because extraordinary research into cancer may have turned up a possible weight loss medication and it’s recently been tried out on a group of obese chimpanzees.
Kirstin Barnhart is a pathologist at the Keeling Center for Comparative Medicine and Research in Texas where they study non-human primates. It’s part of the MD Anderson Cancer Center in Houston.
Kirstin Barnhart: The obese monkeys I’ve been famous now for calling them couch potatoes, they are obese entirely on their own. They’re in the same housing, the same husbandry and nutritional conditions that the other primates are, they just choose not to exercise and they love their food.
Norman Swan: They’re naughty monkeys.
Kirstin Barnhart: They’re naughty monkeys. They’re kind of like humans aren’t they?
Norman Swan: How fat are they?
Kirstin Barnhart: They’re all considered obese. The heaviest monkey would be considered morbidly obese by human standards with a BMI of 53.
Norman Swan: And are they really waddling around and having trouble, do they get diabetes and everything like humans do?
Kirstin Barnhart: They can. They can get pre-type 2 diabetes, which is just insulin resistance, and it really depends on how heavy they are. The largest monkey with a BMI of 53, we can’t get him to exercise. Most monkeys love to jump up and down and hop on their perches and fly from side to side, this monkey is on the ground with his elbows on his knees waiting for the next treat to come to him. But some of the heavier ones, they can still go up and down and do some of the normal monkey activities, they just choose not to.
Norman Swan: And how does a medication to help obesity emerge out of a cancer lab?
Kirstin Barnhart: We chose to treat fat essentially like a tumour. It’s uncontrolled growth that nobody wants and if we can use the same mechanisms we use to starve cancer cells, why can’t we do that in fat? Doctors Pasqualini and Arap, their drug platform was based on blood vessels. Blood vessels provide nutrition, oxygen to all of our tissues. Cancers are very capable of creating their own blood supply which nourishes and sustains their undesirable growth. Drs Pasqualini and Arap identified specific zip codes, specific little peptide sequences that were unique to vessels. In other words if you had a prostate tumour they could find a zip code in the blood vessels supplying your prostate tumour that were unique to that. In this case they were able to identify a specific sequence in the blood vessels that supply fat, white fat, which is the bad fat and only white fats and once they showed in animal models the specificity of this peptide, this generated the immense excitement, that ‘wow guys, we have something that uniquely targets fat’.
Norman Swan: So they had a bullseye on fat vessels.
Kirstin Barnhart: Correct.
Norman Swan: So it’s one thing having a bullseye, the other thing is having an arrow that’s going to hit it.
Kirstin Barnhart: We found the bullseye you’re exactly right, they developed then a peptide sequence that would hone to the bullseye.
Norman Swan: So a peptide sequence is a -
Kirstin Barnhart: It’s a line of things called amino acids. They identified a peptide, a small chain of amino acids that knew exactly how to hone to the bullseye and then they took it one step further. They took what we call a payload. The arrow took the payload to the bulls eye.
Norman Swan: And blew up the blood vessel.
Kirstin Barnhart: And blew up the blood vessel. So now what happens to the fat when you’ve blown up the blood vessels? It has no nourishment, it has no oxygen and it’s slowly going to lose its ability to sustain itself in such a large overgrown fashion. And that’s their drug.
Norman Swan: And so they showed that it worked in mice and you’ve tried it in your fat monkeys?
Kirstin Barnhart: Yes, what we saw in the mice and then subsequently some rat studies was that all of them lost weight. Today we’ve never had an animal, a mouse, a rat or a monkey get the drug that hasn’t lost a substantial amount of weight.
Norman Swan: And it’s killing the fat cells or destroying the fat inside the cells?
Kirstin Barnhart: How the fat subsequently breaks down and is absorbed by the body and eliminated those mechanisms haven’t been elucidated yet. What we do know is that there are no adverse effects associated with all this rapid breakdown and removal of fat. We’ve looked in the blood, we’ve looked in the liver, we’ve looked in many, many, many tissues in many primates and rodents and the mechanism just does not seem to induce any toxicity in the fat.
Norman Swan: And it’s the fat everywhere, the dangerous fat inside the abdomen, the fat in your arms, the fat on your breast, fat everywhere?
Kirstin Barnhart: It’s white fat and the predominance of white fat for most people who are overweight is what we call visceral fat, that’s the fat that’s inside your abdomen, it’s around your internal organs, it’s around your liver that is the most metabolically bad fat.
Norman Swan: Does the fat regrow in your monkeys?
Kirstin Barnhart: I can’t answer that question as specifically as you probably would like. What I can say is that when the drug stops within several weeks the weight plateaus and about six months after treatment all the monkeys are up to their pre-treatment weight.
Norman Swan: So the drug’s got to be given continuously to have a long-term effect?
Kirstin Barnhart: The drug has to be given continuously to have a long-term effect and currently we have only looked at the effect of a certain dose level given for 28 consecutive days. In non-human primates given 28 consecutive days we know that they’re going to lose between seven and a half and 15% of their body weight. But I think this drug and any weight loss drug that gets developed has to be looked at as a way to get people back to a healthy weight and a healthy lifestyle. You give them a year to learn to eat well again, to lose enough weight to be able to exercise again. You give them a fighting chance to implement the lifestyle changes that they need, so that when they come off the drug they can maintain that.
Norman Swan: And no damage to other organs?
Kirstin Barnhart: There has been damage to the kidneys associated with the actual clearance of the drug. We’re actively working on modifying the drug to take away that property. One of the other things to point out that was demonstrated in our monkeys which we’re very excited about is we also saw an average of 50% improvement in insulin resistance. And in a large part it’s probably due to the decreased volume of visceral fat that these monkeys on MRI clearly show they have a lot. This is a huge lifestyle improvement and a reduction in a risk factor for people who are overweight and subsequently at risk for cardiovascular disease, thrombotic disease and some pretty undesirable sequelae.
Norman Swan: Dr Kirstin Barnhart is a pathologist at the Keeling Center for Comparative Medicine and Research which is part of the MD Anderson Cancer Center in Houston Texas.
Barnhart KF et al. A Peptidomimetic Targeting White Fat Causes Weight Loss and Insulin Resistance in Obese Monkeys. Science Translational Medicine 9 November, 2011;3(108):108ra112
- Dr Kirstin Barnhart
- Assistant Professor and Pathologist,
MD Anderson Cancer Center,
University of Texas,
- Dr Norman Swan
- Brigitte Seega