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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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August 7, 2006

A Vaccine Against Putting on Weight?

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Posted by Derek

I wrote here on the appetite hormone ghrelin, the target of much research over the last few years. The short background on it is that it's important in feeding behavior, growth hormone secretion, brain development, and probably several other things we haven't stumbled on yet. Drug companies have taken notice, synthesizing ligands for the ghrelin receptor in hopes of finding a new therapy for obesity (and in hopes that its other activities won't lead to unacceptable toxicity).

Now a team from Scripps reports in PNAS on a rather forceful approach: vaccination. They developed several candidate vaccines to induce an immune response against various regions of the ghrelin peptide, and tried them out on rats. The most effective ones caused the rats to gain much less weight than their non-immunized control partners, despite chowing on just as many calories. Consistent with what's known about ghrelin's actions, the change in weight was almost entirely achieved through smaller fat deposits - lean body mass was spared. The group is still working on figuring out what happens to the extra calories, but some ghrelin experiments have shown that animals become more active and have higher resting metabolic rates when its signaling is blocked.

The effects correlated well with the circulating antibody titers, which argues well for a real immune effect, and there were no signs of a general off-target inflammatory response. That's important, because messing with the immune system, as I like to say, is like the medieval attempts to summon demons from Hell. Unfortunately, black magicians had at least a vague idea of how they'd send back down whatever they called up, but calling off the immune system is another thing entirely. Once activated, it doesn't stand down easily. We're a long way from trying this out in humans, particularly given some of the recent troubles with cutting-edge immunulogical ideas.

Still, these results are quite interesting and exciting. But they're also confusing, though, and don't those three always seem to travel together. The odd thing is that experiments had already been done by other workers who infused anti-ghrelin antibodies into directly into the brains of test rats, who rather dramatically stopped eating. Those results were one of the things that got the drug companies excited, in fact. The present authors advance several possible reasons for the difference between their results and the earlier ones - perhaps ghrelin has a direct effect on feeding inside the brain compartment, but not out in the periphery, for one. Or perhaps the immunization in these experiments didn't have much effect inside the central nervous system, which is immunologically rather separate from the rest of the body. Another possibility is that some other feeding mechanism kicked in to compensate for any appetite decrease that might have otherwise been seen. These are just some of the possibilities; the paper has half a dozen more.

What's clear is that ghrelin signaling is powerful stuff, and that altering is might lead to just the sort of phenotype that many potential customers dream about: eat the same amount of food, but don't put on any fat. But it's also clear that ghrelin signaling is very poorly understood, and any number of things could come along to change the story completely. No, there are a lot of questions to be answered before people start lining up to be vaccinated against getting fat. But just the thought of it is going to have the headline writers cheering.

Comments (9) + TrackBacks (0) | Category:


COMMENTS

1. Chrispy on August 8, 2006 2:27 PM writes...


Weren't ghrelin agonists supposed to be the new smart drugs? Oh well -- I am sure that most Americans would rather be thin and stupid, anyway...

Permalink to Comment

2. clazy on August 8, 2006 5:21 PM writes...

Totally off topic, but since you've had some interesting things to say about Vioxx liability, I'd be interested in what you think about this piece that appeared in the NY Sun, called Justice Scams:
http://www.nysun.com/article/37517

Do you think completely fraudulent claims are a problem on the scale that this guy, who was a Merck Vioxx lawyer, says they are? Whether you want to comment, I figured you'd be interested in the piece.

Permalink to Comment

3. Greg Hlatky on August 8, 2006 5:55 PM writes...

Waiter! Steak! And make mine a double!

Permalink to Comment

4. JayP on August 9, 2006 7:49 AM writes...

Besides the scientific thrill about the existence of a "fat vaccine", lies the mere evidence that for the very large majority of people diagnosed as obese, excess calories intake coupled to lack of exercise is the sole reason of their condition. While the majority of mankind is suffering from hunger and dying from curable diseases (if existing medicines were made affordable), we have the luxury to spend billions in drug lowering cholesterol (convenience drugs) because we eat too much, or to think of developping vaccines so as to be able to eat as much as we can without getting fat. Again, only a very small fraction of patients are genetically prone to developp hypercholesterolemia, with its dangerous consequences, whereas the vast majority of people taking cholesterol-reducing drugs are just not making any efforts to control their diet. And now we are thinking of spending money on a "hunger" vaccine: I am clearly ashamed and disgusted that society in western countries can think of spending money to such futile goals, while the solution lies within reach of everyone! And to be complete, I don't feel the slightest sorrow for overweighted people besides those for which genetics has the last word.

JayP

Permalink to Comment

5. JayP on August 9, 2006 7:50 AM writes...

Besides the scientific thrill about the existence of a "fat vaccine", lies the mere evidence that for the very large majority of people diagnosed as obese, excess calories intake coupled to lack of exercise is the sole reason of their condition. While the majority of mankind is suffering from hunger and dying from curable diseases (if existing medicines were made affordable), we have the luxury to spend billions in drug lowering cholesterol (convenience drugs) because we eat too much, or to think of developping vaccines so as to be able to eat as much as we can without getting fat. Again, only a very small fraction of patients are genetically prone to developp hypercholesterolemia, with its dangerous consequences, whereas the vast majority of people taking cholesterol-reducing drugs are just not making any efforts to control their diet. And now we are thinking of spending money on a "hunger" vaccine: I am clearly ashamed and disgusted that society in western countries can think of spending money to such futile goals, while the solution lies within reach of everyone! And to be complete, I don't feel the slightest sorrow for overweighted people besides those for which genetics has the last word.

JayP

Permalink to Comment

6. Milo on August 9, 2006 11:27 AM writes...

JayP,

I hate to say this, but... Welcome to the U.S. of A.

Like you said, the science is great... but I see obese people at the local price club buying platters of Ding-Dongs and chicken wings. Something is wrong with this whole picture.

Permalink to Comment

7. Canuck Chemist on August 9, 2006 2:53 PM writes...

JayP, you may be right. But your belief that people are obese solely by choice is quite contentious. I personally don't see a big problem with helping people to lose some weight and get back in shape via pharmaceuticals, though of course permanent lifestyle changes would be much preferred in most cases. Don't forget about the huge health costs associated with obesity-- primarily diabetes and cardiovascular complications. Developing drugs to treat obesity could certainly be a net benefit to society under the present circumstances.

Permalink to Comment

8. Pam on August 12, 2006 12:31 AM writes...

Amen to Canuck Chemist!

Permalink to Comment

9. T on January 30, 2010 9:01 PM writes...

Answered a Scripps Ad 2 years ago for test subjects for human testing. Not chosen. Assume it was done. Any published outcome?

Permalink to Comment

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