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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.
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