Research Review: Get vaccinated… against obesity
What if there were a vaccine that prevented obesity?
This fall, many of you undoubtedly wonder whether you should get the H1N1 flu vaccine.
Many of you have decided to get vaccinated and you may have waited in long lines to get it. (Or you took up hockey.)
I’m not going to get into the great H1N1 vaccine debate, but I’m going to start a new vaccine debate.
If there was a vaccine against obesity, would you get vaccinated?
What if it meant you could eat whatever you want?
Is there an obesity vaccine?
Yes, it seems that researchers have made a vaccine to treat obesity. The vaccine doesn’t go after an obesity virus, but a small protein (aka peptide) that facilitates uptake of glucose and fat.
This peptide is called gastric inhibitory protein, or GIP, also known as glucose-dependent insulinotropic polypeptide.
It’s the Holy Grail of obesity. Okay, I might be exaggerating a bit, but it comes darn close. You see, GIP is a peptide hormone made by the large intestine (the duodenum, to be exact) that helps your body take in glucose and fat.
GIP tells the beta-cells of the pancreas to release insulin. That tells the tissues to take up glucose that is in the blood. GIP also gets triglycerides out of the blood and into tissue – such as fat cells (adipocytes).
If you have no GIP then you can eat as much as you want and not get fat – at least if you’re a mouse (1).
In 2002, a group made genetically modified mice that had no GIP receptor. In that case, GIP became ineffective.
Instead of getting rid of the key (GIP), they broke the lock (GIP receptor). Without a working GIP receptor, (GIPR) then GIP couldn’t work to unlock the metaphorical door. No GIPR = no GIP activity.
When they got rid of GIPR (GIPR-/-) it turned out these mice couldn’t get fat – even on a high fat diet that made normal mice fat. Using what is called receptor agonists, researchers could block GIP activity and make getting fat nearly impossible (2-4).
Note: Receptor agonists are decoys. Instead of the proper protein attaching to the receptor, this agonist attaches, which blocks the proper protein and thus causes the signal to be blocked. It’s like someone stealing your parking spot, leaving you (the proper protein) driving around the lot, quietly cursing.
In the case of GIP, a GIP agonist would attach to the GIPR (GIP receptor), which then blocks GIP from attaching to the receptor and triggering a chain of events.
Where does the vaccine fit in? I’ll tell you in the Methods section.
Fulurija A, Lutz TA, Sladko K, Osto M, Wielinga PY, Bachmann MF, Saudan P. Vaccination against GIP for the treatment of obesity. PLoS One. 2008 Sep 9;3(9):e3163.
What are non-genetically engineered organisms supposed to do if they want to block GIP? Researchers have to come up with another way to make this process work.
They decided to use the host’s own immune systems. Usually, your body doesn’t go after its own proteins or anything that it considers “self”. Your body knows its own cells and everything they make.
However, sometimes your body gets confused and starts attacking itself — a situation known as autoimmunity. With this experiment the scientists, in sense, create a very specific autoimmune disease – one that attacks GIP.
Tricking the immune system – a GIP vaccine
The first step in creating an autoimmune disease for a specific protein is to get the attention of the immune system. How do you do that? You attach a virus-like particle (VLP).
Your immune system doesn’t like viruses. It’s always on the lookout for them. Anything that looks even remotely like a virus gets red-flagged.
VLPs get the attention of the immune system. Once flagged, the immune system makes antibodies against VLPs and anything attached to VLP – like, say, GIP.
Thus, VLP-GIP protein is basically a vaccine against GIP. Once injected, the body attacks GIP the same way it would attack any other known virus.
So you probably figured out that this experiment wasn’t done on humans. Causing any sort of autoimmune disease, no matter how specific, is considered a no no. Like most studies of this nature, the “participants” were mice.
Researchers injected mice with the VLP-GIP protein like an immunization.
Then, some mice were put on a high fat diet (35% fat w/v) and some were put on standard mouse chow (4% fat w/v).
First, the researchers checked that the mice were making antibodies against GIP using a technique call ELISA (enzyme-linked immunosorbent assay or enzyme immune-assay). This is important to make sure the vaccine actually worked.
The researchers weighed and checked body fat by dual energy X-ray absorption (DEXA) scans to figure out body fat (yes there are mouse X-ray machines and MRIs).
And they figured out how much energy each mouse expended by putting them in special metabolic cages that measured all the oxygen used and all the carbon dioxide produced.
There were four main findings in this experiment:
- Good news! The vaccination worked! The mice made GIP antibodies.
- The vaccinated mice were less fat (35% less) than the unvaccinated mice while on a high fat diet.
- However, there was no difference between the groups when on a normal diet of mouse chow.
- Now the cool part. Being vaccinated against GIP increased how much energy the mouse used. In other words, GIP vaccination increased the vaccinated mice’s metabolism.
The first three points are pretty straightforward. But the increase in metabolism needs a bit more explanation.
When fed the high fat diet, the GIP-vaccinated mice used more oxygen (VO2) at any given time and they had a higher metabolic rate, but there was no difference in activity (figured out by how often the mice broke a light beam) and no difference in food intake. Thus, the GIP-vaccinated mice had a higher metabolism.
And even though activity levels weren’t considered statistically different, they appeared to be “real-world” different. The vaccinated mice tended to be more active. With more mice the researchers could figure out if there were, in fact, any real activity differences.
A few important things to point out:
- Differences between unvaccinated and vaccinated mice didn’t occur until they were fed a high fat diet.
- Vaccinated mice on a high fat diet gained less weight then their unvaccinated friends, but they still gained weight.
- There was no change in lean tissue despite the increase in metabolism.
You might be asking yourself how could there be an increase in metabolism without an increase in lean (i.e. muscle) tissue? Chances are, the subtle differences in activity levels are what caused the change in metabolism.
Before you run off looking for the human version of the GIP vaccine, remember that the differences between vaccinated and unvaccinated mice only happened on a high fat diet. The vaccinated mice still gained weight. And you’re not a mouse.
As interesting as these experiments are, they are limited in how well they translate to humans… but they’re still pretty cool.
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