CRP Blocks Action of Leptin in the Obese

Occassionally it happens - I'm stumped by something published in a research paper or from a study. I'm usually stumped because something within the findings or conclusions don't sit right with my understanding of the subject at hand or I don't have enough foundation of the subject at hand to completely "get" the gist of things.

Today, MyDNA's article, What Causes Obesity?, stumped me with the researchers' conslusions. Maybe one or more of my readers will have some insights that will help me better understand why the conclusions are valid - how's that for a teaser? I'm obviously stumped on this one because it's not sitting right with my understanding of the subject at hand!

First though, some background from the article above:

Research data from the University of Pittsburgh suggests that obesity is due — at least in part — to an attraction between leptin, the hormone that signals the brain when to stop eating, and a protein called C-reactive (CRP). The amount of fat regulates the amount of leptin produced by the body: the more fat, the more of the hormone. Obese people produce higher levels of leptin, but somehow they're resistant to its effects. This has led researchers to focus on the interaction between CRP and leptin, which is actually Greek for the word "thin."

Zhao said that the binding of CRP, which is also elevated in obese people, to leptin might help explain why the hormone is not effective.

Zhao said his study suggests researchers should focus their attention on an approach that disrupts the interaction between leptin and CRP, which would allow the hormone to resume its regulatory role.

You may be wondering - why is she stumped?

I'll explain.

Everything above sounds reasonable - someone is obese, they have high levels of leptin being excreted which should be signaling the brain and regulating energy intake well...but CRP is binding the leptin and effectively blocking its path....so, let's block the CRP action and the leptin can get back to doing its job.

Something with this screams out to me this is the wrong and I base that on my understanding of C-Reactive Protein and its role in what's called "complement biology."

As a simple definition, CRP is a plasma protein - an acute phase protein - produced by the liver. It's a marker in the blood that indicates an inflammatory response to injury - like an overt injury when you sprain your ankle or when something is going on internally in your body - an obscure injury or assault - like when you come in contact with bacteria that can make you ill. Both of these inflammatory responses resolve and the levels of CRP decline again once the potential for permanent harm are no longer an issue.

In both cases, the CRP acted in its complementary role with the immune system to target and destroy or neutralize a potentially harmful situation. In the example of the sprained ankle, the inflammatory response was stimulated to help "clean up" the injured site and limit movement during that process - the pain limits mobility to the body can take care of the injury. In the example of the bacteria, the inflammatory response was stimulated to flag the invading microbes for destruction and elimination from the body.

I hope this detail provides some insight to my understanding of the role of CRP - it works together with the immune system to neutralize something that has the potential to negatively affect well being. The target of inflammatory response is any substance that stimulates an immune response. The substance most often the cause, when the injury is not overt physical injury - proteins or polysaccarides (although any type of molecule that has potential for harm can trigger it).

The reason I'm stumped by the idea we should block the CRP if it's binding the leptin is that leptin is a protein, produced by adipose tissue (fat). The more adipose tissue an individual has, the more leptin they secrete. The findings from the University of Pittsburgh tell us that this leptin is being blocked because it is being bound by CRP and the suggestion is that if we can block the action of the CRP, we can allow the leptin to do its work in regulating appetite again.

Why are the researchers not asking the question "is the leptin levels causing the inflammatory response?"

To me, it seems like the assumption is that the higher levels of leptin are good - what's bad is its not able to do its job because the CRP is inhibiting its action when it binds to it.

But what if the higher levels of leptin are bad - harmful - and that is causing the inflammatory response in an effort to limit damage?

What if the inflammatory response is exactly what we are supposed to see - and the cause of that inflammatory response is what we must resolve for the body to regain equilibrium?

On its face, the issue to be resolved is rightly the obesity. What I don't understand is how blocking the action of the CRP binding the leptin will resolve that. Perhaps a better approach isn't to block the inflammatory response that is limiting the high level of leptin, but to resolve the cause of the weight gain in the first place!

The research conclusion leads one to see:

Leptin => Appetite Control => Weight Regulation

CRP blocks Leptin => Block CRP Action => Leptin Appetite Control => Weight Loss

But....what if the path is this instead:

Poor Diet => Weight Gain => Elevated Leptin => Inflammatory Response to limit damage from high Leptin

Food for thought, isn't it?