Friday, April 14, 2006

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, 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?


  1. Very interesting post! Good detective work. I see what you've uncovered as another example of the disease management mindset of contemporary medicine in which scientists and researchers feel no compunction whatever about disrupting an important metabolic pathway to achieve a particular result. Blocking CRP may restore appetite control to the obese, but what other horrific consequences may result from poorly controlled inflammation? Unfortunately, inventinging a designer molecule to block the action of CRP will be worth billions to some pharmaceutical company.

  2. Thank you for pointing out another one of the flawed or at least preoccupied mindsets of common scientists. I still try to grasp the mening behind it al. I've read that sleeping badly decreases leptin levels... or sleep yourself slim. How does this fit the bill? It is a rather complex problem (and I guess the fact that rather common problems such as female hormones or ADD come into the equation for people like me doesn't make things easier) and I feel that the narrow minded view of traditional 'research' doesn't help , really...

  3. Seems like this is the way to treat "diseases" today. Block the production, and if you can't then block the action, stimulate the production or enhance the action! Forget about figuring out why something is "too high" or interferes with something else, etc. It's so much easier to make money on drugs.....and hey, you might even get a bonus when many have to get other drugs to handle the side effects of the first drug!

    I bet those poor guys in England would be wary of trying anything that interferes with the body's normal function! (The men who tested the immune system "stimulant" which proceeded to stimulate the immune system into trying to destroy their own bodies!)

  4. If this is true, and I hesitate to accept it on the basis of unpublished research, then anything that blocks CRP should have a slimming effect. This is where it breaks down, because it is well known that steroids and NSAIDS's cause, if anything, weight gain rather than weight loss. Come again? We block the production of CRP and it causes weight gain. As I said before, we need to see the research and consider whether the researchers are oversimplifying the biochemical pathways involved. Thanks for your time and attention.

  5. In response to Mark, this research was published in the April issue of Nature Medicine.

    Yes, it is an oversimplification to say that disrupting the CRP-leptin interaction will be a panacea for all those suffering from obesity. It's primarily the media that interprets it as such, based on press releases. The actual paper is far more conservative in its discussion of potential therapies.

    True, a drug company may try to market a "miracle drug", but the true benefit will probably mostly be limited to people with specific deficiencies. For example, a person may have a polymorphism in their leptin gene that forces an excessively tight CRP-leptin assocation.

  6. At the risk of turning this into a group discussion, my point was that steroids, the most potent anti inflammatory drugs, are associated with weight gain. NSAID's, non steroidal anti inflammatory drugs are cited by the late Dr. Atkins as a potential culprit in weight stalls. These are anti inflammmatories, which would, presumably, tend to block the actions of C reactive protein(CRP). If the hypothesis is that CRP blocks that action of leptin in signalling satiation and therefore weight control, then anti inflammatories which interfere with the effects of CRP should allow leptin to do its job when in actual fact they appear to have the opposite effect. This is not to say that the research may not be valid, but that the situation may be considerably more complex.

  7. Mark, I think you are correct when you point out how complex the situation is. That's why I think it's important to notice key terms in this news, such as when they say obesity is due- at least, "IN PART" and that crp binding leptin "might help" explain why the hormone is not effective. The press release also specifically mentions that a therapeutic approach would disrupt the interaction between leptin and CRP (as opposed to lowering inflammation thus reducing PRODUCTION of CRP). By this, he means the actual physical interaction, not necessarily interfering with upstream regulatory points that will have far more complex consequences, as is the case with steroids.
    Anti-inflammatories don't interfere with the effects of CRP, they REDUCE the effects of CRP by reducing its production (thereby reducing its level in the blood). Such a downstream effect is just one of many generalized effects in the body, and it's obvious, with respect to weight gain, that there are other systems that compensate for lower CRP in individuals that gain weight while taking steroids.

    An unfortunate fact is that misinterpretation of this press release will give false hope to some for a "miracle cure" while for others it'll produce further skepticism about modern medicine (which is not always misplaced). But, hey, it's obesity, and such a hot topic helps sell papers. The reality is that this is simply a piece of information about a previously unknown regulation point in a very complex network regulators and feedback loop. It's almost certain that at least SOME of the population would benefit from therapies utilizing this information, it just remains to be seen who exactly those are and how we will identify them.

  8. Greg, Thanks for your thoughtful and analytical response. You are clearly reading these press releases more carefully than I am.

  9. Mark and Greg - I found your comments interesting. What Regina wrote was quite interesting also.

    Maybe you can help me. I am 58, and in the last 3 years since my father died and my going through menopause, have put on 25 kg. The psychological effect of seeing his body (predominantly a skeleton with skin stretched over it) so thin, created an imbalance in my life. I survived on cups of tea and bread rolls throughout the day and ate very little protein, and vegetables etc. For a while now I have been eating better, yet still very small portions, and no junk food. Can't for the word of me lose that weight, and searching frantically for something, that's how I stumbled over this site. Yes I exercise.

  10. What if the response is from an actual infection or virus. The result would be identical. I believe that many people are walking around with infections, bacteria and viruses. It is possible that many Americans are overweight because of these things that is causing inflamation which then causes in increase in CRP.

  11. Ivo Kattestaart5:53 PM

    What food in high doses causes inflammatory response and hart diseases? Its vegetable oils, like sunflower. Or worst Fast food fat. And we western people use a lot in our food chain. Indeed something to think about!

  12. Anonymous10:41 PM

    Great post.