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The Molecular Mechanism of Sleeve Gastrectomy



sharma-obesity-verticalsleevegastrectomyIn recent year, vertical sleeve gastrectomy (VSG), which involves removing large parts of the stomach, thereby reducing it to the size of a small banana, has gained in popularity in bariatric surgery.

Although slightly less efficacious, it is a far simpler procedure to perform than the “classic” Roux-en-Y gastric bypass.

According to popular wisdom, the reason why VSG works has to do with mechanically reducing the volume of the stomach (thereby creating a physical “restriction”), whereby effect on gastric ghrelin secretion may or may not also play a role in reducing hunger (the science on this is somewhat unclear).

Now, a paper by Karen Ryan and colleagues from the University of Cincinnati, published in Nature, provides a completely new explanation for the molecular mechanism by which this surgery appears to work.

The study was prompted by the observation that VBG leads to profound changes in circulating bile acids. Bile acids are now known to bind to a nuclear receptor (farsenoid-X-receptor or FXR for short) which plays an important role in fat and glucose metabolism.

Using a rather elegant series of studies in mice, Ryan and colleagues demonstrate that the weight loss effect of sleeve gastrectomy has little to do with reducing the size of the stomach. Rather, almost all of its effect on body weight appears to be mediated by the effect of this surgery on circulating bile acids and accompanying changes in gut microbial flora.

The researchers also clearly demonstrate that much of the weight loss with SVG is dependent on a functional FXR, without which (as in FXR knockout mice) the surgery has little effect on body weight or glucose metabolism.

This demonstration of the importance of bile acids and FXR signalling as an important molecular mechanism for why VSG actually works is important because it means that this surgery could possibly be mimicked by pharmacological interventions that target bile acid and/or FXR.

In fact drugs that stimulate FXR (e.g. obeticholic acid) are already being considered for other indications including fatty liver disease and type 2 diabetes.

Given the remarkable efficacy of VSG surgery, the possibility of providing the same benefits in a pill are clearly attractive.

@DrSharma
Edmonton, AB

ResearchBlogging.orgRyan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R, Wilson-Pérez HE, Sandoval DA, Kohli R, Bäckhed F, & Seeley RJ (2014). FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature PMID: 24670636

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10 Comments

  1. That is very interesting, but it does somewhat (recklessly IMHO) disregard the overwhelming first hand testimony of people who have had VSG and who find the physical restriction a very useful tool in the fight against over-eating. In my 1st hand experience, physically being unable to eat a large meal has been a huge help, meaning that I and forced to split meals or choose a much smaller portion, knowing I cannot physically eat a large one. Of course I have experienced biological/chemical effects as well, such as feeling sick after a relatively small amount of processed sugar, but to say “the weight loss effect of sleeve gastrectomy has little to do with reducing the size of the stomach” is very wrong in my 1st hand experience. Ultimately, VSG is a tool that helps you achieve your weight loss goals and it’s by no means a 100% easy fix, so any positive effect it has shouldn’t be casually dismissed, especially not the physical restriction which has a measurable effect even when the stomach isn’t sectioned (as with a gastric band).

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  2. As a patient who is looking forward to VSG this summer, and having lost 80lbs in establishing a lifestyle, I have to agree with Keith in that I think the physical capacity feedback on intake volume is important. I trust and hope that patients reading your blog continue to discuss their concerns with their medical team or doctor to ensure that this research is framed not only in potential and grounded in reality – that a pill protocol for obesity management is many years away and perhaps up to a decade before we see one.

    Now that researchers have identified the mechanism of FXR, there appears at this point no way to predict the efficacy of FXR and the extent of potential weight loss. As a patient, this finding is very interesting but many questions remain as well as an established approved pharmaceutical protocol. I hope others in line for VSG are not going to postpone their surgeries in hope of a taking a pill. It will be many years before taking a pill will solve the obesity issue – and even then I suspect vigilance and satiety awareness will remain as a factor contributing to weight loss.

    Keep up the good work Dr. Sharma! I would only state here that in this article a bit of a disclaimer for patients awaiting VSG shouldn’t abandon having their surgeries based on this research. Not all folks reading this blog are lucky enough to be cared for an multi-disciplinary team that can and will field questions and concerns of their patients.

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    • Thanks for the comment Mark – yes, FXR therapy is still somewhere in the future – no reason to cancel your surgeries just yet.

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  3. In N.S. surgery for VSG is up to 10 years wait. Now in my 4th year.

    Humour…….pills may be here before surgery.

    Would be wonderful though. Thanks for your site.

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  4. Wow. How incredibly interesting.
    I’m an obesity clinic nurse, I had been under the impression that restricting stomach size was the key factor in VSG’s success. I didn’t know that about bile acids before. It’s interesting to note that things are changing on a molecular level as well.
    As I learn more about how the liver and pancreas work together, it becomes quite clear that the liver is important in glucose regulation and fat metabolism. Fascinating stuff.

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  5. Thanks Dr. Sharma! LOL! No I certainly not going to cancel it all! I have worked far too hard and and waited patiently (pun intended).

    Chelsey and Dr. Sharma…I know this isn’t the purpose of this blog…but how does this FXR mechanism relate to the Krebs cycle – which is all about cell metabolism.

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  6. If FXR indirectly suppresses the rate limiting enzyme in bile acid production, CYP7A1, why does removing a fraction of the stomach (where FXR presumably lives) lead to a higher level of bile acids? I’d think a diminished number of gastric FXR sites postop would lead to diminished suppression of CYP7A1, and thus a greater blocking of bile acid production?

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  7. I have a Duodenal Switch, so I have both a Sleeved stomach and an intestinal bypass. 10+ years post-op, I still have significant restriction, but I can eat enough food that without the malabsorption of calories my DS gives, I’d be fat again.

    I think this is great news, and hopefully it will reverse the trend towards making ever-smaller Sleeves. Back when I was researching. no one complained of developing GERD post-op, but as Sleeves have become smaller and smaller, I see more and people with this problem.

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  8. Nice post!!! Thanks for sharing a such kind of information with us. Sleeve Gastrectomy has reduce the size of stomach.Keep Posting..

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