FXR receptor key to success of sleeve gastrectomy

The therapeutic value of vertical sleeve gastrectomy is not a result of the mechanical restriction of a smaller stomach but the result of increased circulating bile acids that are known to bind to the nuclear receptor farsenoid-X receptor (FXR), according to researchers from the University of Cincinnati (UC), the University of Gothenburg, Sweden, and Cincinnati Children's Hospital Medical Center.

Randy Seeley

"There are very large debates over how small to make the sleeve," said co-principal investigator, Dr Randy Seeley, professor in the endocrinology, diabetes and metabolism division at UC and director of the Cincinnati Diabetes and Obesity Center. "Conventional thought is when you make the stomach smaller, patients lose more weight because they have less room to put more food and, therefore, eat fewer calories. But as it turns out, the reason why the surgery works is that you are changing the bile acids."

The research, 'FXR is a molecular target for the effects of vertical sleeve gastrectomy' was published online in Nature, showed that following vertical sleeve gastrectomy, there is a change in bile acids that bind to a nuclear receptor called FXR. In the absence of FXR, weight-loss success and improvement in diabetes from vertical sleeve gastrectomy was reduced.

Although substantial changes in circulating total bile acids are known to occur after sleeve gastrectomy and bile acids are known to regulate metabolism by binding to the nuclear receptor FXR (farsenoid-X receptor, also known as NR1H4), the underlying molecular mechanisms are unknown.

As a result, the researchers examined the results from sleeve gastrectomy applied to mice with diet-induced obesity and targeted genetic disruption of FXR. Despite having a smaller sleeve, the rodents without the FXR receptor did not lose weight.

Because bile acids and FXR receptors interact with gut microbial communities, the researchers also looked at gut bacteria after sleeve gastrectomy. They found that the surgery also results in changes in the gut bacteria.

"Importantly, we observed changes in several key bacterial groups that have been previously linked to the risk of Type 2 diabetes, and these changes were related to FXR and bile acids," said Dr Karen Ryan, lead author and assistant professor of endocrinology, diabetes and metabolism at UC.

"Manipulating the gut bacteria is another way we think that we might be able to mimic how surgery works without having to do the cutting and stapling," said Seeley. "There are not enough surgery tables or surgeons to treat the obesity epidemic, so we need to understand how bariatric surgery works so that we can offer more scalable solutions.”

This work was supported by grants from the UNIK Food Fitness and Pharma for Health and Disease research programme, the Torsten Söderberg and Novo Nordisk foundations, Ethicon Endo-Surgery, and the National Institute of Health’s National Institute of Diabetes and Digestive and Kidney Diseases and National Heart, Lung and Blood Institute

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