When the gut senses too many calories, a pathway that promotes the feeling of fullness becomes blocked, according to researchers from Thomas Jefferson University in the US.

They looked at mice who were overfed, and saw that the small intestines of these mice had stopped producing uroguanylin.

The receptors for uroguanylin that reside in the brain were intact, and had even increased in number, but hormone itself was no longer being made, suggesting that overeating had caused its production to shut down, researchers said.

However, when the animals were put on a diet, the guanylin production resumed, they said.

"What is interesting is that it did not matter whether the mice were lean and overfed, or obese and overfed – urogaunylin production stopped in both groups of animals when they got too many calories," said Scott Waldman from Thomas Jefferson.

To find out how overeating shuts off uroguanylin production, researchers looked at the cells in the small-intestine that produce the hormone.

They suspected that the endoplasmic reticulum (ER) might be involved. The ER is an cellular organelle that serves as the production line for many of the body's proteins and hormones, and can stop functioning when it is stressed.

When researchers applied a chemical, tunicamycin, known to cause ER stress, mice stopped producing uroguanylin, much as they did when they were overfed.

Finally when overfed, obese, mice were given a chemical that was known to relieve ER stress, the animals once again began producing uroguanylin, suggesting that overfeeding caused the ER stress that in turn shut down uroguanulin production, researchers said.
    
"Taken together, these experiments show that excess calories - either from fat or carbohydrates - stress small intestinal cells so that they stop producing uroguanylin, which helps people feel full after eating," said Waldman.

"Like in cancer, there are many steps on the way to becoming obese that are not easily reversed. In combination with other approaches, hormone replacement of uroguanylin may become an important component of therapy to reverse obesity, he said.

The findings were published in the journal Nutrition & Diabetes.

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