Overeating can lead to more eating, setting up a vicious cycle that promotes obesity. Now, a new study suggests one way this cycle works is that when the gut senses too many calories, it shuts off a hormone that tells the brain we are full.

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The new study suggests that when we eat too many calories, our gut stops producing a hormone that tells the brain we are full.

In the journal Nutrition & Diabetes, researchers at Thomas Jefferson University, Philadelphia, PA, describe how they came to this conclusion after observing mice on high-calorie diets.

In previous research on colon cancer using non-obese mice, the team had come across a hormone called uroguanylin that is produced in the small intestine and then travels to the brain where it signals fullness.

Building on their earlier work, senior author and professor Scott A. Waldman, chair of pharmacology and experimental therapeutics, and colleagues decided to explore how uroguanylin might be involved in promoting obesity.

They put mice on high-calorie, obesity-inducing diets for 14 weeks and monitored what happened to uroguanylin in their guts and brains.

The researchers found that the small intestines of the overfed mice stopped producing uroguanylin. Prof. Waldman notes:

“What’s interesting is that it didn’t matter whether the mice were lean and overfed, or obese and overfed – uroguanylin production stopped in both groups of animals when they got too many calories.”

When they examined the animals’ brains, the team found the receptors for the hormone were intact – and had even increased in number – showing it was lack of production rather than poor reception that had stopped the fullness signal reaching the brain.

When the overfed mice were then put on a low-calorie diet, their small intestines began producing the hormone again.

These effects are the opposite of what we know about other obesity-related hormones like insulin and leptin, Prof. Waldman explains. Production of these hormones goes up as weight increases, but here, “it’s not the obese state that’s causing the problem but rather it’s the calories,” he adds.

To discover what the underlying mechanism might be, the team examined the cells in the small intestine responsible for uroguanylin production.

They had a hunch that it might have something to do with the endoplasmic reticulum (ER) – a cell compartment that acts like a mini factory for proteins and hormones. The ER can stop working if it gets stressed.

When the researchers gave the mice tunicamycin, a chemical that causes ER stress, the animals stopped producing uroguanylin.

The team also found that giving overfed, obese mice a chemical known to relieve ER stress caused their gut to resume production of the hormone.

The researchers suggest in combination with other approaches, hormone replacement of uroguanylin may become an important component of therapy to reverse obesity.

However, a lot more research needs to be done first. As with cancer, there are many steps to becoming obese that are not easily reversed. Future studies need to find out, for example, whether the uroguanylin pathway is important early or late in the process, and how big an influence it has compared with other pathways.

Taken together, these experiments show that excess calories – either from fat or carbohydratesstress small intestinal cells so that they stop producing uroguanylin, which helps people feel full after eating. What we don’t know is how much is too much and what molecular sensor makes that decision.”

Prof. Scott A. Waldman

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