Overeating shuts down gut satiety hormone and blocks calorie sensing pathway, research suggests

A new study on the role of gut incretin hormones in preventing overeating behaviours has found that the lack of production of one of them can interfere with post-prandial gut-brain axis signalling of the feeling of fullness.
Pathways by which the gut senses how much food we eat and relays that information to the brain are well-documented, but the biochemical reasons why they can become dysfunctional were unclear until now.
These findings, published in the journal Nutrition and Diabetes, add new insights to the existing body of knowledge on gut hormones, also called incretin hormones that are secreted by the small intestines in response to a meal.
Under normal circumstances, when the gut senses too many calories, some of these hormones promote the feeling of fullness that naturally stops us from overeating.
This new research elaborates on a particular hormone, known as uroguanyli, which has been the subject of earlier obesity-related studies.
These showed that in non-obese mice, uroguanylin travels to the brain to induce satiety. But what happened to this default signalling in obese animals was not clear-cut.
In the current study, researchers from the Sidney Kimmel Cancer Center at Jefferso, noticed that the small intestines of mice who were overfed had stopped producing uroguanylin.
They were able to rule out an inefficiency or absence of receptors for uroguanylin in the brain of the animals, as those were intact and had even increased in number. The hormone itself was just not being made anymore.
The team tested whether overeating had caused its production to shut down and found that when the mice were put on a diet, the uroguanylin production resumed.
The re-synthesis of this hormone was not dependent on the mice’s fitness either, as its production stopped in animals that were lean and overfed, like it did in those obese and overfed. It is the opposite of what’s been observed for other obesity-related hormones like insulin and lepti, whose production increases as weight increases.
Dr Waldma, the head of the research department, concluded that it’s not the obese state that’s causing the problem but rather the calories. In further research, he and his team discovered how overeating shuts off uroguanylin production via a very important organelle found in the cells of the small-intestine.
The endoplasmic reticulum (ER), helps produce many of the body’s proteins and hormones, can stop functioning when it is stressed. Animals that were overfed and obese could override the overeating-induced uroguanylin down-regulation when given a chemical that relieved ER stress. This suggests that ER stress can be caused by overeating.
Although these experiments haven’t determined how much excess calories – either from fat or carbohydrates – is too much and what other molecular sensor makes that decisio, hormone replacement of uroguanylin is thought to become an important component of therapy to reverse obesity.