Obesity is a major public health issue in America complicated by genetic factors and increasingly sedentary lifestyles, but overeating is also part of the problem. Though binge eating can be a serious disorder, overeating every once in a while is something we’ve all done. You overindulge a bit at Thanksgiving, and then you’re hit with that full feeling, which tells you not to eat any more.

This feeling is produced by several hormones that flow through your digestive tract, and a team of researchers from Thomas Jefferson University has just discovered that consistently overeating can stop this feeling and the hormones from working altogether.

“What’s interesting is that it didn’t matter whether the mice were lean and overfed, or obese and overfed,” said Dr. Scott Waldman, of the Sidney Kimmel Cancer Center at Jefferson, in a press release. “Here, it’s not the obese state that’s causing the problem but rather it’s the calories.”

In previous studies, the researchers noticed that a hormone called uroguanylin may be involved in obesity. In mouse experiments, non-obese subjects showed uroguanylin traveling to the brain to help produce a full feeling after eating. In obese mice, though, the way in which this signaling system operated was murkier. To explore this, Waldman led a new experiment involving more mouse subjects.

The team overfed a group of mice and observed that uroguanylin signaling was consequently disrupted. After taking a look at the small intestines of the mice, they saw uroguanylin was no longer being secreted. The brain still had its receptors for the hormone, and they had in fact increased in number. This meant the signaling disruption had been caused by a shutdown of uroguanylin production. When the researchers placed the mice on a diet, this production resumed.

After a closer look at the small intestine, the scientists discovered that the endoplasmic reticulum (ER), a network within cells that’s responsible for creating many proteins and hormones, was the root of the problem. If the ER gets too stressed, it can stop functioning.

The researchers applied a chemical known to cause stress to the mice’s ER, and saw their uroguanylin production halted just as much as when they had been overfed. On the flip side, overfed mice that weren’t producing the hormone were dosed with an ER stress-relieving chemical, and they began uroguanylin production normally again.

“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,” Waldman said. “What we don’t know is how much is too much and what molecular sensor makes that decision.”

Waldman explained that, like cancer, there are many factors that contribute to obesity, some of which are irreversible. The hormone leptin, for example, signals to the brain that the body has sufficient energy to go about the day. Being resistant to this hormone can contribute to overeating, and subsequently, obesity. Now, uroguanylin has become another targeted hormone.

“We don’t know yet whether it’s important early on in the process, or later, and how much of a role it plays,” he said. “But in combination with other approaches, hormone replacement of uroguanylin may become an important component of therapy to reduce obesity.”

Source: Kim G, Lin J, Snook A, Aing A, Merlino D, Li P, et al. Calorie-induced ER Stress Suppresses Uroguanylin Satiety Signaling in Diet-induced Obesity. Nutrition & Diabetes. 2016.