The findings are in response to the burgeoning global obesity crisis, where public policies and industry commitments have been accompanied by a range of studies which target biological mechanisms.
It is hoped that research outcomes may pave the way for new management approaches for obesity and its associated conditions.
Appetite outcomes
Published in the Nutrition and Diabetes journal, researchers from Thomas Jefferson University, isolated the hormone uroguanylin as a central protagonist in regulating appetite.
Previous studies by the team had shown that in non-obese mice, uroguanylin would travel to the brain where it produced a feeling of fullness. However, this signalling remained a mystery in obese subjects.
Here, the intestines of overfed mice were found to cease production of uroguanylin. However, when the animals were put on a diet, the uroguanylin production resumed.
Obesity is a global pandemic and more than 1.5 billion adults are overweight, 500 million of whom are obese. According to the UN Food and Agriculture Organisation, the UK has the highest level of obesity in Western Europe, ahead of countries such as France, Germany, Spain and Sweden.
Obesity levels in the UK have more than trebled in the last 30 years and, on current estimates, more than half the population could be obese by 2050.
The team also found the brain’s uroguanylin receptors had even increased in number, suggesting that overeating had caused the hormone’s production to be switched off.
“It didn't 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 Dr Scott Waldman of the Sidney Kimmel Cancer Center at the university.
This is in contrast to what has been observed for other obesity-related hormones like insulin and leptin, which are produced in greater quantities as weight increases.
Here, it's not the obese state that's causing the problem but rather it's the calories.
Waldman and his colleagues began the second stage of their experiments, identifying the endoplasmic reticulum (ER) as a gateway for uroguanylin and hormone production.
When the team gave a chemical called tunicamycin to the mice, they stopped producing uroguanylin, similar to when they were overfed.
When overfed, obese mice were given another chemical so that they began producing uroguanylin again, indicating that overfeeding caused the ER stress that had switched off uroguanulin production.
"These experiments show that excess calories 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 aren't easily reversed. The uroguanylin pathway appears to be one of those steps, we don't how much of a role it plays," he added.
"In combination with other approaches, hormone replacement of uroguanylin may become an important component of therapy to reverse obesity."
Hormone’s brain links
The uroguanylin hormone pathway has emerged as central to the regulation of feeding, energy homeostasis, body mass and metabolism in normal physiology in rodents.
In addition, like mice, the consumption of nutrients promotes uroguanylin secretion into the circulation as part of the gut–brain axis in humans as well.
“The observations seen in this study suggest a novel mechanism that contributes to obesity in which diet disrupts the uroguanylin gut–brain endocrine axis,” the study noted.
“However, preservation of the uroguanylin receptors in the brain in diet-induced obesity suggests the feasibility of a therapeutic involving hormone replacement to manage obesity and its comorbidities.”
Source: Nutrition & Diabetes
Published online ahead of print, doi: 10.1038/nutd.2016.18
“Calorie-induced ER stress suppresses uroguanylin satiety signaling in diet-induced obesity.”
Authors: GW Kim et al.