The way the stomach detects and tells the brains it’s full becomes desensitised in people with high-fat-diet-induced obesity and doesn’t return to normal once the weight is lost, according to a study my colleagues and I recently published in the International Journal of Obesity.
When we eat, nerves within the stomach wall signal to the central nervous system, indicating how much our stomach needs to distend and that we feel satiated or full.
Our previous laboratory experiments showed that these nerves are desensitised in mice that became obese via high-fat diets. As a consequence, their stomachs need to be a lot fuller before they feel full.
In the latest study, we found this dampening of nerve signalling is not reversible, which may explain why it’s so hard to maintain weight loss after reaching your goal weight.
Obesity is a serious risk to both physical and mental health, increasing the likelihood of heart disease, high blood pressure, diabetes and even some types of cancer. It is these health risks that often prompt obese or overweight individuals to modify their diet and lose weight.
But the experience of most obese people who lose weight through modifying their diet, is they return to at least their previous weight within two years. In fact, 80% of people who use a diet regime regain the weight (plus some extra) within two years.
So far, drug treatments mainly aimed at appetite control in the central nervous system have had limited efficacy or come with unacceptable adverse effects.
Targeting the initiation of the satiety signal in the gut – which tells the brain we’re full – is an attractive therapeutic option. However, before we can develop therapies for the treatment of obesity we need to fully understand how satiety signals in the gut are initiated; this is the research we are undertaking.
It’s a complex process, but in summary, the satiety signal from the gut involves the integration of both gastric and intestinal feedback signalling. Vagal nerves are a major pathway by which food-related signals, from the stomach and small intestine, access the brain to modulate food intake and associated behaviour.
Our brain’s perception of fullness following food intake depends on activation of these vagal sensors via two principle routes:
mechanical distension of the stomach (in other words, the stomach stretching)
the presence of nutrients which trigger hormone secretions from the stomach and small intestine.
A hormone in the body, leptin, known to regulate food intake, can change the sensitivity of the nerves in the stomach that signal fullness. In normal conditions, leptin acts to stop food intake. But in the stomach of those with high-fat-diet-induced obesity, leptin further desensitises the nerves that detect fullness.
These two mechanisms combined suggest that obese people need to eat more to feel full, which in turn continues their cycle of obesity.
We aimed to focus on how the nerves in the stomach respond to stretching of the stomach, how this is changed in high-fat-diet-induced obesity and importantly, whether any changes were reversible.
We designed an experiment with three groups of laboratory mice. Group one, the control group, was placed on a standard diet (with 12% of its energy derived from fat) for 24 weeks. The second group was placed on a high-fat diet (60% of the total energy of the food was from fat) for 24 weeks. And the third group was placed on the high-fat diet for 12 weeks and then put back onto the standard diet for a further 12 weeks.
At the end of the 24-week diet period, we tested the stomach’s response and found the high-fat diet group’s nerve response was dramatically reduced compared to the control group. In the group that was initially fed a high-fat diet then put back on to the standard diet for an equivalent amount of time, the response was still dramatically reduced. There was no sign of reversal.
In addition, this group ate considerably more food than the other two groups and though they initially lost weight, by the end of the 24-week diet period, they were on a trajectory to regain all of the weight lost.
Although we studied animals, the results help explain the lack of success of weight-loss management. This leaves one key conclusion: prevention is better than cure.
The fundamental mechanisms involved in the activation of these sensors are just beginning to be understood, with more work to be done in investigating the role of these physiological processes in appetite regulation.
Further studies by myself and colleagues aim to determine how early this desensitisation occurs and thus whether it is the high-fat diet or the obese state that is causing the changes in nerve responses. We also need to investigate whether nerves regain their sensitivity in longer experiments.
Finally, and perhaps most importantly, we need to determine what is causing this desensitisation and whether it can be targeted as a therapy for obesity.