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The Stomach as a Target for Obesity

Credit: MartesiaBezuidenhout/adobe

Credit: MartesiaBezuidenhout/adobe

By Amanda Page

Obesity permanently changes the way our body processes gastrointestinal signals about satiety. While appetite suppressants have had limited success, the identification of an appetite-regulating nerve channel offers a new approach to keeping weight off.

Australia is now ranked as one of the fattest nations in the world, with 14 million Australians currently overweight or obese. By 2025 it is predicted that about 80% of Australians will be overweight or obese (

Due to the increasing prevalence of diseases associated with obesity, it is now the biggest threat to public health in Australia. It has overtaken smoking as the leading cause of illness and premature death. To put this into perspective, the World Health Organisation estimates that overweight and obesity are responsible for about 45% of diabetes, 23% of heart disease and 7–41% of certain types of cancer globally.

One of the major problems is that obesity is very resistant to behavioural interventions such as diet and exercise. Of the individuals who manage to lose weight, only about 5% maintain that weight loss – and this only with a high degree of self-monitoring.

People who become obese no longer regulate their appetite or metabolism in the same way as an individual who has never been obese. While drug therapies have targeted the central nervous system to control appetite, they have had limited effect or unacceptable side-effects.

Currently the most effective treatment for obesity is bariatric surgery. However, surgery is not a practical solution for the increasing number of obese people due to the high costs and associated mortality rates. Bariatric surgery is reserved for severely obese individuals with a body mass index (BMI) greater than 40, or individuals with a BMI greater than 35 but with obesity-related comorbidities where drug therapies or lifestyle changes, such as diet and exercise, have been unsuccessful.

If we can develop safe and relatively inexpensive medications that mimic the effect of bariatric surgery then perhaps we can prevent the onset of severe obesity and the co-morbidities associated with it. With this in mind there is renewed interest in the role of the gastrointestinal tract in appetite regulation, energy intake and blood glucose control.

The stomach and small intestine play complementary but distinct roles in appetite regulation. In the stomach wall there are vagal afferent nerves that detect stretching as food enters and gradually fills the stomach. The activated nerves signal to the brain where stretching is occurring, leading to changes in gastrointestinal motility, movement of food through the gastrointestinal tract and also feelings of fullness and satiety.

In the wall of the small intestine there are specialised enteroendocrine cells that detect specific nutrients. In response they release peptides or hormones that affect appetite and play a role in the control of blood glucose. Released hormones can either enter the circulation or act directly on vagal afferent nerves in the small intestine.

Enteroendocrine cells are also present in the stomach, but the hormones released modulate the response to mechanical stretch rather than having a direct effect on the nerves. For example, ghrelin is an appetite-stimulating hormone produced by the stomach. Ghrelin reduces the response of stretch-sensitive nerves in the stomach, and thus reduces the satiety signals generated in the stomach.

Vagal afferent nerves represent a highly plastic connection between the gastrointestinal tract and the central nervous system, responding to both nutrients and appetite-regulating hormones. This plasticity is essential to ensure appropriate functionality in the everyday control of food intake.

However, this system is extremely susceptible to disruption by a high-fat diet and obesity. Our laboratory studies of obesity in mice have shown that the responses of these nerves to stretching of the stomach is significantly dampened in obesity induced by a high-fat diet. As a result, the stomach needs to be much more full to give the same feelings of satiety.

This is a common feature along the gastrointestinal tract. The response of small intestinal nerves to certain gastrointestinal hormones is also reduced in high fat diet-induced obesity.

Reducing or delaying the satiety signal generated in the gastrointestinal tract will delay the cessation of eating, thus perpetuating the obese state. If we can understand the mechanisms behind these changes then perhaps we can target a therapy to prevent the onset of obesity and the complications associated with this disease.

The transient receptor potential vanilloid channel (TRPV1) is best known as a mediator of noxious or painful stimuli. Activation of TRPV1 in pain-sensing nerves leads to painful burning sensations. For example, activation of TRPV1 channels by capsaicin, a component of hot chilli peppers, is responsible for the hot burning sensation experienced when eating hot chillies.

However, TRPV1 also has physiological roles that aren’t associated with pain, including a possible role in the regulation of metabolism. It’s been suggested that targeted activation of TRPV1 channels might provide a pharmacological therapy for the treatment of obesity.

TRPV1 channels are expressed in the vagal afferent nerves innervating the gastrointestinal tract. In mice that have been genetically modified so they have no TRPV1 channels, the response of nerves to stretching of the stomach is significantly reduced, indicating that TRPV1 channels play a role in satiety signalling from the gut.

There is also an increase in daily food intake in these mice. While this may be due to reduced satiety signalling from the stomach, at present there is no direct evidence for this.

If these mice are then fed a high-fat diet there is no further reduction in the response to stretch. This suggests that the dampened satiety signalling in cases of obesity induced by a high-fat diet is due to disrupted TRPV1-mediated responses within nerves innervating the stomach.

If we can restore or improve the function of TRPV1 channels in these nerves then perhaps we can enhance the feelings of fullness and terminate food intake sooner. This is particularly relevant because an individual’s metabolic response after weight loss does not return to its pre-obesity state.

If mice are placed back on a normal diet for an equivalent amount of time that they were on the high-fat diet then the response to stretch is not returned to normal; the dampened response of nerves innervating the stomach to stretch remains. Therefore it’s possible that the disruption in function of TRPV1 channels is maintained even after weight loss.

This may be one of the reasons it is so difficult to maintain weight loss. If we can restore or improve the function of TRPV1 channels it will have implications not only on weight loss but also weight maintenance.

In addition to the dampened response to mechanical stretch there are also changes in the effect of gastric hormones on nerves innervating the stomach. As mentioned before, the gastric hormone ghrelin reduces the response of gastric nerves to stretch. This reduction is enhanced in high-fat diet-induced obesity, further reducing the satiety signal from the stomach.

Perhaps more significant is the change in effect of the satiety hormone leptin, which is secreted by fat cells. Leptin circulates to the brain, where it controls the long-term regulation of food intake.

Leptin is also found in the stomach, where it modulates the activity of nerves in response to mechanical stimulation. Interestingly, the effect of leptin on gastric nerves switches from appetite suppression in lean conditions to appetite stimulation in high-fat diet-induced obesity.

The mechanism behind this switch in effect is unknown and currently under investigation. An understanding of this switch could have huge implications for the pharmacological treatment of obesity.

In summary, vagal nerves relay information about food intake from the gastrointestinal tract to the central nervous system, where it is processed and initiates feedback on the control of food intake. It is a highly plastic system that adapts to changes in energy levels and appropriately signals the requirements for food intake.

However, this system is susceptible to disruption by conditions such as high-fat diet-induced obesity. Understanding the mechanisms behind these disruptions in function will reveal ways to overcome the changes observed in high-fat diet-induced obesity and establish new peripheral targets for the pharmacotherapy of obesity.

Amanda Page is a Senior Research Fellow at The University of Adelaide’s Centre for Nutrition and Gastrointestinal Disease.