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Diet and lifestyle

Hope for overweight people: one hunger signal stands out

Signals from our stomach and intestines control how hungry we feel. Incorrect signals can lead to overeating and eventually overweight. Blood levels of appetite-regulating hormones usually increase when we eat, but one hormone stands out. Blood levels of ghrelin, a hormone released from the stomach, increase between meals, increasing our appetite. Researchers hope to be able to develop more effective forms of treatment for overweight people by understanding how the body regulates the secretion of ghrelin.

Everyone knows the feeling of hunger. However, we do not know enough about the mechanisms that regulate appetite and food intake. A complex system of hormones and nerve impulses manages the communication between the brain and the gut. Disturbances in this signal path can lead to developing lifestyle-related diseases such as obesity and diabetes. The path back to normal weight can be both long and torturous.

“Although the secretion of most appetite-regulating hormones increases while we eat, the concentration of ghrelin rises in the period leading up to meals, and this is believed to be one of the triggers of food intake. Ghrelin levels in blood decline immediately after a meal, and various gut hormones are implicated as possible mediators. However, the findings have been inconsistent. If we can clarify the mechanisms underlying the reduction in ghrelin levels after food intake, we may be able to develop new strategies to reduce the feeling of being hungry among overweight people,” explains main author Simon Veedfald, Department of Biomedical Sciences, University of Copenhagen.

The gut’s symphony orchestra

Gastric bypass surgery has been used to combat severe obesity in recent years. This intervention reduces the size of the stomach and bypasses the duodenum. This means that nutrients arrive at a part of the small intestine to which they normally do not, and this is the part with the greatest density of cells that secrete the appetite-inhibiting hormones.

“This stimulates the intestines to release remarkable amounts of appetite-lowering hormones. Ghrelin levels are also altered after gastric bypass surgery. The ghrelin concentration in the blood declines after the surgery but then increases again after some time. The mechanism behind this is still unexplained. It is an incredibly complicated system of hormones and neural pathways – almost like a symphony orchestra – each contributing to the whole.”

Previous studies have shown that the vagus nerve, the primary nerve pathway between the stomach and the brain, influences the secretion of ghrelin. The vagus nerve is similar to two thick electrical cables that run on either side of the oesophagus.

“It is like an information highway between the brain and the gut and other organ systems. The nerve fibres in the vagus nerve collect information on the state of the gut. After integrating these inputs, the brain formulates relevant responses, which the vagus nerve then transmits back to the intestine. The vagus is involved, among other things, in regulating gastrointestinal motility and acid secretion in the stomach. A study carried out in rats has also suggested a role for the vagus. This led us to examine the importance of the vagus for fasting and postprandial regulation of ghrelin in humans.”

A new treatment?

When a person fasts, the concentration of ghrelin in the blood rises. However, previous studies with rats showed that this does not happen to the same extent in the absence of the vagus nerve. Researchers confirmed this among people whose vagus nerve had been severed as a result of previous duodenal ulcer or cancer. Their concentrations of ghrelin were lower than those of people in the control group.

“The concentration of ghrelin in the blood among the people with a severed vagus nerve, however, still declined after they had eaten. The vagus nerve is therefore not essential for eating-related declines in the concentration of ghrelin. This is an important finding because it suggests that the factor regulating postprandial ghrelin secretion is more likely to be a circulating factor. Although we do not fully understand this complicated mechanism, we have made some progress.”

The new study also sheds light on understanding the regulation of ghrelin, and this may turn out to be very important for treating obesity in the future. Another gut hormone, glucogen-like peptide-1 (GLP-1), has previously been reported to suppress the secretion of ghrelin, but the new study does not support this.

“This suggests that the effect of GLP-1 on appetite regulation is separate from that of ghrelin. GLP-1 is already being used today to create an artificial feeling of satiety in the brain. The fact that GLP-1 does not act via ghrelin indicates that additive effects might be elicited by exploiting the GLP-1 signalling pathway together with an approach that lowers circulating ghrelin.”

Ghrelin secretion in humans – a role for the vagus nerve?” has been published in Neurogastroenterology and Motility. Several authors are employed by the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

Simon Veedfald
Assistant Lecturer
Ghrelin, an orexigenic peptide, is secreted from endocrine cells in the gastric mucosa. Circulating levels rise in the preprandial phase, suggesting an anticipatory or cephalic phase of release, and decline in the postprandial phase, suggesting either the loss of a stimulatory factor or inhibition by factors released when nutrients enter the intestine. We hypothesize that vagal signals are not required for the (i) preprandial increase or (ii) postprandial suppression of ghrelin levels. We investigate the hypothesis that (iii) glucagon-like peptide-1 might be implicated in the postprandial decline in ghrelin levels.