Oxyntomodulin: a new therapy for obesity? Understand article

Katie Wynne and Steve Bloom from Imperial College London, UK, describe their work on a hormone that could tackle the causes of obesity.

The obesity epidemic has overtaken Europe. It is estimated that 200 million of the 350 million adults living in the EU are overweight or obese. In fact, the proportion of overweight and obese men is even higher in some European countries than it is in the USA. Of greatest concern is the fact that the number of overweight children in the EU is increasing by 400 000 every year, a warning that the obesity problem will be far worse in the future.

Obesity increases the risk of heart disease, diabetes, stroke, respiratory disease, arthritis and cancer. This disease burden has a disastrous effect on health and costs 7% of the total EU health-care spending. The risk of developing obesity-related conditions can be reduced by losing as little as 5% of body weight. However, public-health campaigns to promote healthy eating and exercise have not stopped Europeans becoming progressively fatter. Currently available drug treatments in combination with diet produce only modest short-term weight loss and are limited by side-effects. Major gastro-intestinal surgery for obesity can result in permanent weight reduction, but the frequency of severe post-operative complications limits its use to extreme cases. Research groups worldwide are urgently searching for an effective anti-obesity treatment. The Department of Metabolic Medicine at Imperial College London has led the field in appetite research and has recently published exciting work regarding the role of the gut hormone oxyntomodulin as a novel therapy for obesity.

Oxyntomodulin is one of a group of gut hormones: small molecules released from the gastrointestinal tract with several physiological actions including effects on digestion and appetite. Oxyntomodulin was identified over two decades ago, when it was found to reduce stomach acid and delay emptying of stomach contents in rodents. However, the available data showed no effect on gastric emptying in humans and its role in the control of appetite has only recently emerged. Oxyntomodulin is released from the small intestine after each meal in proportion to the calories eaten. Early studies showed that administration of synthetic oxyntomodulin reduces appetite, suggesting that natural oxyntomodulin signals to the brain a feeling of ‘fullness’ or ‘satiety’ after eating (see below).

This research stimulated interest in developing the peptide as a possible anti-obesity therapy, harnessing the body’s own satiety signal in order to reduce food intake. Body weight is maintained by the balance between food intake and energy used, or ‘energy expenditure’ (see right). Total energy expenditure can be divided into the energy used by the body for metabolic processes at rest and that used during activity. Obesity occurs when overeating and low levels of physical activity tip the balance in favour of weight gain. We have recently performed studies in healthy overweight and obese volunteers to investigate the effect of oxyntomodulin on food intake, energy expenditure and body weight.

A double-blind, placebo-controlled study was performed in which 15 healthy overweight and obese volunteers were trained to give themselves oxyntomodulin injections under the skin, just before each meal, three times daily. Food intake and energy expenditure were measured over four days and compared with a similar period during which the same volunteers administered a saline placebo. During the study, the volunteers and investigators were unaware of the identity of the administered substance. Food intake was recorded at a study meal in which food was provided in excess and the volunteers ate until they felt full. Activity-related energy expenditure was calculated from combined heart rate and movement monitoring in the participant’s normal environment using a new biosensor. Resting energy expenditure was calculated using indirect calorimetry, which measures the amounts of oxygen consumed and carbon dioxide produced in each breath by the volunteer.

The results of this study showed that after an injection of oxyntomodulin, volunteers ate on average 128 Kcal or 17.3% less (see below, A) without altering their enjoyment of food. In addition, the participants’ energy expenditure due to activity was markedly increased by 143 Kcal/day or 26.2% during the period of oxyntomodulin treatment (see below, B). The increase in activity resulted in an increase in total energy expenditure of 9.4% (see below, C), although resting energy expenditure was unchanged. These overweight and obese people started with expected low levels of physical activity, but oxyntomodulin administration increased physical activity back toward normal levels (see below, D), resulting in more energy being used each day. These findings suggest that oxyntomodulin could be an ideal intervention for the obese, as it has a double effect of suppressing appetite and concurrently increasing physical activity toward normal

The results of this study showed that after an injection of oxyntomodulin, volunteers ate on average 128 Kcal or 17.3% less (see below, A) without altering their enjoyment of food. In addition, the participants’ energy expenditure due to activity was markedly increased by 143 Kcal/day or 26.2% during the period of oxyntomodulin treatment (see below, B). The increase in activity resulted in an increase in total energy expenditure of 9.4% (see below, C), although resting energy expenditure was unchanged. These overweight and obese people started with expected low levels of physical activity, but oxyntomodulin administration increased physical activity back toward normal levels (see below, D), resulting in more energy being used each day. These findings suggest that oxyntomodulin could be an ideal intervention for the obese, as it has a double effect of suppressing appetite and concurrently increasing physical activity toward normal

The obesity crisis is fuelled by the easy availability of highly palatable, calorie-dense food and a lack of physical activity. Normal dieting tends to reduce the amount of energy each individual uses, making it particularly difficult for obese people to lose weight. Oxyntomodulin, by contrast, reduces food intake and also increases energy usage back toward normal levels, an effect thought to be mediated via the hypothalamus (see box). Appetite suppression is well maintained over a four-week period. During this time, we observed considerable weight loss in the obese subjects accompanied by changes consistent with a loss of body fat.

Currently, the only successful treatment for obesity is surgery, but its use is limited by the dangers of the operation and subsequent side-effects.

Surgery which causes food to bypass part of the intestinal tract alters the levels of circulating gut hormones, including increasing the levels of oxyntomodulin, which results in a loss of appetite. The successful weight loss observed after surgically induced modulation of oxyntomodulin suggests that drug treatment with oxyntomodulin over many years may be effective without the complications that restrict the use of surgery.

Large clinical trials are now needed to confirm the therapeutic potential of oxyntomodulin over a longer period. These Phase III trials (see box) would involve testing the effectiveness of the hormone in hundreds and thousands of volunteers over a period of several years. This large-scale research is needed to be certain that the treatment will be effective and to look carefully for any uncommon side-effects that may not have been noted in smaller studies. Using the body’s own method of controlling weight may be a viable method of treating obesity without the serious side-effects caused by currently licensed drugs. In the future, this could provide a new way to tackle the obesity epidemic, with oxyntomodulin providing an effective weapon.

Download

Download this article as a PDF