It takes guts to fight obesity: how hormones could hold the key to sustainable weight loss

To mark National Obesity Awareness Week, Professor Tricia Tan explains how new research is harnessing the power of hormones to treat obesity more effectively.

Obesity has been an issue for centuries. However, it has transformed from a disease that once only touched a small number of people to a major health concern that currently affects one in four adults in the UK. As a result, obesity is now always in the news. Although many obese people are reasonably healthy, we know that obesity increases the risks of developing heart disease, diabetes mellitus (high blood sugar), cancer, respiratory problems (such as sleep apnoea and asthma) and arthritis. Obesity and its related health problems threaten to reverse the gains in lifespan that we have seen through the 20th century. So, how can we begin to tackle it?

Myth vs science

In order to identify the best solutions, it’s important that we tackle some of the most widely-held misconceptions about obesity. Perhaps the most pervasive is that obesity is somehow the fault of the sufferer, and that they are in some way lazy. The increasing levels of obesity in our society is the product of multiple factors, including: i) our famine-surviving genetic makeup, which makes it easy to gain weight but difficult to lose it, ii) an ‘obesogenic’ environment, in which there is much less physical activity compared to our ancestors, and iii) 24-hour availability of pre-prepared, delicious, and calorific food.

For many years, doctors have been telling people with obesity to exercise more and eat less. Although some individuals can lose remarkable amounts of weight in the short term with intensive diet and exercise, this approach does not lead to sustained weight loss for most people. The entire multibillion diet industry is testament to this: there are multiple diet books and products, with none clearly being superior to the others.

People also tend to believe that those with obesity simply lose willpower and slip back into old habits. However, we know that when you lose weight, the body can detect this and puts into motion two specific changes to drive the weight back up again. It does so firstly by increasing appetite – so that you eat more – and secondly by reducing the amount of energy the body uses to heat itself – so that you save energy. This means that people commonly fall into a ‘yo-yo’ pattern of losing weight and regaining it again; this is simply a matter of biology rather than being personal weakness or laziness. It also means that the diet industry has an inexhaustible supply of repeat customers!

In light of all of this, how can we fight obesity more effectively? The best current treatment that we have is bariatric surgery. These are surgical procedures, for example the gastric bypass, that have been performed for over 40 years. There are a number of studies that demonstrate that people with obesity who undergo this kind of surgery live longer as a result, have fewer heart attacks, fewer cancers and – remarkably – can be cured of diabetes without any medication in some cases.

So, why doesn’t everyone with obesity have surgery? There are a number of important reasons to consider. Many people, including those in the medical profession, simply don’t know enough about these operations and their benefits. They view surgery as a last resort, despite there being increasing evidence that early surgery is more beneficial. Another reason is that there aren’t enough specialist surgeons to do the number of operations required. Also, the surgery does have its complications, including, paradoxically, causing blood sugar levels to drop too low, and in some cases this can be serious. Finally, the fact that the surgery is irreversible does give people pause, and in many cases my patients decide not to undergo the surgery because of this factor. Therefore, it would be hugely beneficial to create a drug that is able to give us the benefits of surgery without needing to go under the knife.

Harnessing the power of hormones

One clue we have that might help us in achieving this so-called ‘medical bypass’ is that bariatric surgery appears to work its magic by increasing the secretion of satiety hormones from the gut. These hormones – such as glucagon-like peptide-1, oxyntomodulin and peptide YY – work normally to control our appetite and regulate the systems in the body that digest, absorb and store food. The levels of these hormones in our blood increases whenever we eat, and the hormones in turn affect the parts of our brain that control eating and appetite. They also increase the amount of insulin produced by the pancreas, hence reducing blood sugar levels. The remarkable thing about the surgical gastric bypass is that it pushes gut hormone levels up by three to four times normal levels after patients eat. We think this enhanced gut hormone secretion is one of the major ways by which the surgery causes patients to eat less, and can improve their blood sugar levels if they are diabetic. We asked ourselves the question: what if we could give our patients these hormones together as a combination to reproduce what happens during a gastric bypass? Could this give us the benefits of surgery without doing the surgery itself?

Losing the pounds and normalising blood sugar

The way I have approached creating a surgery-free bypass is to use a pump device, like the devices that some diabetic patients use to give themselves insulin. We load the pump with a mixture of hormones – GLP-1, oxyntomodulin and peptide YY, or GOP for short – and this is given painlessly under the skin using a soft plastic tube for up to 12 hours per day. We taught people with diabetes and obesity how to set up the device and carry on with their daily lives for up to four weeks at a time. Our latest study shows that the volunteers using the GOP pump didn’t eat as much, as the hormones suppressed their appetite. As a result, in just four weeks they lost about 4.5 kg on average. We also found that their blood sugar levels, which were quite high in some cases, became more normal and fluctuated less. When we compared these results with those of patients who had undergone gastric bypass surgery, our GOP pump volunteers’ ability to absorb and process the sugar from a meal was even better. Far from simply imitating surgery, in many respects the GOP pump is better!

I think using mixtures of gut hormones shows a lot of promise for future treatment of diabetes and obesity. Working with Professor Sir Steve Bloom, we are now trialling long-acting combination hormones with a single injection for the first time in humans. It could be that within the next five years or so, we will be using injections, pumps, or similar devices to dispense customised mixtures of gut hormones to help us achieve our goals, whether this is losing weight, controlling our metabolism or both.

Tricia Tan is a Professor of Practice (Metabolic Medicine & Endocrinology) in the Department of Medicine at Imperial College London, a Consultant in Diabetes, Endocrinology and Metabolic Medicine at Imperial College Healthcare NHS Trust, and Clinical Lead for Biochemistry, North West London Pathology.

Following the launch of the Faculty of Medicine’s reorganised academic structure on 1 August 2019, this post was recategorised to Department of Metabolism, Digestion and Reproduction.

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