The discovery that launched a new wave of weight loss drugs

From the gut to the brain and back

Professor Bloom's introduction to gut hormones was an act of kindness by the Swedish endocrinologist Viktor Mutt, who in the late 1960s offered him some of the hormone secretin to work on. “He’d only made 10 milligrammes, extracted from thousands of pig guts, and he offered me 8 milligrammes, which was amazing,” Professor Bloom recalls. “I was young and he wanted to help a youngster, which he did.”

This early work led to an interest in the proglucagon family of hormones, including glucagon itself, oxyntomodulin and importantly GLP-1. At this stage, researchers were still exploring the broad physiological role of these substances. Professor Bloom was one of the first scientists to show that GLP-1 was capable of amplifying the secretion of insulin in response to eating carbohydrates.

“We did a lot of work on what gut peptides might do elsewhere in the body, such as affecting blood pressure and the inhibition of gastric acid,” Professor Bloom says. “Food intake was just another thing to look at.”

The discovery that these gut hormones did indeed affect food intake coincided with work on where else in the body they could be found. “We were amazed to find that they were also present in the brain, in particular GLP-1. This led to the general concept that they were acting as control agents, sometimes from the gut, sometimes from the brain or other tissues in the body.”

Having established that GLP-1 was present in brain areas that control appetite, Professor Bloom and his group designed a complex set of experiments to establish its role. “This involved micro-injections into specific nuclei of the brain, which was the very cutting edge of what was possible at the time,” Professor Bloom recalls.

These nuclei are about the size of a pinhead, but the injections of different peptides, blocking agents and controls had to be made precisely, over and over again, in order to produce reliable results. But the results were decisive. When GLP-1 is injected into the area of a rat’s brain that controls appetite, the animal stops temporarily eating, even if it has not eaten for some time. When a substance is injected to block the GLP-1 receptor, the animal eats more, even if it is already full.

Creating new therapies

These findings were published in Nature in January 1996, the final line of the paper signalling their clinical significance. “Understanding the function of these centrally acting regulators should ultimately lead to new and more effective agents for the management of appetite disorders,” it read.

Part of the attraction was that GLP-1 is part of the body’s natural control system for eating. “Human beings eat less when they have a release of GLP-1 due to gut infections and so on. It’s a natural circuit, and it works like a dream,” Professor Bloom explains. GLP-1 and other hormone levels are also increased after weight loss surgery, explaining why people eat less after these procedures.

Using the natural hormone as a therapy is not practical, however, since it is broken down within minutes. So the next challenge was to develop a long-lasting form of GLP-1. This meant Professor Bloom’s group again had to develop new skills. “We had to do research on cross-coupling lipids, so that we could make GLP-1 last a week rather than six minutes. And we succeeded in doing that,” Professor Bloom says.

“Steve’s group was an amazing place to be because we could do things that few other people could not do,” recalls Professor Tricia Tan, Chair in Metabolic Medicine and Endocrinology in the Department of Metabolic Medicine and Endocrinology at Imperial College London and Consultant in Diabetes, Endocrinology and Metabolic Medicine at Imperial College Healthcare NHS Trust, who did her PhD with Professor Bloom before joining the group as a post-doctoral researcher. “We would synthesise peptides, we would bottle them and then do all the testing ourselves,” she says. “We were able to take our findings from the bench to humans, and then back to the bench for refinement.”

Professor Gary Frost, Chair in Nutrition & Dietetics in the Department of Metabolism, Digestion and Reproduction at Imperial, agrees that the Bloom’s group’s approach to science was remarkable. “The translation of the work from understanding of GLP-1 aminno acid structure, initial mouse investigation and then into a clinical trials was a game changer,” he says.

"Professor Bloom was a great mentor not only giving me experience in working in the  research programme to understand the role of GLP-1 on human physiology.  He also encouraged me to develop broader studies of how diet and food influence the release of gut hormones. At that time I was a clinical dietitian and  created a small research group within the  dietetics department that undertook this research, which was unique at that time.” he says.

Spinning out

Moving this work towards clinical application eventually meant adopting a more commercial approach. “Being entrepreneurial ourselves was important,” Professor Bloom says. He had seen too many ideas licensed by academics left on the shelf by industry. “If you want something you’ve discovered to actually be useful, you have to do it yourself.”

A first spinout company, Thiakis, was set up in 2005 to develop the hormone oxyntomodulin as a potential treatment for obesity. A second spinout, Zihipp, followed in 2019, this time developing a broad range of diabetes and obesity therapies. In both cases, the academic teams were closely involved in running the companies, raising tens of millions of pounds from investors in the process.

The spinouts developed potential treatments to the point where established pharmaceutical companies could take them on with confidence. Thiakis was sold to Wyeth in 2008, and Zihipp was sold to Metsera Therapeutics in 2023. Crucially, the initial laboratory and clinical studies for these treatments were conducted by Professor Bloom and his team within the National Institute for Health and Care Research (NIHR) Imperial Biomedical Research Centre and the NIHR Imperial Clinical Research Facility.

“I enjoy the entrepreneurial side, but if you want something to become a drug that people are getting benefit from, eventually you have to spin it out to a pharmaceutical company,” Professor Bloom says. “They have the resources to do all the toxicity studies, the licensing, the patenting and so on.” And it was thanks to their immense resources that large pharmaceutical companies were able to create, manufacture, test and market the now-familiar GLP-1 based weight loss drugs such as Wegovy and Mounjaro.

As a former clinician, Professor Bloom is pleased that these treatments are now available, but he is frustrated by their short supply and restrictions on their prescription. “Most patients are not getting these very effective treatments, which is infuriating, but it will happen in due course, when they come off patent,” he says. He also sees the potential to develop further treatments that mirror more closely the body’s control of food intake.

“Our research has found several other peptides that reduce food intake and which are also raised after you have bariatric surgery,” he says. “A combination of these peptides is going to be more useful, in my opinion, so that you can mimic bypass surgery by an injection, without the side effects that you get with drugs.”

Three hormones are better than one

Administering gut hormones in combination has been a focus of Professor Tan’s work, with the aim of multiplying weight loss effects and improving health. For example, if people are given GLP-1 in combination with glucagon, their appetites are suppressed while the amount of energy they burn is raised.

Professors Tan and Bloom were also the first to show that the combination of three hormones, GLP-1, oxyntomodulin and peptide YY was able to help people living with obesity and diabetes to lose weight and control their blood sugar, i.e. they were mimicking weight loss surgery with the injections. “These experiments were the crucial proof that showed the pharmaceutical industry the combination approach was a good one, and both double and triple agents are now coming through,” she says.

She is also continuing to work to understand how weight loss surgery helps people living with obesity and diabetes to lose weight and reduce their blood sugar levels. This is partly because of the increases in gut hormones that occur after surgery, but may also be due to changes in the way other chemicals in the gut such as bile acids are processed.

In parallel, Professor Tan has been looking at the difficulties some patients experience accessing the new class of weight loss drugs. One marginalised group is women of reproductive age who want to become pregnant, who have historically been barred from participating in clinical trials of weight loss drugs.

“About 1 in 3 people who are taking these drugs are women who might become pregnant, and yet they are ‘invisible’ to the drug companies,” she says, “so my focus now is to prove that the weight loss drugs actually help women to conceive, to have healthy pregnancies and healthy children.”

Enhanced foods

The connection between diet, appetite and the gut hormones remains a fruitful area of research for Professor Frost. “If we can understand which molecules within foods may be responsible for the release of GLP-1, then perhaps we can go back and enhance those foods,” he says.

This work involves trying to build up a picture of the molecular environment in different areas of the gut, and determining how that relates to local hormone production and signalling. “With foods you have thousands of metabolites, and understanding the interplay between them and the many receptors present is very challenging.”

The hope is that this information will make it possible to grow food crops that naturally suppress appetite. This effect would not be as dramatic as that seen with GLP-1 drugs,  and would play a different clinical role. “Rather than a treatment of obesity, these food systems may have a role in preventing weight gain or, if you’ve been on a GLP-1 drug, it may help to  stop weight being regained,” Professor Frost says.

The close cooperation between basic and clinical science makes Imperial the perfect place to conduct this kind of work. “The beauty of Imperial is that you have this huge multi-disciplinary team in all different fields that comes together like a jigsaw to solve a particular problem,” he says. “And people are very happy to collaborate if they can see the value of the project.”

Obesity and diabetes

To make the best use of GLP-1 drugs we need to have a better understanding of obesity and the conditions it causes. This is where the work of Dr Shivani Misra, Clinical Associate Professor in the Department of Metabolism, Digestion and Reproduction at Imperial, comes in. She is studying the epidemiology and genetics of early-onset type 2 diabetes, a condition closely connected with early-onset of obesity. Exploring what makes young people, adolescents and children gain weight from an early age has become an important question in her work.

“Ultimately the aim is to better prevent and treat young type 2 diabetes, and that’s where the GLP-1 drugs come in,” she says. “They are the single most effective intervention for obesity that is not surgical.”

Their suitability for young patients is a question Dr Misra hopes to explore in a future study. “These drugs do have side effects, and so far we have mostly given them to middle-aged and older people,” she says. “We are still uncertain about when and how to use these medicines to prevent type 2 diabetes in youth, and about the risks and benefits of long-term use from young ages.”

So, she is also interested in other ways to help young people living with obesity. “We need to give them nuanced advice and support to change behaviours, and there is an opportunity here for digital solutions, for example involving apps, AI and wearable devices.”

Behaviour in transition 

Further insight into youth and obesity comes through the work of Dr Eleanor Winpenny, Assistant Professor in Early Life Epidemiology in the School of Public Health at Imperial, a specialist in early life epidemiology. “Early adulthood is the period where obesity prevalence is developing the fastest,” she says. More than half of the UK population are either overweight or obese by the time they are in their early thirties.  “I focus on what is going on during that period and what contributes to that rapid weight  gain across the population, and then think about prevention and policy changes to support people to live more healthily.”

She is particularly interested in how social inequalities can develop over that period and how they may influence changes in diet and other health behaviours. “We know that diet tends to get worse in adolescence, and then gets better as people become young adults, but there are particular groups that maintain a poor diet and don’t improve as quickly as young adults.”

Important factors include the social cohorts young people belong to, and the constraints on their lives. For example, Eleanor's research has found that young people who go straight into employment from school, and those who work part-time in lower level jobs already have higher body fat by age 24, compared to other groups.

Although we don't understand yet why this is, Eleanor suggests that working irregular hours or juggling multiple jobs may make it harder for young people to live well. “They maybe don’t have the time or the energy left at the end of the day for a healthy lifestyle, and I’d like to unpick that a bit, because I think what is happening now may be different from 10 years ago.”

Knowing more about the factors that are shaping diet and eating behaviour should lead to new ideas for positive interventions, either in government policy or by the organisations that frame young people’s lives, such as employers and universities.

Obesity and cancer

Meanwhile, the growing link between obesity and certain cancers has raised hopes that GLP-1 drugs may have a role to play in their prevention. “We know that they are very effective in helping people to lose weight, so that alone may mean they are potentially cancer preventive,” explains Professor Marc Gunter, Chair in Cancer Epidemiology and Prevention in the School of Public Health at Imperial. “But there is also a suggestion that some of their metabolic effects and the mechanisms by which these drugs act might also have cancer preventive effects, independent of weight loss.”

But GLP-1 drugs are still relatively new, so any cancer preventive effect will likely not yet show up in population studies , and clinical trials for cancer prevention will also need long timescales to produce results. The alternative is to look more closely at effects on the tissues implicated in obesity-related cancers.

Professor Gunter is working with bariatric clinics at Imperial College Healthcare NHS Trust and Manchester University NHS Foundation Trust, collecting tissue samples from patients before surgery, when they are obese, and then 9-12 months later, once they have lost weight. “We are looking for changes in their tissues, to see how weight loss and weight change affect the biological pathways that we think link obesity with cancer,” he says. 

Knowing more about the biology involved might suggest new targets for possible cancer prevention treatments. “We would also like to extend this work to do similar studies on people taking GLP-1,” he says.

When fat talks

Obesity is not a risk factor for developing prostate cancer, but it can affect its progress. “The amount of fat around the prostate is linked to having a worse outcome from the disease,” explains Dr Claire Fletcher, Assistant Professor in Molecular Oncology in the Department of Surgery & Cancer at Imperial.  “The cancer can be more aggressive, responds less well to treatment and is more likely to spread beyond the prostate.”

Dr Nil Grunberg, a research fellow in Dr Fletcher’s lab, is working to understanding this relationship. Thanks to a collaboration with the urology department at Imperial College Healthcare NHS Trust, the lab has access to fat tissue, known as adipose, sampled with consent during operations to remove cancerous prostates.

“We grow that adipose in the lab and investigate the signals it secretes, to understand how the fat communicates with the prostate,” Dr Fletcher says. These signalling secretions are then tested on prostate cancer cells. “What we see is that those prostate cancer cells grow faster, they move more, and they have a greater tendency to migrate, when exposed to signals from fat” she says.

Since both the prostate and the adipose contain GIP and GLP-1 receptors, the group is also asking what effect anti-obesity drugs might have on communication between the two. “We are trying to understand whether using those drugs could allow us to slow down the growth of the prostate cancer cells or disrupt communication with the fat that allows it to become more aggressive,” Dr Fletcher says.  

Research and teaching

Imperial's obesity's work is wide ranging and researchers are collaborating and working across disciplines to explore future uses of GLP-1 drugs.

For Professor Bloom who initiated and developed this work he continues to lead a research group at Imperial, and to supervise PhD students. Teaching comes naturally to me, and I find it very satisfying,” he says. “I guess I like to direct, telling people what to do!”  

And the research and teaching community he helped to build continues to expand, deepening our knowledge about the fundamental processes of eating and appetite, and showing new directions for possible treatments and approaches to managing obesity in individuals, and the broader population.