Pioneering endocrinologist discusses ‘new type of human metabolic disease’

Renowned endocrinologist Prof Sir Stephen O’Rahilly presented at the recent RCPI Institute of Medicine Winter Symposium

Prof Sir Stephen O’Rahilly, an Irish endocrinologist responsible for several major biochemical discoveries, gave the Stearne Lecture at the RCPI Institute of Medicine’s Winter Symposium on 28 November. In his talk, Prof O’Rahilly explored how our understanding of obesity has evolved.

Since the 1990s, Prof O’Rahilly’s research has focused on elucidating the basic causes of obesity and type 2 diabetes at a molecular level and translating discoveries into improved diagnosis and therapies. His work has uncovered several previously unrecognised genetic causes of these diseases, including some that are amenable to specific treatment.

Originally from Dublin, Prof O’Rahilly is Professor of Clinical Biochemistry and Medicine at the University of Cambridge, UK, where he has worked for 33 years.

He qualified in medicine from University College Dublin and completed an internship at the Mater Hospital, Dublin. From 1982 to 1991 he undertook specialist training in general medicine and endocrinology, and in diabetes research, in London, Oxford, and Harvard.

Prof O’Rahilly arrived at Cambridge as a clinical endocrinologist with funding from the Wellcome Trust to conduct laboratory research. A focus of his early work was insulin resistance. “I was looking at how insulin goes wrong in human diseases and how it contributes to common metabolic disease,” he says. 

“This interest continues to the current day, in terms of discovering new causes of why the body doesn’t respond to insulin and how we might use some of those discoveries in terms of making new drugs to improve insulin sensitivity.”

Groundbreaking

In the 1990s, Prof O’Rahilly’s research provided groundbreaking new insights into the pathogenesis of obesity. At the time, there was suspicion that obesity had an inheritable trait, but this lacked concrete evidence. It was the hormone leptin that opened new doors.

His early research found that children with rare homozygous mutations in the leptin gene, and complete leptin deficiency, developed extreme hyperphagia and obesity soon after birth. However, they responded with normal eating and a selective loss of excess body fat upon being given small amounts of leptin.

Prof O’Rahilly’s research uncovered that a person’s appetite and eating behaviour can be linked to specific genes.

“What I discovered was leptin doesn’t control metabolism; what it controls is behaviour. It controls hunger and appetitive behaviour.”

This paved the way for further studies that have established a substantial genetic contribution to the regulation of body weight.

“That’s what was considered fascinating: That you can have a purely genetic defect, but it was exhibiting itself through a behaviour. That’s still something people can find hard to get their head around. They still ask me – is it the genes or is it what they eat? It’s both. The genes are making them eat,” he says.

Prof O’Rahilly is the recipient of numerous awards recognising his pioneering research in the 1990s and early 2000s. By 2008, he and epidemiologist Prof Nick Wareham established the Institute of Metabolic Science at the University of Cambridge – with an £11 million donation by Irish-American philanthropist Mr Chuck Feeney.

“We were one of a very few set of institutes to build a building and in the same building place patients on the ground floor; a laboratory next door to study patients; another floor where we had people doing population science with huge data-sets and powerful computers; and then two other floors where we had lab scientists working on cells, mice, and animal models,” says Prof O’Rahilly.

“We could all have conversations in the same building, the same coffee room, and take things down from an atomic level to a public health conversation about what we should do with the built environment to reduce the risk of obesity.”

The institute has a research staff of over 400 and more than 30 labs. Prof O’Rahilly’s own team have discovered almost 30 previously unrecognised metabolic diseases. In 2013, he was knighted by Queen Elizabeth II for his research on the causes of human obesity.

New research

At the RCPI Institute of Medicine symposium, he presented on a yet-to-be published, new type of human metabolic disease: “You can become metabolically very sick if you have inherited abnormalities in the scaffold proteins of your fat cells. That’s something we’ve discovered in the last few months.”

“Your brain regulates not only your food intake but where you put your nutrients – whether you put them into growth or into lean mass. There’ll be insights into how that works through the brain,” he comments.

Prof O’Rahilly says the field of endocrinology has been transformed by the use of gut hormones as safe and effective anti-obesity therapeutics. “We’re now entering a new era of obesity therapeutics that will change the world,” he says.

However, Prof O’Rahilly is wary of the misuse of the groundbreaking GLP-1 receptor agonists. He says the medications should be used properly and safely and treated as potentially dangerous drugs if used badly.

Prof O’Rahilly is working on multiple research projects, some of which have potential for therapeutic developments. In recent years, there has been a lot of attention on the hormone GDF15, which has been found to be linked to nausea and cancer cachexia.

“The most recent discovery we’ve made – the one that’s likely to rapidly be a revolutionary treatment – is that it [GDF15] is pretty much entirely responsible for the nausea and vomiting that women experience in pregnancy, including the most severe form, hyperemesis gravidarum,” he says.

“We believe that our work, combining with work in industry, will lead to effective treatment and prevention of that in the next few years.”

This article was produced by the RCPI.