The BBVA Foundation Frontiers of Knowledge Award goes to Coleman and Friedman, discoverers of the appetite hormone

Their work showed conclusively that leptin is a hormone made by fat which acts on the hypothalamus in the brain, in order to “maintain control of food intake, energy expenditure and the amount of fat that accumulates,” the citation continues. “The absence of leptin or its receptor leads to obesity,” a mechanism initially identified in mice but that also “holds true for humans, and is therefore of obvious critical importance.”

Coleman and Friedman’s findings, in the view of the jury, have not only opened up a new era of research into the biological roots of obesity, but have also brought about a paradigm shift in social attitudes by showing that obesity is not due to “inappropriate behavior, but is the consequence of imbalance in a hormone-driven process,” the citation concludes.

Douglas Coleman (1931, Ontario, Canada) holds dual Canadian-American nationality and is Senior Staff Scientist Emeritus at The Jackson Laboratory in Maine (United States). Jeffrey Friedman (1954, Orlando, United States) is a professor at The Rockefeller University in New York. Their names were put forward for the award by Paul Greengard, winner of the 2000 Nobel Prize in Medicine and a professor at The Rockfeller University, Alexander Varshavsky, professor at the California Institute of Technology and 2011 BBVA Foundation Frontiers of Knowledge laureate in Biomedicine, and Robert E. Braun, Chair of Research at The Jackson Laboratory.

Although the two men have not worked together, their relationship is about as close as one can get in science, for it was Friedman who proved that Coleman’s scientific hypotheses were in fact correct.

Hence Coleman’s insistence, on hearing of the award, that he was “especially delighted” to be sharing it with Jeffrey Friedman: “We are good friends, and have known each other for many years. One day he called me to say he wanted to work with the mice I was studying, and, several decades later, it was he who found the hormone that I had predicted.”

In the late 1960s, Coleman had demonstrated the existence of a still unknown hormone that regulated food intake and body weight. He had done so through his studies of mice carrying a mutation that made them morbidly obese. And his team could tell from the genetic crosses that the defect lay in a single gene. Then Friedman took up the baton in the mid 1980s, determined to find and name the guilty gene.

“Back then we didn’t have the technology we have now to isolate genes,” remarked Friedman on the phone, “so I knew it was going to be a hard task and decided to call Coleman to get more background.” Eight years later, in 1994, Friedman discovered the gene of the leptin hormone, which functions just as Coleman had anticipated.

Informed of the jury’s decision, Friedman said yesterday: “It is a great honor to receive this particular award, which emphasizes such diverse aspects of science. And I couldn’t be happier than to share it with Douglas Coleman, who laid the foundations for this work.”

The action of leptin

“Leptin is designed to maintain a certain body weight,” explains Friedman. The way the system works is that the more fat you have, the more leptin your body makes and the less hungry you feel. The ultimate goal is to shut down the appetite of individuals with a lot of fat, so they eat less and stop gaining weight. And vice versa. If you lose weight, your body produces less leptin and your appetite increases. The fact that the body possesses this mechanism has an evolutionary origin: “It would be very dangerous to have no fat, because you would risk dying of starvation, but it would also be dangerous to be too fat, because you would be at the mercy of predators. So the system tries to maintain an optimal level.”

The lab also discovered that leptin “circulates in the blood and acts on centers in the brain to regulate appetite, just as Coleman predicted,” adds Friedman, an admirer of his colleague’s work: “His observations were very non-obvious. There were probably thousands of scientists looking at the same problem, but he was the one who got it right.”

The discovery of leptin opened up a whole new field of research into the causes of obesity, propelled by a radical change of mentality in society and science: “Before people thought that how much we ate was completely a matter of willpower,” Friedman reflects, “but we now know that body weight, in humans and other animals, is regulated by cells in the brain that receive important signals such as leptin and then unconsciously regulate appetite. And this system is absolutely crucial for the survival of any species.”

This means, ultimately, that obesity is “in the mind”: “As well as leptin and the leptin receptor, we know that 10% of morbidly obese individuals carry defects in genes that regulate food intake, metabolism and body weight. And all these genes act on the brain, which tells us that the main reason people get fat is an alteration of their brain chemistry.”

Leptin, in other words, is not the only gene linked to obesity – Friedman predicts that more will come to light – but it does play a leading role, and will certainly be important in future drug therapies against obesity: “There is a lot left to be learned about the regulation of obesity, but the identification of leptin will undoubtedly lead us to a better understanding of the factors controlling appetite, which will lead, in turn, to new avenues for treatment.”

For Friedman, however, the objective is not to get everyone who is obese to lose weight, but “to make unhealthy people more healthy.” And this, he points out, can be achieved with even moderate weight loss.

International jury

The jury in this category was chaired by Werner Arber, winner of the Nobel Prize in Medicine and Emeritus Professor of Molecular Microbiology at Biozentrum, an interdisciplinary research institute belonging to the University of Basel (Switzerland). The secretary was Robin Lovell-Badge, Head of the Division of Stem Cell Biology and Developmental Genetics at the National Institute for Medical Research (Medical Research Council, United Kingdom). Remaining members were Dario Alessi, Director of the Protein Phosphorylation Unit, a Medical Research Council center in the College of Life Sciences at Dundee University (United Kingdom); Mariano Barbacid, AXA-CNIO Professor of Molecular Oncology in the Spanish National Cancer Research Centre (CNIO)(Spain); Óscar Marín, Principal Investigator in the Department of Developmental Neurobiology of the Instituto de Neurociencias de Alicante (Spain); Ursula Ravens, Chair of the Department of Pharmacology and Toxicology at Dresden University of Technology (Germany); Angelika Schnieke, since 2003, Chair of Livestock Biotechnology in the Department of Animal Science at the Technical University of Munich (Germany); and Bruce Whitelaw, Head of the Developmental Biology Division at The Roslin Institute in Edinburgh (United Kingdom).