The findings implicate the hormone in the maintenance of normal body weight and suggest that drugs that mimic the chemical might offer a new avenue for obesity treatment, report the studies' lead authors Stephen O'Rahilly, of the Cambridge Institute for Medical Research in the United Kingdom, and Heiko Krude, of Charité Universitätsmedizin Berlin in Germany.
The hormone's important role in maintaining body weight had been overlooked primarily because mice and rats, the subjects of much obesity research, do not produce the chemical, they added. Earlier studies had focused their attention almost entirely on the related chemical α-MSH, a hormone derived from the same precursor protein that is known to suppress appetite in humans and rodents.
"The assumption had been that α-MSH was most important at keeping energy balanced in people," O'Rahilly said. "The new studies point the finger at the neglected sibling, ß-MSH."
Both α-MSH and ß-MSH are derived from a protein complex known as proopiomelanocortin (POMC). The POMC protein is produced by neurons that play a central role in weight regulation in the brain. Earlier studies had demonstrated that loss of POMC leads to severe obesity, a phenomenon that researchers had assumed resulted from the loss of α-MSH.
In order to determine whether mutations within the melanocortin hormones might predispose people to obesity, O'Rahilly's group screened the protein-coding regions of the POMC gene in 538 Caucasian children from the U.K. with severe early-onset obesity. The group found an abnormal variant of ß-MSH in five of the children studied.
Further investigation demonstrated that the aberrant gene was also more often present in overweight or obese family members of the children than in relatives of normal weight. They further showed that the mutation--a single amino acid change--altered the melanocortin hormone's structure and its ability to stimulate the brain receptor MC4R, which earlier studies had also linked to energy balance.
Krude's group first identified the same gene variant in a small group of 15 obese children. They then extended the study to include 722 obese children and adolescents and uncovered the mutation in two people.
Although rats do not normally produce ß-MSH, previous studies indicated that the animals respond to the administered hormone by eating less. Krude's team now reports that the mutant version of the hormone failed to reduce food intake in animals, consistent with its link to increased obesity risk.
"The findings tell us that human body weight regulation is particularly dependent not only on α-MSH, but also on ß-MSH," Krude said.
"Our studies show that even subtle changes in POMC can lead to obesity, and that the potential role for ß-MSH had been unfairly neglected," O'Rahilly added. "The findings add weight to the notion that drugs that target the melanocortin system might be beneficial in the treatment of obesity."
After the discovery that α-MSH played a significant role in energy balance, there were many efforts to develop a drug that would mimic the hormone, Krude said. While studies confirmed that the drugs did reduce body weight and food intake in animals and people, they came with an unfortunate side effect, he said. They also induced sexual behavior.
"It became clear that drugs based on α-MSH could not be used on an everyday basis to treat disorders of body weight," Krude said. "It was a big disappointment. Now there is hope that ß-MSH might work better."
Both studies suggest that ß-MSH--a product of POMC processing--plays an unanticipated role in body weight control in humans, Rudolph Leibel of Columbia University in New York wrote in a Preview. The findings also highlight an important point, he added, for the study of human physiology: "Carefully selected human subjects can reveal processes/mechanisms not discoverable (or even present) in an experimental animal."
The researchers include Yung Seng Lee, Ben G. Challis, Giles S.H. Yeo, Julia M. Keogh, Vicki Wraight, Anthea Blackwood, Chiao-Chien Connie Hung, Stephen O'Rahilly, and I. Sadaf Farooqi of Cambridge Institute for Medical Research and Addenbrooke's Hospital in Cambridge, United Kingdom; Darren A. Thompson, Michael E. Madonna, and Glenn L. Millhauser of University of California, Santa Cruz in Santa Cruz, CA; Matthew Sims and Nicholas J. Wareham of the MRC Epidemiology Unit in Cambridge, United Kingdom; Vincent Vatin, David Meyre, and Philippe Froguel of the Pasteur Institute in Lille, France and Imperial College London in London, United Kingdom; Julian Shield and Christine Burren of the Bristol Royal Hospital for Children in Bristol, United Kingdom; Zala Ibrahim of Wordsley Hospital in Stourbridge, West Midlands, United Kingdom; Tim Cheetham of Royal Victoria Infirmary in Newcastle, United Kingdom; Peter Swift of Leicester Royal Infirmary in Leicester, United Kingdom; Heike Biebermann, Frederike Escher, Annette Gruters, Heiko Krude, Frank van Landeghem, and Andreas von Deimling of Charite Universitatsmedizin Berlin in Berlin, Germany; Tamara R. Castaneda and Matthias H. Tschop of the University of Cincinnati in Cincinnati, Ohio and the German Institute of Human Nutrition in Nuthetal, Germany; Georg Brabant of Medizinische Hochschule Hannover in Hannover, Germany; Johannes Hebebrand and Anke Hinney of the University of Duisburg-Essen in Essen, Germany.
This work was supported by the Wellcome Trust (G.S.H.Y., I.S.F., and S.O.R.); Medical Research Council (S.O.R., N.J.W., and P.F.); U.S. National Institutes of Health (G.L.M., DK64265); Deutsche Forschungsgemeinschaft, SFB 577, TP A9; Bundesministerium fur Bildung und Forschung (BMBF) NGFN-2 01GS0482/TP1 and 01GS0492TP13.
Lee et al.: "A POMC Variant Implicates ß-Melanocyte Stimulating Hormone in the Control of Human Energy Balance." Publishing in Cell Metabolism 3, 135–140, February 2006. DOI 10.1016/j.cmet.2006.01.006 www.cellmetabolism.org
Biebermann et al.: "A role for ß-melanocyte stimulating hormone in human body weight regulation." Publishing in Cell Metabolism 3, 141–146, February 2006. DOI 10.1016/j.cmet.2006.01.007 www.cellmetabolism.org
Journal
Cell Metabolism