Discovery raises hopes for obesity treatment

A Kiwi researcher is one of a team to discover a gene that controls expression of the MC4R gene, which in turn regulates food intake and bodyweight, raising hopes for new and effective treatments for obesity.

“It will be a challenge, but it offers a potential way of treating obesity in the general population,” says Associate Professor Kathy Mountjoy, who researches molecular medicine and pathology at the University of Auckland.

“For more than two decades now, it's been shown from genetic studies in both mice and in humans, that the Melanocortin 4 Receptor, or MC4R, is a gene that plays a pivotal role in regulating appetite and bodyweight,” Mountjoy says.

Subtle changes in the gene can cause obesity, she says.

“That shows that the amount of the MC4 receptor that is expressed is important in regulating appetite and bodyweight.”

“For years, drug companies have attempted to target the MC4 receptor to find molecules that could activate it to treat obesity. In large part, they have failed, because the drugs they have discovered have had unwanted side effects.

“So very little, is known about what regulates the expression of the MC4 receptor, the abundance of the MC4 receptor, and that's what prompted this study,” Mountjoy says.

Mountjoy was on sabbatical at the University of Texas Southwestern Medical Center when she heard Dr Chen Liu present about his planned research on the MC4 receptor gene and how it was regulated.

Having researched in the same area in the 1990s, she contacted Chen and offered to contribute DNA. So some DNA used for the study came from New Zealand.

Technology has come a long way since the 1990s, especially with respect to genetics, which supported these new findings.

The newly discovered gene, orthopedia (OTP), controls the expression of the MC4 receptor gene in only specific neurons in the brain’s hypothalamus, where it regulates appetite and body weight.

“It is just the beginning of refocusing research on how you can target the MC4 receptor to treat obesity – to look at the gene expression rather than activating the MC4 receptor,” Mountjoy says.

After the researchers, led by Dr Chen Liu at the University of Texas, discovered OTP regulated appetite and bodyweight in mice, they collaborated with Dr Sadaf Farooqi at the University of Cambridge in the UK to look at the human OTP gene.

The UK scientists had previously identified the OTP gene in the UK Biobank, which holds genetic data on more than half-a-million people.

They had found five mutations in the OTP gene. Four of those mutations were in individuals who had obesity. But, at that stage, they didn't know what the OTP gene was doing.

“This mouse study indicated that OTP was regulating the MC4 receptor, and hence the collaboration with the University of Cambridge to look at the human OTP gene,” Mountjoy says.

“The key point in this paper is that the OTP gene regulates the expression of the MC4 receptor gene in the brain’s hypothalamus and its disruption causes obesity in mice and humans,” Mountjoy says.

While there haven’t been drugs in the past that target genetic regulators like OTP, Mountjoy says this study is likely to prompt drug development in this area.

To read the paper, see Science Translational Medicine.