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Hormone Receptor's Little Helper Makes Mice Get Bigger

By Anette Breindl
Science Editor

Back-to-back papers have reported new insights into the role of the melanocortin receptor, and proteins that modulate its signaling, melanocortin receptor accessory proteins (MRAPs) in the control of feeding.

One paper showed that knockout mice lacking the MRAP2 gene became obese.

Fish, on the other hand, don't get obese – they keep growing instead. And that's what happened to fish with an inactive version of MRAP2, as detailed in a separate paper by researchers at Vanderbilt University.

Both papers appeared in the July 19, 2013, issue of Science.

One of the surprises of his team's work, Joseph Majzoub told BioWorld Today, was the apparent reasons why MRAP2 knockout mice gained weight. At least in their adolescence, they did not eat any more than lean controls whose MRAP2 gene was not knocked out.

"There's a real enigma here," he said. "They were gaining weight, but not eating more, and that's very different from how we think about obesity," which is still by and large seen as a simple issue of calories in exceeding calories out.

Majzoub is at Boston Children's Hospital and co-corresponding author of one of the papers, which looked at mice, and obese individuals. Later in life, however, the animals did eat more – perhaps as a response to homeostatic cues aimed at maintaining their size. Whatever the reason, the increase in feeding provided an unfortunate synergy with their apparent ability to extract more calories from food, leading to grossly overweight animals.

The melanocortin system, which consists of five G protein-coupled receptors (GPCRs), various hormones that bind to those receptors, and a group of accessory proteins that modulate their signaling, is something of a physiological jack-of-all trades. Various family members play roles in processes from skin pigmentation to exocrine gland function.

Two family members, MC3R and MC4R, are involved in energy homeostasis, and earlier work had shown that defective signaling by the MC4R is the most common cause of severe, early onset obesity. Such defective signaling can be caused by mutations in the receptor itself, and Roger Cone and his colleagues, who authored the zebrafish paper, are collaborating with Glaxosmithkline plc. to develop compounds that increase MC4R activity, as part of the company's Discovery Partnerships in Academia (DPAc) program. (See BioWorld Today, May 22, 2013.)

G protein-coupled receptors are mainstays of the drug discovery venture, being the target of approximately one-third of currently marketed drugs. But they cannot always be successfully targeted. Previous attempts to develop direct activators of MC4R, for example, failed because the receptors are expressed throughout the brain, leading to troublesome side effects.

One possibility, which is being pursued by the Vanderbilt group, is to develop drugs that only kick in when the receptor is already activated by natural stimuli.

The papers now published in Science suggested that another possibility could be to target the accessory proteins, or develop activators that mimic them. Majzoub said that his team's long-range plan is to search for such activators.

The impact of the accessory protein is anything but trivial – Majzoub said that both the mouse and the zebrafish studies appeared to show a fivefold increase in the ability of the MC4 receptor's binding partner to activate the receptor when its "helper protein" MRAP2 was present.

Majzoub and his team also sequenced MRAP2 in both normal-weight and obese individuals from two separate obesity studies, and found four separate instances of mutations in the protein in obese individuals, while there were no such mutations in controls.

Those mutations are rare, and previous work has suggested that mutations in the MC4 receptor itself that severely impair its function account for no more than 5 percent of severe, early onset obesity.

But the authors ccontended that less obvious variants that affect signaling to a lesser degree may also play a role in weight control, which would mean that drugs aimed at increasing signaling could benefit all patients, not just those with mutations in the gene in question. National Institutes of Health director Francis Collins has argued that when SNPs are used to identify pathways, the resulting drugs can benefit those with low-risk as well as those with high-risk spelling. (See BioWorld Today, May 7, 2007.)