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Once-Promising Receptor May Be Obesity Drug Target After All, Says UCSF Scientist

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The melanocortin-4 receptor may yet prove to be a viable anti-obesity drug target now that its normal functioning is better understood, said a University of California at San Francisco researcher studying the receptor.

Adverse human reactions have stopped several appetite-suppressor candidates, possibly because MC4R was treated “as an on/off switch,” instead of the rheostat it appears to be, said Supriya Srinivasan, a UCSF Gladstone Institute of Cardiovascular Diseases researcher and author of a recent study of the receptor. The receptor is active at a basal level during normal operation, while mutations in one portion of the gene may slow this activity, resulting in greater hunger, said Srinivasan.

Earlier drugs targeted at MC4R worked in vitro and in mice, but were possibly “too severe” to work in humans without side effects, said Srinivasan. “It’s possible that something more subtle ... that mimics the basal activity of the receptor might be more effective,” she added.

The MC4R mutations the group studies — isolated in obese humans — affect basal activity, with “completely normal” ligand activation and agonist inactivation, said Srinivasan.

The agonist of the receptor “might be more important than we previously recognized,” said Srinivasan. The agonist may switch off sustained MC4R signals to help produce hunger, “and if that’s the primary mode of regulation, then it makes sense that the drugs used previously didn’t work,” she said.

No drug companies have approached the group yet, but the work is very new, said Srinivasan.

Raised plasma levels of leptin activate MC4R, causing satiety, while it relieves MC4R suppression caused by agouti-related peptide, a hunger-related hormone. Found on hypothalamic nuclei cells, MC4R is indirectly activated by leptin.

Published in the Oct. 15 issue of the Journal of Clinical Investigation, the UCSF researchers’ work builds on previous research associating MC4R mutations with about 2.5 percent of extremely obese subjects. Srinivasan’s group studied the level of cyclic AMP, which rises when MC4R is off, to look at receptor variants.

— CW

 

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