Earlier research has shown that this protein, called MC4R, is a receptor on neurons in the hypothalamus region of the brain and receives signals through at least two pathways about the status of the body's fat reserves. If fat stores are increasing, theses signals stimulate MC4R, triggering physiological responses that decrease appetite. If fat reserves are decreasing, these signals turn off, deactivating MC4R and increasing appetite.

Pioneering genetic studies of extremely obese people carried out since 1998 by Christian Vaisse, MD, PhD, assistant professor of medicine at UCSF, have revealed that mutations that impair MC4R's response to the signals are the most common genetic cause of severe obesity. The protein has become a prime target in efforts to develop drugs to combat obesity.

But the new research at UCSF and the UCSF-affiliated Gladstone Institute of Cardiovascular Disease shows that MC4R also affects appetite in a way unrelated to the signaling loop that has been the focus of most appetite-suppression research. Scientists found a new group of mutations in this receptor that cause obesity not by interrupting the MC4R receptor's response to the appetite signals, but by affecting its intrinsic, or baseline, level of activity.

"The notion that the subtle basal activity of the receptor is also crucial to maintain normal body weight is unveiling new ways to think about how energy homeostasis is maintained," said Supriya Srinivasan, a postdoctoral fellow at the Gladstone Institute and co-lead author of the study.

The discovery suggests a promising new strategy to combat obesity, the scientists report. Rather than developing drugs that significantly boost MC4R's response to the ap
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Contact: Wallace Ravven
wravven@pubaff.ucsf.edu
415-476-2557
University of California - San Francisco
15-Oct-2004