A brain protein already known to play a central role in the "feast or fast" signaling that controls the urge to eat has now been found to influence appetite in a second way. The discovery identifies a potential new target for drugs against obesity.
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, these 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 appetite-suppression signals -- a strategy that has so far proved difficult to carry out -- a better approach may be a drug that assures the sustained, low-level MC4R activity that the researchers showed is essential for the protein to regulate appetite.
"These findings provide a whole new way of thinking about how hormone receptors could cause disease, and suggest different types of drugs for treating these diseases," said Bruce Conklin, MD, UCSF associate professor of medicine and also of cellular and molecular pharmacology, and an investigator at the Gladstone Institute. Conklin is a co-author on the paper reporting the research in the October 15 issue of The Journal of Clinical Investigation.
"Finding this second route by which mutations to MC4R cause obesity strengthens our understanding that this receptor sets the level of food intake to match exactly our long-term energy output," said Vaisse, senior author on the new study and a scientist in the Diabetes Center at UCSF.
"Obesity results from the interaction of a genetic predisposition and environmental factors that include decreased levels of exercise and increased access to foods high in fat," Vaisse said. "The importance of the genetic predisposition is thought to be larger in patients with a more severe obesity."
Extreme obesity affects about five percent of people in the U.S. Research by Vaisse and colleagues has found that mutations in MC4R account for about 2.5 percent of these cases -- far more than the number caused by mutations in any of the four other genes so far discovered to affect the cascade of appetite-controlling brain signals. The research has convinced Vaisse that there is no predominant genetic cause of obesity. Rather, the condition is caused by any one of a number of mutations that can arise in the brain signaling pathway. As a result, he says, no single treatment is likely to be effective for all obese people.
Still, MC4R must be a central player, he says, since mutations that cause even subtle changes in this protein now appear sufficient to increase food intake, ultimately leading to obesity.
"Clearly, this receptor is crucial to the body's highly sensitive ability to balance food intake and energy expenditure," Vaisse said.
In the on-going UCSF Genetics of Human Obesity Study directed by Vaisse, researchers have so far studied the genetic profiles of about 2,000 patients. Of these, 50 have been found to have MC4R mutations -- most of them in different locations along this protein that weaves in and out of the neuron's membrane.
The new study reports six mutations -- in six different obese patients -- in the tail-like strip of the protein that extends outside of the neuron, called the N-terminal domain. This small part of the protein is not involved in the much-studied brain signaling that controls appetite. Rather it maintains the protein's intrinsic activity.
The effort to tease apart the network of signals that controls appetite got a big boost in 1994 with the discovery of leptin. This protein circulates in the body at concentrations proportional to the mass of body fat. It initiates the signaling pathway that determines whether or not MC4R will trigger the body's urge to eat.
MC4R is known as a G-protein coupled receptor (GPCR), about 350 of which are present in the human genome. These receptors sense signals such as light, chemicals or hormones, and mutations in the receptors are implicated in many diseases. The new research provides the first evidence of an essential role for the basal activity of a GPCR in controlling a normal human physiological function, the scientists report.
"Our genetic findings highlight the importance of patient participation in genetic research aimed at understanding obesity and developing treatments for this condition," Vaisse says.
For more information regarding how to participate in the UCSF Genetics of Human Obesity Study directed by Vaisse, call toll-free 1-866-857-1145.
Cecile Lubrano-Berthelier, PhD, post-doctoral fellow at the UCSF Diabetes Center, is co-lead author of the paper. Co-authors and collaborators on the research are Cedric Govaerts, PhD, postdoctoral fellow in cellular and molecular pharmacology, UCSF; Frank Picard, BS, graduate student, UCSF Diabetes Center; and Pamela Santiago, BS, research assistant at the Gladstone Institute.
The research was supported by the National Institutes of Health and the American Diabetes Association.