QnAs with Roger D. Cone.

The factors underlying obesity are multifaceted, but recent research suggests that the brain’s melanocortin circuits, which play a key role in controlling the balance between energy consumption and use, lie at the heart of obesity. According to Roger D. Cone, elected to the National Academy of Sciences in 2010 and chair of the Department of Molecular Physiology and Biophysics at Vanderbilt University Medical Center, mutations in one melanocortin receptor in particular, known as MC4, are among the most common causes of severe obesity in humans. PNAS recently spoke with Cone about his research on the MC4 receptor and the implications for developing effective obesity treatments. PNAS: Your research explores the neural mechanisms of obesity—specifically the phenomenon of energy homeostasis—in humans as well as other species, such as fish. Describe some of the differences between species. Cone: The vast majority of research on obesity and energy homeostasis takes place in three species: rats, mice, and humans.When you look beyond our laboratory models at the millions of species in the world, you realize there is a vast diversity in the regulation of food intake and energy expenditure. Humans eat three meals a day, mice eat many more meals during a couple major bouts of feeding during the nighttime, some ungulates eat continuously during the day with a few breaks to nap and chew their cud, while some reptiles, such as the emerald tree boa, Corallus caninus, may have as few as fourmeals a year. So throughout the animal kingdom, animals have vastly different modes of nutrient intake and expenditure that allow them to adapt to their environments. PNAS: The zebrafish seems an unlikely model for the study of obesity. Can you explain how you became interested in this species? Cone: We became interested in studying the MC4 receptor and melanocortin signaling in the zebrafish to see if we could explore the mechanics of this circuit in a genetically tractable model system. We recently discovered a major neuroanatomical difference in the larval fish compared with mice and humans, where the system has been much better studied: In the larval fish, the melanocortin circuits send dense projections to the pituitary and control multiple endocrine axes. This has profound implications because it identifies a neural substrate in which single mutations allow organisms to adapt their feeding and reproductive strategies to optimally match their environment. This work explains the very beautiful findings of Manfred Schartl in Xiphophorus fish. Multiple size morphs exist in many fish species. Xiphophorus, for example, have two size morphs in males. There are little males and there are big males, and these differ by just one allele at a locus called “P.” The large males and the small males obviously have different growth and feeding, and completely different reproductive strategies, and this all maps to one locus. This didn’t make any sense until Schartl cloned the gene and showed that it’s theMC4 receptor. Dominantnegative mutations in the MC4 receptor, transposed to the Y chromosome, essentially increase growth but they also change reproductive behaviors. So what we’ve learned is that the melanocortin system is a wonderful substrate for allowing species to adapt to different environments: to develop different growth and reproductive strategies that enhance their survival. PNAS: What changes the level of MC4 activity? Cone:Yes, an interesting question has been, “How does the MC4R act as a rheostat on energy storage?” because G protein-coupled receptors don’t normally work that way. You typically see a large amplification of the signal when a hormone or a ligand binds aGprotein-coupled receptor, and you can significantly reduce the number of receptors on the cell and still see a full signal. When you knock out one copy of a G protein-coupled receptor gene allele, in almost all of the cases nothing happens, unlike what we see with the MC4 receptor. The amount of MC4R protein on the surface of neurons seems to have a somewhat linear relationship with the amount of food intake, autonomic outflow, and energy expenditure. So the MC4 actually engages in a very unusual signaling mechanism, and I believe we may be close to unraveling the molecular mechanism for this. PNAS: What’s next for your research? Cone: A long-term goal is to figure out a way to treat melanocortin obesity syndrome. About 90 different mutations in the MC4 make people morbidly obese. Typically the syndrome has a very early onset. Now, a very nice parallel can be made with the leptin story: Leptin mutations also create morbid obesity. In humans lacking the hormone, you can cure leptin insufficiency with hormone-replacement therapy. Our goal is to try to treat melanocortin obesity syndrome, which is far more common than leptin insufficiency. However, this is not a hormone deficiency; it’s a hormone receptor deficiency. Can we figure out a way to treat the disease by increasing the amount of receptor activity on the cell surface? If we can take that one healthy copy of the receptor that they have and make it stay longer on the cell surface or become more active, I think the disease will be treatable. We published a technology for finding compounds, known as positive allosteric modulators, which have exactly that property. A long-term goal is to develop these compounds into safe and effective therapeutics so that we can potentially treat the disease, and we have just entered into a collaborative research and development program with GlaxoSmithKline to work together on this approach. Roger D. Cone. Image courtesy of John Russell, Vanderbilt University.