What Drives Food Intake?
New Research Program Targets the Brain’s Role in Obesity

The following story was written by Beth Hanson for "Connections", a quarterly newsletter published jointly by the Departments of Pediatrics and Obstetrics and Gynecology at Columbia University Medical Center.  

When people eat more calories than they expend, they gain weight and may become overweight or even obese—that’s a basic law of physics, says molecular geneticist Rudolph Leibel, MD, co-director of CUMC’s Naomi Berrie Diabetes Center. Determining why people consume more energy than they require is more complex, but answering this question has become increasingly urgent as obesity rates among adults and children continue to rise, as do rates of associated health problems including diabetes, high blood pressure and disordered blood lipids.

Food intake is controlled almost entirely through mechanisms in the brain—“the nal common pathway to the regulation of body weight,” according to Dr. Leibel. To deepen our understanding of how the brain controls and responds to body weight, he recently launched a program called the Obesity Research Initiative to promote collaborative studies of the regulatory, cognitive and emotional aspects of food intake. The initiative is funded by an $8.25 million gift from the Russell Berrie Foundation. Dr. Leibel’s co-leader in the effort is CUMC neuroscientist Charles Zuker, PhD, who studies neurological aspects of sensory systems including taste.

Dr. Leibel notes that over the past couple of decades researchers have identified a number of very important genes that regulate “homeostatic” aspects of body weight regulation, “the unconscious processes that control the drive to eat or rates of energy expenditure,” he explains. “But very poorly understood still are the higher mechanisms—sometimes called the hedonic mechanisms—that regulate people’s selection of food, their willingness or drive to eat without appetite and their preferences for certain types of food.”

Last year, Drs. Leibel, Zuker and a team of extramural investigators selected eight research projects for the initial round of funding. An underlying theme of these projects is the use transformative technologies to understand processes in the brain at a molecular level.

Through one advanced technique called optogenetics, for example, researchers can manipulate and turn genes in the brain on and off instantaneously. (This work is currently done primarily in mice.) “The technique uses something equivalent to a very tiny flashlight that can be embedded in the brain. By turning specific genes on or off, we can study genetic processes in very specific parts of the brain in ways that were not possible before.” Researchers also now have the capability of inserting various molecules into genes, enabling them to trace the gene product from its source to its destination. “Using this technique we can end the connections between different parts of the brain that regulate aspects of food intake,” Dr. Leibel says.

The initiative is also funding the work of researchers who are using RNA sequencing, in which they take cells from specific regions of the brain and can determine every gene that is being turned on or off in those cells, says Dr. Leibel. This enables them to identify the molecular basis for the function of cells that ultimately control preference for sweet foods or those with a high-fat content. This kind of testing was not possible as little as five years ago, he adds.

Technologies such as these will permit researchers to dissect the complicated mechanisms related to “hedonic” controls of food intake. As they learn which pathways and molecules are implicated, their analyses could, in turn, point to specific products or drugs that might interfere with those molecules, and prevent the responses to food that lead to obesity, Dr. Leibel says.

Obesity not only affects individuals’ health and lives but is the progenitor of many other diseases that threaten to overwhelm the healthcare budgets of countries around the world, “so this initiative is very timely and very much needed,” Dr. Leibel concludes.