Scientists Probe Brain’s Role in Obesity

Chicago—Genetic and environmental influences on the brain may contribute to obesity, suggests research presented at the Society for Neuroscience's annual meeting here in October.

The meeting provided a timely forum for bringing together basic and clinical researchers who conduct studies of the causes of overeating and obesity, which largely support the concept of obesity as a biological problem rather than an issue of overindulgence.

Ilia Karatsoreos, PhD, a postdoctoral fellow at Rockefeller University in New York, and colleagues studied the effects of changing the circadian rhythm in mice by artificially creating a 20-hour day (10 hours of light and 10 hours of dark). After 6 to 8 weeks, the mice experiencing these shorter days showed weight gain, changes in body temperature rhythms, and levels of metabolic hormones (including leptin and insulin) when compared with the control group. Behavioral changes, which included increased impulsivity and decreased cognitive flexibility (meaning the mice were less able to adopt new strategies in new situations), occurred in conjunction with neural changes in the prefrontal cortex, an area known to be important for regulating these behavioral traits. The findings may be relevant to humans, given the widespread occurrence of both shift work and jet lag.

Several studies explored the role of epigenetic changes—heritable changes in gene expression that act independently of changes in DNA sequence—in obesity. For instance, Tracy Bale, PhD, associate professor of neuroscience at the University of Pennsylvania, and colleagues showed that pregnant mice not only get fatter and show elevated glucose, leptin, and insulin, when fed a high-fat diet, they also produced pups that were longer, weighed more, and had reduced insulin sensitivity (Dunn GA and Bale TL. Endocrinology. 2009;15[11]:4999-5009). These traits persisted into the next generation, although only females were affected. Further study revealed that these second-generation mice had altered programming of their growth hormone axis, a key gene pathway that controls growth and metabolism. In an interview with JAMA, Bale stated that the changes seen in the second generation of mice have “nothing to do with the diet itself as they have never seen the diet. Thus it has to be inherited by an epigenetic mechanism.”

Similarly, studies by Teresa Reyes, PhD, research assistant professor at the University of Pennsylvania, and colleagues suggest that a high-fat diet in pregnant and lactating mice can affect their pups' brain development, increasing their vulnerability to becoming obese and to engaging in addictionlike behaviors in adulthood. Such pups exhibited a greater preference for sugar solution and a greater physical response to cocaine than did pups of mothers that were fed a standard diet.

Clinical researchers presented other possible mechanisms for overeating and for the preference of high-sugar and high-fat foods. This research was based on the premise that innate biological factors interact with the environment to predispose individuals to eat.

Kathleen L. Keller, PhD, of the New York Obesity Research Center of Saint Luke's-Roosevelt Hospital Center and Columbia University College of Physicians and Surgeons, and colleagues followed up on animal studies by French researchers demonstrating that dietary fat may be one of the basic tastes (such as sweet, salty, and bitter) and is associated with expression of the gene encoding CD36, a receptor in the tongue found to play a role in fat detection and preference (Faugerette F et al. J Clin Invest. 2005;115[11]:3177-3184). In their work, Keller and colleagues are the first group to report the relevance of the CD36 gene to humans. They found that those who were heterozygous for the gene were less likely to be able to discriminate fat and tended to dislike low-fat and fat-free foods. In their study, humans who could not discriminate fat ate more high-fat meats, sweets, and spreads.

Dana M. Small, PhD, assistant professor at Yale University, and colleagues identified brain regions where response to ingestion of a milkshake may represent a biomarker of weight-gain susceptibility in humans, and that the response is moderated by the Taq1A A1 polymorphism, which is associated with fewer dopamine receptors. In subjects carrying Taq1A A1, the relative activity (as measured by event-related functional magnetic resonance imaging) of the caudate nucleus, part of the brain's reward system and an important area for habit learning, predicts an individual's future weight gain over the next year. The researchers also found that response in the dorsal striatum is inversely related to trait impulsivity.

“This means that overweight people with the A1 allele do not experience less food reward but rather that they may be more prone to impulsive eating,” Small said in an interview with JAMA.