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Brain Control of Obesity-related Behaviors

Two studies in mice have demonstrated new links between nerve cell activity in specific brain regions and both physical activity and the drive to eat, further defining the critical roles of hormonal signaling in obesity-related behaviors.

The first study focused on understanding the association between obesity and physical inactivity. Although it is well known that physical activity benefits overall health, it is not known why people with obesity have reduced physical activity levels. In other words, does obesity cause physical inactivity, or does physical inactivity cause obesity? To begin to address this question, researchers fed male mice either a standard, low-fat diet or a high-fat diet for 18 weeks. As expected, mice on the high-fat diet gained more weight and were less physically active than the animals eating the standard diet. Next, the researchers sought to identify the mechanisms underlying the observed physical inactivity in obese mice and focused on studying dopamine signaling. The chemical dopamine is produced by neurons (nerve cells) and binds to protein “receptors” found on the surface of nerve and other cells to exert its effect of transmitting signals. Experiments showed that obese mice had deficits in the function of dopamine D2-type receptors (D2R) in the brain’s basal ganglia, meaning that the animals had less active dopamine signaling. Experimentally restoring signaling in obese mice increased their physical activity, whereas lean mice genetically altered to lack D2R in a subset of nerve cells in the basal ganglia were not as physically active as control animals. When the researchers further studied those genetically altered mice, they uncovered a surprising finding: the animals did not gain more weight on a high-fat diet compared to control mice eating the same diet. That is, even though the experimental mice were less active, they did not gain more weight than control mice with intact dopamine signaling. This result suggests that inactivity is more a consequence than a cause of obesity in mice.

A second study examined hunger and the drive to eat in relation to other competing behaviors in mice. Previous research has primarily studied feeding behavior in isolation. However, in nature, mice must navigate feeding while engaging in other behaviors, such as avoiding predators. The scientists hypothesized that hunger could suppress other behaviors in favor of eating. To test this, they used three different groups of male mice: (1) fed (sated) mice, (2) hungry (fasted) mice, and (3) fed mice with experimentally-activated AgRP neurons found in the arcuate nucleus (ARC) of the brain’s hypothalamus (or fed-ARCAgRP-activated mice). It is known that ARCAgRP neurons play an important role in feeding behavior, as experimentally activating them promotes feeding even when mice are not hungry. Confirming prior results, the researchers first demonstrated that activating ARCAgRP neurons in fed mice promoted feeding, and thus their fed ARCAgRP-activated mice represented a model of hunger. The researchers then conducted several behavioral tests using the three different groups of mice to see where hunger/feeding would rank related to engaging in other behaviors. It turns out that, when food is present, hunger wins. For example, the scientists found that when housed in a large open-field apparatus, hungry mice and fed ARCAgRP-activated mice were more likely to spend time in the center—a location that is anxiety-provoking in mice—compared to fed mice when food was placed there. Similarly, when placed in a two-chamber apparatus with a chemical produced by a predator, foxes, in one chamber, the hungry mice and fed ARCAgRP-activated mice were more likely to venture over to the “unsafe” side if that side also had food. By contrast, the fed mice tended to stay on the safe side, which had no food but also lacked the fear-inducing chemical. Other experiments showed that hunger won over other behaviors, such as drinking water and promoting social interactions. The scientists suggest that it is possible that ARCAgRP neurons produce signals to suppress these other behaviors in favor of feeding.

These studies shed important new light on the complex neurological signaling pathways that regulate obesity-related behaviors such as physical inactivity and the drive to eat. Future research could help determine whether the same results are observed in women and men, as well as delve deeper into the underlying molecular mechanisms toward finding safe strategies to modify behavior to prevent or treat obesity.