Regulating Obesity: Specialized brain cells promote fat storage in mice

Mouse models are valuable tools for Alzheimer’s researchers. In this study, the Alzheimer’s mice harbored the APP gene, which causes plaque buildup in the brain. Image courtesy of Daniel Wesson.

Obesity is an increasingly common and significant health concern that affects greater than one in three adults in the United States. It can cause numerous complications, including heart disease, diabe­tes, or cancer. Development of obesity is the result of an increased number and size of fat cells in the body. However, the processes that drive the growth and expansion of fat cells are highly complex and influenced by several contributing factors. One known cause of the development of obesity can be attributed to an energy imbalance— when caloric intake, such as in the form of food or drinks, exceeds the amount of energy expended by the body in activities such as ex­ercise. An additional contributing factor is the type of energy source, such as fats (lipids) or carbohydrates, that the body chooses to utilize. However, scientists do not yet fully understand the mechanisms that govern which source our bodies use in regulating energy balance.

Regulation of energy balance is at least partially controlled by a spe­cific region of the brain called the hypothalamus—specifically, by spe­cialized brain cells called Agouti-related peptide producing (Agrp) neurons. These cells are important in regulating feeding behavior by becoming more active in response to food deprivation as well as by inhibiting other brain systems that suppress appetite. Although they were already known to play an important role in managing the body’s energy balance through control of food intake, the function of Agrp neurons in determining which energy source the body uses had pre­viously been unknown. In a study recently published in Nature Com­munications, Joao Paulo Cavalcanti-de-Albuquerque, a member of Marcelo Dietrich’s lab at Yale University School of Medicine, investi­gated this question by activating Agrp neurons in mice.

When Calvacanti-de-Albuquerque and colleagues activated these murine Agrp neurons, they observed that the mice utilized more car­bohydrates and fewer fats as their sources of energy. These findings were independent of the effects of sugar given to the mice or ingestion of food, demonstrating that activation of Agrp neurons is sufficient to promote shifts in the utilization of carbohydrates over fats. They also found that activation of Agrp neurons increased the expression of genes involved in producing lipids and decreased the expression of genes involved in breaking down lipids. Furthermore, the effects of activated Agrp neurons on lipid metabolism were blocked by the inhi­bition of fatty acid synthase, a key protein in the production of lipids, suggesting that Agrp neuron activation normally promotes the gen­eration of lipids in mice. These researchers realized that the effects of Agrp neuron activation were mediated by a specific part of the nervous system known as the sympathetic nervous system, which is turned on in a “fight-or-flight” situation. Finally, activation of Agrp neurons also increased the mass of the fat pads in these mice, while depleting the mice of Agrp neurons decreased their fat gain. These results further highlight the important role of Agrp neurons in regulating obesity.

“[This study shows] the importance of Agrp neurons during di­et-induced obesity and regulating the deposition of fat in the adi­pose tissue,” Dietrich said. The researchers’ findings provide insight into the mechanisms controlling energy source utilization when the energy intake exceeds expenditure. “From a physiological point of view, this really rapid shift in substrate use is very interesting. I think there are very few examples of such a rapid shift driven by a neuronal population [which] tells a lot about the complexity of the biological system,” Dietrich said. Dietrich is hopeful that his team’s research will one day help us to gain a more thorough understanding of the neuronal networks and triggers that drive hunger. By elucidating the role of Agrp neurons in this process, we will be able to gain addition­al insights into how the nervous system controls metabolism. More­over, we will also gain a better understanding of the development of obesity and potential approaches to combat this health concern.