Ancient Enzyme Guides Healthy Eating In Mammals

David Ron, of the New York University School of Medicine, and his colleagues found in mice that an enzyme known as GCN2 kinase sets off a cascade of events that relays information to the brain about the amino acid content of foods, enabling the animals to adjust their intake in favor of a more balanced meal. The same enzyme in yeast also acts as an amino acid sensor, earlier work has shown.

"This ancient pathway in mice recognizes drops in blood amino acid levels that occur following consumption of food with an imbalanced composition," said Ron. "That recognition culminates in a behavioral response that limits consumption of the imbalanced food and favors, by default, a more balanced diet."

The new findings confirm and extend a recent report by Dorothy Gietzen at the University of California, Davis, detailing the same pathway in rats.

Amino acids are the building blocks of proteins. While many of the 20 amino acids can be synthesized internally, eight "essential" amino acids must be obtained from food. Scientists have long known that omnivorous animals will consume substantially less of a meal lacking a single essential amino acid, in comparison to an otherwise identical meal that is nutritionally complete.

To explore the role of GCN2 kinase in this feeding behavior, the researchers inactivated the enzyme in the brains of mice. GCN2 kinase, known to be an important amino acid sensor, elicits a stress response by modifying a second protein called translation initiation factor 2 (eIF2a).

Mice without the normal complement of GCN2 in the brain failed to exhibit an aversion to imbalanced food, the researchers reported. The protein inactivation also led to a decline in modified eIF2a in a key part of the brain following consumption of an imbalanced meal.

The findings reveal that the ancient amino acid-sensing pathway affects feeding behavior by activating a brain circuit that biases consumption against imbalanced food sources, the researchers said.

While the findings are in mice, "there's no reason to believe that the same mechanism isn't at work in humans," Ron said. However, he suspects that cultural influences coupled with an instinctual drive to consume foods rich in calories might often override the amino acid gauge that would otherwise promote a balanced diet.

The researchers include Anne-Catherine Maurin, Céline Jousse, Julien Averous, Laurent Parry, Alain Bruhat, Yoan Cherasse,and Pierre Fafournoux of the Institut National de la Recherche Agronomique de Theix in Saint Genès-Champanelle, France; and Huiqing Zeng, Yuhong Zhang, Heather P. Harding, and David Ron of the Skirball Institute of Biomolecular Medicine at New York University School of Medicine in New York, New York. This work was supported by an NIH grant.

Anne-Catherine Maurin, Céline Jousse, Julien Averous, Laurent Parry, Alain Bruhat, Yoan Cherasse, Huiqing Zeng, Yuhong Zhang, Heather P. Harding, David Ron, and Pierre Fafournoux: "The GCN2 kinase biases feeding behavior to maintain amino acid homeostasis in omnivores"

Publishing in Cell Metabolism, Volume 1, Number 4, April 2005, pages 273-277. www.cellmetabolism.org