Sensing essential amino acid deficiency: behavioral and

BIOCHEMICAL MECHANISMS, Dorothy W. Gietzen, Shuzhen Hao, Catherine M. Inta, and
James W. Sharp, School of Veterinary Medicine, University of California, Davis, Department of
Anatomy, Physiology and Cell Biology, Davis, California 95616, USA.
Maintenance of IAA (Indispensable Amino Acids) homeostasis is crucial for survival. In
motile animals a complete supply of IAA is assured by diet selection. In humans the use of
complementary proteins, such as rice and beans, predates the discovery of IAA. In the rat the
threshold for sensing IAA using differing limiting IAAs is in the range of 90-120 ppm, showing
exquisite sensitivity to IAA depletion. The response is quick: the time course for detecting IAA
depletion was determined on the basis of time to meal termination: 90% of the rats eating an IAA
deficient meal terminate that meal in 20 min, whereas 50% of the control rats continue eating their
balanced meal. Several other studies have shown sensing of IAA deficiency in less than 30 min.
The involvement of the brain in sensing IAA depletion was suggested by the finding that the
rate of decrease of the limiting IAA in brain tissue is as rapid as that in plasma. The limiting IAA
reverses the feeding response to an IAA imbalanced diet at much a lower concentration when
infused into the carotid artery than into the jugular vein. Using classical brain lesioning techniques
in the late 1960s, the chemosensor for IAA depletion was shown to be in the anterior piriform
cortex (APC). Given saline injections into the APC, rats terminate a threonine-devoid meal within
20 min, but those injected with 2 nmol of threonine into the APC continue to eat the IAA-devoid
food, as do injected animals given a complete diet.
The detection system for depletion of IAA is conserved across eukaryotic species. The initial
event, after ingestion of an imbalanced or deficient diet, is a decrease in the concentration of the
limiting IAA; the limiting IAA is decreased in APC tissue by 56% at 21 min. The role for
uncharged tRNA in sensing IAA deficiency by animals was shown directly by injecting tRNA
synthetase inhibitors into the rat APC and observing the behavioral response. Injection of Lthreoninol or L-leucinol, but not D-threoninol or a dispensable L-AA-alcohol, into the APC
decreases food intake at 20 min and increases other downstream events the same as eating a
threonine-devoid diet. The effects of L-AA-alcohols are stereospecific, competitive, and selective
for their respective IAA. Next is the activation of GCN2, which then phosphorylates the alpha
subunit of eIF2. The rat not only rejects a threonine-devoid diet, but also responds by increasing
the phosphorylation of eIF2 in APC neurons. The level of phosphorylation is in proportion to the
amount of IAA-devoid diet eaten prior to detection of the deficiency. Phosphorylation of eIF2 is
associated with interruption of global protein synthesis, including the restoration of transporters
important to the inhibitory circuitry in the APC. This may be important in the overall activation of
the APC and its downstream circuitry. The activation of the APC is associated with increased
intracellular calcium and activation of the ERK1/2 proteins in the MAP kinase system.
Downstream of ERK1/2 we find activation of the system A amino acid transporter.
After detection of IAA deficiency, the behavioral strategies for dealing with limiting amounts
of IAA include altered food choice, meal termination, foraging for food sources that will
complement or correct the deficiency, the development of a learned aversion to a deficient or
imbalanced food in order to avoid that food in the future, and memory for the place associated with
repleting food. Signals downstream from the APC, which activate these behaviors, are carried by
the APC's glutamatergic output cells. Brain areas activated by these outputs will be discussed.
Supported by NIH NS 043210 to DWG.
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