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(Journal of Nutrition. 2001;131:839S-840S.)
© 2001 The American Society for Nutritional Sciences

Supplement

Introduction1

Susan M. Hutson* and Robert A. Harris{dagger}

* Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157 {dagger} Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122

2To whom correspondence should be addressed. E-mail: shutson{at}wfubmc.edu.


   INTRODUCTION
TOP
 INTRODUCTION
REFERENCES
 
Although the anabolic effects of amino acids originating from dietary protein on protein synthesis and cell function were first reported over 20 years ago, until recently the molecular basis for many of these observations remained elusive. Now there is convincing evidence that amino acids are actually participants in signal transduction pathways, activating in selected cells some of the same signaling cascades as the anabolic hormone insulin. This symposium was organized to provide the opportunity for ASNS members to learn about new findings that demonstrate how amino acids mediate regulation of important cellular functions. These results may provide the key to understanding how dietary protein exerts its anabolic effects on body tissues and how protein interacts with the other nutrients.

Activation of signaling pathways is now recognized to be an important nonprotein function of amino acids. This can be and often is studied with amino acid mixtures. In most instances, however, the indispensable branched-chain amino acid leucine can exert the same effects as amino acid mixtures. For this reason, the symposium focused primarily on leucine as a signaling molecule.

Historically, leucine has always seemed special and more important than the other two branched-chain amino acids, isoleucine and valine. The early work of Harper and collaborators (1954) first demonstrated the adverse effects on growing animals fed a low-protein diet containing an inordinately large amount of an individual amino acid. Both food intake and growth were depressed. This antagonism is most readily observed with leucine versus isoleucine and valine (reviewed in Harper et al. 1970Citation ). We have long known that leucine is ketogenic and is specific among the branched-chain amino acids in its ability to stimulate insulin release from the islet cells of the pancreas (Panten et al. 1974Citation ). Cochrane and coworkers (1956) first reported that leucine precipitated hypoglycemic episodes in infants with "idiopathic hypoglycemia," and Fajans et al. (1963) suggested the description amino acid-induced hyperinsulinemia. As discussed by Harper et al. (1970), the uniqueness of leucine probably stems from the fact that 1) being ketogenic leucine cannot counterbalance the hypoglycemic effect of insulin and 2) the leucine-induced insulin release is presumably magnified in the congenital hypoglycemia case noted above and in conditions where islet cells are activated (Fajans et al. 1963Citation ).

The first paper, "Regulation of Branched-Chain {alpha}-Keto Acid Dehydrogenase Kinase Expression" by Robert A. Harris, reviews the molecular mechanisms by which leucine catabolism is controlled at the level of the branched-chain {alpha}-keto acid dehydrogenase complex. Evidence is presented for nutrient and hormonal regulation of expression of the branched-chain {alpha}-keto acid dehydrogenase kinase. The hypothesis is put forth for the involvement of thyroid hormone in the regulation of the expression of this gene in animals fed low-protein diets.

The second paper, "Function of Leucine in Excitory Neurotransmitter Metabolism in the Central Nervous System" by Susan M. Hutson, addresses the role of branched-chain amino acids in metabolism in the central nervous system. The hypothesis is advanced that branched-chain amino acids have an important role as donors of nitrogen for dispensable amino acid biosynthesis, analogous to their role in glutamine and alanine synthesis in skeletal muscle developed in the 1970s (Odessey et al. 1974Citation , Chang and Goldberg 1978Citation , Garber et al. 1976Citation ). Evidence that BCAA nitrogen is required for formation of the neurotransmitter glutamate are reviewed (Yudkoff et al. 1996Citation , Bixel et al. 1997Citation , Hutson et al. 1998Citation ) and new findings on the special role of branched-chain amino acids in neurotransmitter metabolism in the central nervous system are presented.

The third paper, "Molecular Mechanisms in the Brain Involved in the Anorexia of Branched-Chain Amino Acid Deficiency" by Dorothy W. Gietzen, provides insight into the molecular mechanism underlying the anorexia. Reports of anorexia with indispensable amino acid deficiencies date from the early 1900s (Wilcock and Hopkins 1906Citation ), and evidence for decreased appetite with deficiencies of BCAA were reported by Rose (1957). Early work using limiting diets, popularized by Harper (reviewed in Harper et al. 1970Citation ), and animals with specific brain lesions (Leung and Rogers 1971Citation ) suggested that the anterior piriform cortex is the primary sensor of amino acid deficiency. This paper provides evidence that conditioned taste aversion in response to amino acid deficiency involves synaptic reorganization resulting from changes in gene expression.

The unique ability of leucine to regulate protein synthesis in muscle was first documented in the 1970s (Buse and Reid 1975Citation , Fulks et al. 1975Citation , Li and Jefferson 1978Citation ). Only recently, however, has great insight been gained with respect to molecular mechanisms involved in the stimulatory effects of leucine on protein translation (Hara et al. 1998Citation , Patti et al. 1998Citation , Kimball et al. 1999Citation , Anthony et al. 2000Citation ) and multicellular clustering of adipocytes (Fox et al. 1998aCitation , 1998b). The fourth paper, "Signaling Pathways Involved in Translational Control of Protein Synthesis in Skeletal Muscle by Leucine" by Leonard S. Jefferson, demonstrates stimulation of protein synthesis by leucine is the result of enhancement of the activity and synthesis of proteins involved in mRNA translation. Leucine signals increased translation initiation by a mechanism involving the protein kinase mammalian target of rapamycin (mTOR), a component of the signaling cascade by which insulin likewise promotes protein synthesis. The final paper, "Role of Leucine in the Regulation of mTOR by Amino Acids: Revelations from Structure–Activity Studies" by Christopher J. Lynch, extends the discussion of leucine regulation of the mTOR signaling pathway to adipocytes and other cell types. Evidence suggesting amino acids activate mTOR by more than one pathway is presented.


   FOOTNOTES
 
1 Presented as part of the symposium "Leucine as a Nutritional Signal" given at the Experimental Biology 2000 meeting, held in San Diego, CA on April 18, 2000. This symposium was sponsored by the American Society for Nutritional Sciences and was supported by the National Institutes of Health Division of Nutritional Research Corporation and Division of Digestive Diseases and Nutrition. The proceedings of the symposium are published as a supplement to The Journal of Nutrition. Editors for the symposium publication were Susan M. Hutson, Wake Forest University School of Medicine and Robert A. Harris, Indiana University School of Medicine. Back


   REFERENCES
TOP
 INTRODUCTION
 REFERENCES
 

1. Anthony J. C., Gautsch Anthony T., Kimball S. R., Vary T. C., Jefferson L. S. Orally administered leucine stimulates protein synthesis in skeletal muscle of postabsorptive rats in association with increased eIF4F formation. J. Nutr. 2000;130:139-145[Abstract/Free Full Text]

2. Bixel M. G., Hutson S. M., Hamprecht B. Cellular distribution of branched-chain amino acid aminotransferase isoenzymes among rat brain glial cells in culture. J. Histochem. Cytochem. 1997;45:685-694[Abstract/Free Full Text]

3. Buse M. G., Reid S. S. Leucine: a possible regulator of branched chain amino acids on the ribosomal cycle in muscles of fasted rats. Horm. Metab. Res. 1975;11:289-292

4. Chang T. W., Goldberg A. L. The metabolic fates of amino acids and the formation of glutamine in skeletal muscle. J. Biol. Chem. 1978;253:3685-3693[Free Full Text]

5. Cochrane W. A., Payne W. W., Simpkiss M. J., Woolf L. I. Familial hypoglycemia precipitated by amino acids. J. Clin. Invest. 1956;35:411-422

6. Fajans S. S., Knopf R. F., Floyd J. C., Power L., Conn J. W. The experimental induction in man of sensitivity to leucine hypoglycemia. J. Clin. Invest. 1963;42:216-229[Medline]

7. Fox H. L., Kimball S. R., Jefferson L. S., Lynch C. J. Amino acids stimulate phosphorylation of p70S6k and organization of rat adipocytes into multicellular clusters. Am. J. Physiol. Cell Physiol. 1998a;274:C206-C213[Abstract/Free Full Text]

8. Fox H. L., Pham P. T., Kimball S. R., Jefferson L. S., Lynch C. J. Amino acid effects on translational repressor 4E-BP1 are mediated primarily by L-leucine in isolated adipipocytes. Am. J. Physiol. Cell Physiol. 1998b;275:C1232-C1238[Abstract/Free Full Text]

9. Fulks R. M., Li J. B., Goldberg A. L. Effects of insulin, glucose, and amino acids on protein turnover in rat diaphragm. J. Biol. Chem. 1975;250:290-298[Abstract/Free Full Text]

10. Garber A. J., Karl I. E., Kipnis D. M. Alanine and glutamine synthesis and release from skeletal muscle. II. The precursor role of amino acids in alanine and glutamine synthesis. J. Biol. Chem. 1976;251:836-843[Abstract/Free Full Text]

11. Hara K., Yonezawa K., Weng Q.-P., Kozolwski M. T., Belham C., Avruch J. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J. Biol. Chem. 1998;273:14484-14494[Abstract/Free Full Text]

12. Harper A. E., Benevenga N. J., Wohlheuter R. M. Effects of ingestion of disproportionate amounts of amino acids. Physiol. Rev. 1970;50:428-558[Free Full Text]

13. Harper A. E., Benton D. A., Winje M. E., Elvehjem C. A. Leucine-isoleucine antagonism in the rat. Arch. Biochem. Biophys. 1954;57:1-12

14. Hutson S. M., Berkich D. A., Drown P., Xu B., LaNoue K. F. Role of branched-chain aminotransferase isoenzymes and gabapentin in neurotransmitter metabolism. J. Neurochem. 1998;71:863-874[Medline]

15. Kimball S. R., Shantz L. M., Horetsky R. L., Jefferson L. S. Leucine regulates translation of specific mRNAs in L6 myoblasts through mTOR-mediated changes in availability of eIF4E and phosphorylation of ribosomal protein S6. J. Biol. Chem. 1999;274:11647-11652[Abstract/Free Full Text]

16. Leung P.M.B., Rogers Q. R. Importance of prepyriform cortex in food-intake response of rats to amino acids. Am. J. Physiol. 1971;221:929-935[Free Full Text]

17. Li J. B., Jefferson L. S. Influence of amino acid availability on protein turnover in perfused skeletal muscle. Biochim. Biophys. Acta 1978;544:351-359[Medline]

18. Odessey R., Khairallah E. A., Goldberg A. L. Origin and possible significance of alanine production by skeletal muscle. J. Biol. Chem. 1974;250:290-298

19. Panten U., Christians J., Kriegstein E., Von Poser W., Hasselblatt A. Studies on the mechanism of L-leucine-and alpha-ketoisocaproic acid-induced insulin release from perifused isolated pancreatic islets. Diabetologia 1974;10:149-154[Medline]

20. Patti M.-E., Brambilla E., Luzi L., Landaker E. J., Kahn C. R. Bidirectional modulation of insulin action by amino acids. J. Clin. Invest. 1998;101:1519-1529[Medline]

21. Rose W. C. The amino acid requirement of adult man. Nutr. Abstr. Rev. 1957;27:631-647

22. Wilcock E. G., Hopkins F. G. The importance of individual amino-acids in metabolism; observations on the effect of adding tryptophane to a diet in which zein is the sole nitrogenous constituent. J. Physiol. (Lond.) 1906;25:88-102

23. Yudkoff M., Daikhin Y., Grunstein L., Nissim I., Stern J., Pleasure D., Nissim I. Astrocyte leucine metabolism: significance of branched-chain amino acid transamination. J. Neurochem. 1996;66:378-385[Medline]




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