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Biochemical, Molecular, and Genetic Mechanisms

Leucine Activates Pancreatic Translational Machinery in Rats and Mice through mTOR Independently of CCK and Insulin^1–3,

Maria Dolors Sans^*,4, Mitsuo Tashiro^*,5, Nancy L. Vogel^*, Scot R. Kimball^**, Louis G. D'Alecy^* and John A. Williams^*,

^* Department of Molecular and Integrative Physiology and Department of Internal Medicine, The University of Michigan Medical School, Ann Arbor, MI 48109-0622 and ^** Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033

⁴ To whom correspondence should be addressed. E-mail: mdsansg{at}umich.edu.

Feeding stimulates pancreatic digestive enzyme synthesis at the translational level, and this is thought to be mediated by hormones and neurotransmitters. However, BCAAs, particularly leucine, stimulate protein synthesis in several tissues. We investigated whether BCAA stimulated the translational machinery in murine pancreas and whether their effects were independent of hormones. Rats and mice were administered (i.g. gavage) individual BCAA at 1.35 mg/g (body weight) and rat isolated pancreatic acini were incubated with BCAA under different conditions. Activation of translation initiation factors and total protein synthesis were analyzed. BCAA gavage stimulated the phosphorylation of the initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) and the ribosomal protein S6 kinase (S6K), with leucine being the most effective. Leucine also increased the association of the initiation factors eIF4E and eIF4G, but did not affect the activity of the guanine nucleotide exchange factor eIF2B, nor total protein synthesis. BCAA acted independently of insulin signaling on isolated pancreatic acini from diabetic rats. The ability of leucine to promote phosphorylation of 4E-BP1 and S6K as well as enhance the assembly of the eIF4F complex was unimpaired in CCK-deficient mice. Finally, rapamycin (0.75 mg/kg) administered to rats 2 h before leucine gavage inhibited the phosphorylation of S6 and 4E-BP1 induced by leucine. We conclude that leucine may participate, as a signal as well as a substrate, in activating the translational machinery in pancreatic acinar cells independently of hormonal effects and that this action is through the mTOR pathway.

KEY WORDS: • pancreas • leucine • translation • cholecystokinin • insulin

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