title: Leucine is a direct-acting nutrient signal that regulates protein synthesis in adipose tissue.
abstract: In freshly isolated rat adipocytes, leucine or its analog norleucine activates the mammalian target of rapamycin (mTOR)-signaling pathway. This results in phosphorylation of the ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), two proteins involved in the initiation phase of protein synthesis. The purpose of the studies reported herein was to address the question of whether or not these in vitro effects of leucine and norleucine on adipocytes could be extended to the intact animal and to other tissues. To accomplish this, food-deprived (18 h) male Sprague-Dawley rats were orally administered solutions (2.5 ml/100 g body wt) containing normal saline (0.9% NaCl), a carbohydrate mixture (26.2% D-glucose and 26.2% sucrose), leucine (5.4%), or norleucine (5.4%). The protein synthetic responses of adipose tissue were measured and compared with those of other tissues. In addition, S6K1 and 4E-BP1 phosphorylation was measured, as was the plasma concentration of insulin and tissue ATP concentrations. Leucine administration stimulated protein synthesis in adipose tissue, gastrocnemius, and kidney but not in liver and heart. Norleucine stimulated protein synthesis in all of the tissues tested but, in contrast to leucine, without affecting plasma insulin concentrations. The carbohydrate meal had no effect on protein synthesis in any tissue tested but elicited a robust increase in plasma insulin. These findings provide support for a role of leucine as a direct-acting nutrient signal for stimulation of protein synthesis in adipose tissue as well as other select tissues. In adipose tissue, the effects of the different treatment conditions on the acute regulation of protein synthesis closely correlated with changes in phosphorylation of S6K1 and 4E-BP1; however, this correlation did not exist in all tissues examined. This result implies that leucine or norleucine may acutely stimulate protein synthesis, at least in some tissues, by a mechanism that is independent of both S6K1 and 4E-BP1 phosphorylation.
authors.affiliation: Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA. clynch@psu.edu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lynch
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Patson
authors.forename: Joshua
authors.initials: J
authors.lastname: Anthony
authors.forename: Alain
authors.initials: A
authors.lastname: Vaval
authors.forename: Leonard S
authors.initials: LS
authors.lastname: Jefferson
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Vary
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D007328:Insulin / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins; D007930:Leucine / Q000494:pharmacology*; D008297:Male; D009646:Norleucine / Q000494:pharmacology; D009994:Osmolar Concentration; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D009646:Norleucine; D000255:Adenosine Triphosphate; D019893:Ribosomal Protein S6 Kinases; D007930:Leucine