title: Impaired nutrient signaling and body weight control in a Na+ neutral amino acid cotransporter (Slc6a19)-deficient mouse.
abstract: Amino acid uptake in the intestine and kidney is mediated by a variety of amino acid transporters. To understand the role of epithelial neutral amino acid uptake in whole body homeostasis, we analyzed mice lacking the apical broad-spectrum neutral (0) amino acid transporter B(0)AT1 (Slc6a19). A general neutral aminoaciduria was observed similar to human Hartnup disorder which is caused by mutations in SLC6A19. Na(+)-dependent uptake of neutral amino acids into the intestine and renal brush-border membrane vesicles was abolished. No compensatory increase of peptide transport or other neutral amino acid transporters was detected. Mice lacking B(0)AT1 showed a reduced body weight. When adapted to a standard 20% protein diet, B(0)AT1-deficient mice lost body weight rapidly on diets containing 6 or 40% protein. Secretion of insulin in response to food ingestion after fasting was blunted. In the intestine, amino acid signaling to the mammalian target of rapamycin (mTOR) pathway was reduced, whereas the GCN2/ATF4 stress response pathway was activated, indicating amino acid deprivation in epithelial cells. The results demonstrate that epithelial amino acid uptake is essential for optimal growth and body weight regulation.
authors.affiliation: Research School of Biology, Australian National University, Canberra, Australian Capital Territory 0200, Australia. Stefan.broer@anu.edu.au
authors.forename: Angelika
authors.initials: A
authors.lastname: Bröer
authors.forename: Torsten
authors.initials: T
authors.lastname: Juelich
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Vanslambrouck
authors.forename: Nadine
authors.initials: N
authors.lastname: Tietze
authors.forename: Peter S
authors.initials: PS
authors.lastname: Solomon
authors.forename: Jeff
authors.initials: J
authors.lastname: Holst
authors.forename: Charles G
authors.initials: CG
authors.lastname: Bailey
authors.forename: John E J
authors.initials: JE
authors.lastname: Rasko
authors.forename: Stefan
authors.initials: S
authors.lastname: Bröer
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000502:physiology*; D004044:Dietary Proteins; D004435:Eating / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism*; D006250:Hartnup Disease / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D026921:Amino Acid Transport Systems, Neutral; C081452:Atf4 protein, mouse; D004044:Dietary Proteins; D007328:Insulin; C505021:SLC6A19 protein, mouse; D051701:Activating Transcription Factor 4; C546843:mTOR protein, mouse; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases