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About the Authors:
Jana Drgonova
Affiliation: Molecular Neurobiology Branch, NIH-IRP, NIDA, Baltimore, Maryland, United States of America
Josefin A. Jacobsson
Affiliation: Unit of Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
Joan C. Han
Affiliation: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD-IRP, NIH 10 CRC, Bethesda, Maryland, United States of America
Jack A. Yanovski
Affiliation: Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD-IRP, NIH 10 CRC, Bethesda, Maryland, United States of America
Robert Fredriksson
Affiliation: Unit of Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
Claude Marcus
Affiliation: Division of Pediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
Helgi B. Schiöth
Affiliation: Unit of Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
George R. Uhl
* E-mail: [email protected]
Affiliation: Molecular Neurobiology Branch, NIH-IRP, NIDA, Baltimore, Maryland, United States of America
Introduction
Amino acids can influence weight control by mechanisms that include enhanced postprandial and post absorptive satiety [1], [2], energy expenditure [3], [4] and insulin action [5], [6]. Hypothalamic neurons sense amino acid concentrations and integrate this data with information from other signals [7], [8]. Interest in the ways in which amino acids influence nutrition and body weight is boosted by increasing rates of obesity [9], [10] and elucidation of some of the genetic influences on these processes [11], [12], [13], [14], [15].
Essential branched-chain amino acids (BCAA), including leucine, constitute up to 20% of dietary protein and make significant contributions to the influences of protein on body weight [16]. Hypothalamic concentrations of BCAA rise rapidly after protein ingestion [17], [18]. Dietary administration of leucine or mixtures of BCAA increase thermogenesis, augment protein synthesis and alter insulin actions [6], [19], [20]. Leucine administered into the brain decreases food intake and body weight while increasing hypothalamic signaling through mTOR pathways [21], [22]. Firing rates of key arcuate/mediobasal hypothalamic neurons increase promptly upon application of leucine in ways that correspond to increased cFos expression in these hypothalamic neurons and interconnected neurons of the nucleus of the solitary tract [22].
SLC6A15, a founding member of a subfamily of “orphan neurotransmitter transporters” [23], [24], [25], mediates sodium-dependent, electrogenic transport of leucine and other BCAA [26], [27]. SLC6A15 is expressed in plasma membranes of...