Amino acids inhibit Agrp gene expression via an mTOR-dependent mechanism.
Metabolic fuels act on hypothalamic neurons to regulate feeding behavior and energy homeostasis, but the signaling mechanisms mediating these effects are not fully clear. Rats placed on a low-protein diet (10% of calories) exhibited increased food intake (P < 0.05) and hypothalamic Agouti-related protein (Agrp) gene expression (P = 0.002). Direct intracerebroventricular injection of either an amino acid mixture (RPMI 1640) or leucine alone (1 mug) suppressed 24-h food intake (P < 0.05), indicating that increasing amino acid concentrations within the brain is sufficient to suppress food intake. To define a cellular mechanism for these direct effects, GT1-7 hypothalamic cells were exposed to low amino acids for 16 h. Decreasing amino acid availability increased Agrp mRNA levels in GT1-7 cells (P < 0.01), and this effect was attenuated by replacement of the amino acid leucine (P < 0.05). Acute exposure to elevated amino acid concentrations increased ribosomal protein S6 kinase phosphorylation via a rapamycin-sensitive mechanism, suggesting that amino acids directly stimulated mammalian target of rapamycin (mTOR) signaling. To test whether mTOR signaling contributes to amino acid inhibition of Agrp gene expression, GT1-7 cells cultured in either low or high amino acids for 16 h and were also treated with rapamcyin (50 nM). Rapamycin treatment increased Agrp mRNA levels in cells exposed to high amino acids (P = 0.01). Taken together, these observations indicate that amino acids can act within the brain to inhibit food intake and that a direct, mTOR-dependent inhibition of Agrp gene expression may contribute to this effect.
Morrison
Christopher D
CD
Neurobehavior Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
Xi
Xiaochun
X
White
Christy L
CL
Ye
Jianping
J
Martin
Roy J
RJ
D054369:Agouti-Related Protein; D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D018753:Diet, Protein-Restricted; D004435:Eating / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases
C515197:AGRP protein, rat; D054369:Agouti-Related Protein; D000596:Amino Acids; D036341:Intercellular Signaling Peptides and Proteins; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases