Amino acids inhibit Agrp gene expression via an mTOR-dependent mechanism

Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E165-71. doi: 10.1152/ajpendo.00675.2006. Epub 2007 Mar 20.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agouti-Related Protein
  • Amino Acids / pharmacology*
  • Animals
  • Cells, Cultured
  • Diet, Protein-Restricted
  • Eating / drug effects
  • Gene Expression Regulation / drug effects*
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Male
  • Protein Kinases / metabolism
  • Protein Kinases / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases

Substances

  • AGRP protein, rat
  • Agouti-Related Protein
  • Amino Acids
  • Intercellular Signaling Peptides and Proteins
  • Protein Kinases
  • mTOR protein, rat
  • TOR Serine-Threonine Kinases