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Amino acids inhibit Agrp gene expression via an mTOR-dependent mechanism
Open accessAbstract
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.
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“a number of studies demonstrate that low-protein diets induce hyperphagia, particularly in rodent models”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [73]
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Metadata
- Authors
- Morrison, C. D., Xi, X., White, C. L., Ye, J., & Martin, R. J.
- Affiliations
- Pennington Biomedical Research Center (US)
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2007-07
- Volume
- 293
- Issue
- 1
- Pages
- E165-E171
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC2596875
- OpenAlex
- W2015145490
- Cited by
- 183
- References
- 36
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 4 · 2023: 5 · 2022: 6 · 2021: 4 · 2020: 15 · 2019: 7 · 2018: 9 · 2017: 10 · 2016: 13 · 2015: 7 · 2014: 7 · 2013: 11 · 2012: 16
- FWCI
- 6.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (P20GM103528, P30GM118430)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK072476)
- National Institute of Neurological Disorders and Stroke (NS-051570, R03NS051570)
- National Center for Research Resources (RR 021945, P20RR021945)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Nursing › Nutrition and Dietetics › Biochemical Analysis and Sensing Techniques
- Keywords
- amino acids, agouti-related protein, mTOR signaling, leucine, food intake regulation, hypothalamic neurons, GT1-7 cells, S6K, rapamycin, low-protein diet, energy homeostasis
- MeSH terms
- Amino Acids, Animals, Cells, Cultured, Eating, Gene Expression Regulation, Hypothalamus, Male, Protein Kinases, Signal Transduction, Rats, Sprague-Dawley, Diet, Protein-Restricted, Intercellular Signaling Peptides and Proteins, Rats, Agouti-Related Protein, TOR Serine-Threonine Kinases
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