Glucagon Couples Hepatic Amino Acid Catabolism to mTOR-Dependent Regulation of α-Cell Mass

Mark J. Solloway, Azadeh Madjidi, Chunyan Gu, Jeff Eastham-Anderson, Holly J. Clarke, Noelyn Kljavin, Jose Zavala-Solorio, Lance Kates, Brad Friedman, Matt Brauer, Jianyong Wang, Oliver Fiehn, Ganesh Kolumam, Howard Stern, John B. Lowe, Andrew S. Peterson, Bernard B. Allan

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Understanding the regulation of islet cell mass has important implications for the discovery of regenerative therapies for diabetes. The liver plays a central role in metabolism and the regulation of endocrine cell number, but liver-derived factors that regulate α-cell and β-cell mass remain unidentified. We propose a nutrient-sensing circuit between liver and pancreas in which glucagon-dependent control of hepatic amino acid metabolism regulates α-cell mass. We found that glucagon receptor inhibition reduced hepatic amino acid catabolism, increased serum amino acids, and induced α-cell proliferation in an mTOR-dependent manner. In addition, mTOR inhibition blocked amino-acid-dependent α-cell replication exvivo and enabled conversion of α-cells into β-like cells invivo. Serum amino acids and α-cell proliferation were increased in neonatal mice but fell throughout postnatal development in a glucagon-dependent manner. These data reveal that amino acids act as sensors of glucagon signaling and canfunction as growth factors that increase α-cell proliferation.

Original languageEnglish (US)
Pages (from-to)495-510
Number of pages16
JournalCell Reports
Volume12
Issue number3
DOIs
StatePublished - Jul 21 2015

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Glucagon
Amino Acids
Liver
Cell proliferation
Cell Proliferation
Metabolism
Glucagon Receptors
Endocrine Cells
Medical problems
Serum
Islets of Langerhans
Nutrients
Pancreas
Intercellular Signaling Peptides and Proteins
Cell Count
Cells
Food
Networks (circuits)
Sensors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Solloway, M. J., Madjidi, A., Gu, C., Eastham-Anderson, J., Clarke, H. J., Kljavin, N., ... Allan, B. B. (2015). Glucagon Couples Hepatic Amino Acid Catabolism to mTOR-Dependent Regulation of α-Cell Mass. Cell Reports, 12(3), 495-510. https://doi.org/10.1016/j.celrep.2015.06.034

Glucagon Couples Hepatic Amino Acid Catabolism to mTOR-Dependent Regulation of α-Cell Mass. / Solloway, Mark J.; Madjidi, Azadeh; Gu, Chunyan; Eastham-Anderson, Jeff; Clarke, Holly J.; Kljavin, Noelyn; Zavala-Solorio, Jose; Kates, Lance; Friedman, Brad; Brauer, Matt; Wang, Jianyong; Fiehn, Oliver; Kolumam, Ganesh; Stern, Howard; Lowe, John B.; Peterson, Andrew S.; Allan, Bernard B.

In: Cell Reports, Vol. 12, No. 3, 21.07.2015, p. 495-510.

Research output: Contribution to journalArticle

Solloway, MJ, Madjidi, A, Gu, C, Eastham-Anderson, J, Clarke, HJ, Kljavin, N, Zavala-Solorio, J, Kates, L, Friedman, B, Brauer, M, Wang, J, Fiehn, O, Kolumam, G, Stern, H, Lowe, JB, Peterson, AS & Allan, BB 2015, 'Glucagon Couples Hepatic Amino Acid Catabolism to mTOR-Dependent Regulation of α-Cell Mass', Cell Reports, vol. 12, no. 3, pp. 495-510. https://doi.org/10.1016/j.celrep.2015.06.034
Solloway MJ, Madjidi A, Gu C, Eastham-Anderson J, Clarke HJ, Kljavin N et al. Glucagon Couples Hepatic Amino Acid Catabolism to mTOR-Dependent Regulation of α-Cell Mass. Cell Reports. 2015 Jul 21;12(3):495-510. https://doi.org/10.1016/j.celrep.2015.06.034
Solloway, Mark J. ; Madjidi, Azadeh ; Gu, Chunyan ; Eastham-Anderson, Jeff ; Clarke, Holly J. ; Kljavin, Noelyn ; Zavala-Solorio, Jose ; Kates, Lance ; Friedman, Brad ; Brauer, Matt ; Wang, Jianyong ; Fiehn, Oliver ; Kolumam, Ganesh ; Stern, Howard ; Lowe, John B. ; Peterson, Andrew S. ; Allan, Bernard B. / Glucagon Couples Hepatic Amino Acid Catabolism to mTOR-Dependent Regulation of α-Cell Mass. In: Cell Reports. 2015 ; Vol. 12, No. 3. pp. 495-510.
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