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

64 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Glucagon Couples Hepatic Amino Acid Catabolism to mTOR-Dependent Regulation of α-Cell Mass'. Together they form a unique fingerprint.

  • Cite this

    Solloway, M. J., Madjidi, A., Gu, C., Eastham-Anderson, J., Clarke, H. J., Kljavin, N., Zavala-Solorio, J., Kates, L., Friedman, B., Brauer, M., Wang, J., Fiehn, O., Kolumam, G., Stern, H., Lowe, J. B., Peterson, A. S., & 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