title: Glucagon Couples Hepatic Amino Acid Catabolism to mTOR-Dependent Regulation of α-Cell Mass.
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 ex vivo and enabled conversion of α-cells into β-like cells in vivo. 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 can function as growth factors that increase α-cell proliferation.
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Solloway
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Madjidi
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Gu
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Eastham-Anderson
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Holly J
authors.initials: HJ
authors.lastname: Clarke
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Noelyn
authors.initials: N
authors.lastname: Kljavin
authors.affiliation: Department of Biomedical Imaging, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Zavala-Solorio
authors.affiliation: Department of Biomedical Imaging, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Lance
authors.initials: L
authors.lastname: Kates
authors.affiliation: Department of Bioinformatics, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Friedman
authors.affiliation: Department of Bioinformatics, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Brauer
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Jianyong
authors.initials: J
authors.lastname: Wang
authors.affiliation: The West Coast Metabolomics Center, University of California, Davis, CA 95616, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.affiliation: Department of Biomedical Imaging, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Kolumam
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Stern
authors.affiliation: Department of Pathology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Lowe
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA. Electronic address: peterson.andrew@gene.com.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Peterson
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA. Electronic address: ballan@ngmbio.com.
authors.forename: Bernard B
authors.initials: BB
authors.lastname: Allan
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D005934:Glucagon / Q000378:metabolism*; D008099:Liver / Q000166:cytology* / Q000378:metabolism*; D008660:Metabolism; D051379:Mice; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D005934:Glucagon; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases