Remodeling of Hepatic Metabolism and Hyperaminoacidemia in Mice Deficient in Proglucagon-Derived Peptides

• Published in: Diabetes (New York, N.Y.) Vol. 61; no. 1; pp. 74 - 84
• Main Authors: WATANABE, Chika, SEINO, Yusuke, OISO, Yutaka, MURATA, Yoshiharu, HAYASHI, Yoshitaka, MIYAHIRA, Hiroki, YAMAMOTO, Michiyo, FUKAMI, Ayako, OZAKI, Nobuaki, TAKAGISHI, Yoshiko, SATO, Jun, FUKUWATARI, Tsutomu, SHIBATA, Katsumi
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.01.2012
• Subjects: Amino acid disorder screening; Amino acids; Amino Acids - blood; Amino Acids - metabolism; Aminoacid disorders; Animals; Antibodies; Biological and medical sciences; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzymes; Errors of metabolism; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Food; Gene expression; Gene Expression Regulation, Enzymologic; Glucagon; Glucose; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Health aspects; Homeostasis; Insulin; Kinases; Laboratory animals; Lipid Metabolism - genetics; Lipid Metabolism - physiology; Liver; Liver - enzymology; Liver - metabolism; Male; Mass spectrometry; Medical sciences; Metabolic diseases; Metabolic Diseases - blood; Metabolic Diseases - genetics; Metabolic Diseases - metabolism; Metabolic Networks and Pathways - genetics; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Peptide Fragments - chemistry; Peptide Fragments - deficiency; Peptide Fragments - genetics; Peptide Fragments - metabolism; Peptides; Phosphorylation; Physiological aspects; Proglucagon - chemistry; Proglucagon - deficiency; Proglucagon - genetics; Proglucagon - metabolism; Proteins; Scientific imaging; Up-Regulation; Japan; Endocrinopathy; Peptides; Diabetes mellitus; Rodentia; Metabolic diseases; Metabolism; Enzymopathy; Prohormone; Genetic disease; Hyperaminoacidemia; Vertebrata; Mammalia; Mouse; Animal; Aminoacid disorder; Proglucagon
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db11-0739

Glucagon is believed to be one of the most important peptides for upregulating blood glucose levels. However, homozygous glucagon-green fluorescent protein (gfp) knock-in mice (Gcg(gfp/gfp): GCGKO) are normoglycemic despite the absence of proglucagon-derived peptides, including glucagon. To characterize metabolism in the GCGKO mice, we analyzed gene expression and metabolome in the liver. The expression of genes encoding rate-limiting enzymes for gluconeogenesis was only marginally altered. On the other hand, genes encoding enzymes involved in conversion of amino acids to metabolites available for the tricarboxylic acid cycle and/or gluconeogenesis showed lower expression in the GCGKO liver. The expression of genes involved in the metabolism of fatty acids and nicotinamide was also altered. Concentrations of the metabolites in the GCGKO liver were altered in manners concordant with alteration in the gene expression patterns, and the plasma concentrations of amino acids were elevated in the GCGKO mice. The insulin concentration in serum and phosphorylation of Akt protein kinase in liver were reduced in GCGKO mice. These results indicated that proglucagon-derived peptides should play important roles in regulating various metabolic pathways, especially that of amino acids. Serum insulin concentration is lowered to compensate the impacts of absent proglucagon-derived peptide on glucose metabolism. On the other hand, impacts on other metabolic pathways are only partially compensated by reduced insulin action.