title: L-arginine:glycine amidinotransferase deficiency protects from metabolic syndrome.
abstract: Phosphorylated creatine (Cr) serves as an energy buffer for ATP replenishment in organs with highly fluctuating energy demand. The central role of Cr in the brain and muscle is emphasized by severe neurometabolic disorders caused by Cr deficiency. Common symptoms of inborn errors of creatine synthesis or distribution include mental retardation and muscular weakness. Human mutations in l-arginine:glycine amidinotransferase (AGAT), the first enzyme of Cr synthesis, lead to severely reduced Cr and guanidinoacetate (GuA) levels. Here, we report the generation and metabolic characterization of AGAT-deficient mice that are devoid of Cr and its precursor GuA. AGAT-deficient mice exhibited decreased fat deposition, attenuated gluconeogenesis, reduced cholesterol levels and enhanced glucose tolerance. Furthermore, Cr deficiency completely protected from the development of metabolic syndrome caused by diet-induced obesity. Biochemical analyses revealed the chronic Cr-dependent activation of AMP-activated protein kinase (AMPK), which stimulates catabolic pathways in metabolically relevant tissues such as the brain, skeletal muscle, adipose tissue and liver, suggesting a mechanism underlying the metabolic phenotype. In summary, our results show marked metabolic effects of Cr deficiency via the chronic activation of AMPK in a first animal model of AGAT deficiency. In addition to insights into metabolic changes in Cr deficiency syndromes, our genetic model reveals a novel mechanism as a potential treatment option for obesity and type 2 diabetes mellitus.
authors.affiliation: Experimental Neuropediatrics, Center for Molecular Neurobiology and Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Chi-un
authors.initials: CU
authors.lastname: Choe
authors.forename: Christine
authors.initials: C
authors.lastname: Nabuurs
authors.forename: Malte C
authors.initials: MC
authors.lastname: Stockebrand
authors.forename: Axel
authors.initials: A
authors.lastname: Neu
authors.forename: Patricia
authors.initials: P
authors.lastname: Nunes
authors.forename: Fabio
authors.initials: F
authors.lastname: Morellini
authors.forename: Kathrin
authors.initials: K
authors.lastname: Sauter
authors.forename: Stefan
authors.initials: S
authors.lastname: Schillemeit
authors.forename: Irm
authors.initials: I
authors.lastname: Hermans-Borgmeyer
authors.forename: Bart
authors.initials: B
authors.lastname: Marescau
authors.forename: Arend
authors.initials: A
authors.lastname: Heerschap
authors.forename: Dirk
authors.initials: D
authors.lastname: Isbrandt
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000273:Adipose Tissue; D000579:Amidinotransferases / Q000235:genetics*; D000818:Animals; D001835:Body Weight; D001921:Brain / Q000378:metabolism; D003401:Creatine / Q000378:metabolism; D004789:Enzyme Activation; D007031:Hypothalamus / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D024821:Metabolic Syndrome / Q000201:enzymology / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation
chemical_list: D000579:Amidinotransferases; C020681:glycine amidinotransferase; D000263:Adenylate Kinase; D003401:Creatine