L-arginine:glycine amidinotransferase deficiency protects from metabolic syndrome.
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L-arginine:glycine amidinotransferase deficiency protects from metabolic syndrome. / Choe, Chi-Un; Nabuurs, Christine; Stockebrand, Malte; Neu, Axel; Nunes, Patricia; Morellini, Fabio; Sauter, Kathrin; Schillemeit, Stefan; Hermans-Borgmeyer, Irmgard; Marescau, Bart; Heerschap, Arend; Isbrandt, Dirk.
in: HUM MOL GENET, Jahrgang 22, Nr. 1, 1, 2013, S. 110-123.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - L-arginine:glycine amidinotransferase deficiency protects from metabolic syndrome.
AU - Choe, Chi-Un
AU - Nabuurs, Christine
AU - Stockebrand, Malte
AU - Neu, Axel
AU - Nunes, Patricia
AU - Morellini, Fabio
AU - Sauter, Kathrin
AU - Schillemeit, Stefan
AU - Hermans-Borgmeyer, Irmgard
AU - Marescau, Bart
AU - Heerschap, Arend
AU - Isbrandt, Dirk
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
KW - Animals
KW - Mice
KW - Mice, Inbred C57BL
KW - Mutation
KW - Body Weight
KW - Mice, Transgenic
KW - Enzyme Activation
KW - Magnetic Resonance Spectroscopy
KW - Brain/metabolism
KW - Adenylate Kinase/metabolism
KW - Adipose Tissue
KW - Amidinotransferases/genetics
KW - Creatine/metabolism
KW - Hypothalamus/enzymology
KW - Metabolic Syndrome X/enzymology/genetics
KW - Animals
KW - Mice
KW - Mice, Inbred C57BL
KW - Mutation
KW - Body Weight
KW - Mice, Transgenic
KW - Enzyme Activation
KW - Magnetic Resonance Spectroscopy
KW - Brain/metabolism
KW - Adenylate Kinase/metabolism
KW - Adipose Tissue
KW - Amidinotransferases/genetics
KW - Creatine/metabolism
KW - Hypothalamus/enzymology
KW - Metabolic Syndrome X/enzymology/genetics
M3 - SCORING: Journal article
VL - 22
SP - 110
EP - 123
JO - HUM MOL GENET
JF - HUM MOL GENET
SN - 0964-6906
IS - 1
M1 - 1
ER -
