title: Differential regulation of AMPK activation in leptin- and creatine-deficient mice.
abstract: AMP-activated protein kinase (AMPK) is a key sensor and regulator of energy homeostasis. Previously, we demonstrated that intracellular energy depletion by L-arginine:glycine amidinotransferase (AGAT) deficiency resulted in AMPK activation and protected from metabolic syndrome. In the present study, we show tissue-specific leptin dependence of AMPK activation by energy depletion. We investigated leptin-dependent AMPK regulation in AGAT- and leptin-deficient (d/d ob/ob) mice. Like ob/ob mice, but unlike d/d mice, d/d ob/ob mice were obese and glucose intolerant. Therefore, leptin is a prerequisite for resistance to metabolic syndrome in AGAT-deficient mice. Quantitative Western blots revealed a 4-fold increase in AMPK activation in skeletal muscle of d/d ob/ob mice (P<0.001). However, AMPK activation was absent in white adipose tissue (WAT) and liver. Compared with blood glucose levels in ob/ob mice, fasting levels were still reduced and therefore did not show leptin dependence (wild-type, 79.4±3.9 mg/dl; d/d, 68.4±3.2 mg/dl; P<0.05). In ob/ob mice and wild-type mice, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), in combination with leptin, augmented glucose tolerance compared with AICAR alone, whereas no improvement was found under conditions of high-fat-diet feeding. These findings reveal a previously unknown synergistic AMPK activation by leptin and intracellular energy depletion, suggesting that AMPK activation can be therapeutically effective in metabolic syndrome only if leptin sensitivity is preserved.
authors.affiliation: 1Experimental Neuropediatrics, Center for Molecular Neurobiology and Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany. cchoe@uke.de.
authors.forename: Malte
authors.initials: M
authors.lastname: Stockebrand
authors.forename: Kathrin
authors.initials: K
authors.lastname: Sauter
authors.forename: Axel
authors.initials: A
authors.lastname: Neu
authors.forename: Dirk
authors.initials: D
authors.lastname: Isbrandt
authors.forename: Chi-un
authors.initials: CU
authors.lastname: Choe
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000201:enzymology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives; D000818:Animals; D001786:Blood Glucose; D003401:Creatine / Q000235:genetics / Q000378:metabolism*; D004041:Dietary Fats; D004789:Enzyme Activation / Q000235:genetics / Q000502:physiology*; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology; D009765:Obesity; D012265:Ribonucleotides
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D020738:Leptin; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D003401:Creatine
keywords: AGAT; AICAR; ob/ob; skeletal muscle; white adipose tissue