title: Intracerebroventricular infusion of glucose, insulin, and the adenosine monophosphate-activated kinase activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, controls muscle glycogen synthesis.
abstract: The AMP-activated kinase has been proposed to be an important intracellular energy sensor because the enzyme controls lipid and glucose oxidation. In the corresponding knockout mice, insulin-stimulated muscle glycogen synthesis and glucose tolerance are reduced. In addition, these mice excrete catecholamines in excess, suggesting that the central and autonomic nervous systems are impaired. Indeed, in the brain, fuel sensor mechanisms have been described, and recently, evidence has shown that the AMP-activated kinase could control food intake. We show in this study that the intracerebroventricular infusion of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), a pharmacological AMP-activated kinase activator, increased insulin-stimulated muscle glycogen synthesis and insulin sensitivity during a hyperinsulinemic clamp. Similarly, we infused AICAR in the brain of fasted mice, i.e. when insulinemia was low, and showed that muscle glycogen synthesis was also increased. We then studied the effect of a cerebral infusion of the peripheral signals, i.e. insulin and glucose, known to be detected by the brain. The cerebral infusion of insulin increased muscle glycogen synthesis. This effect was blunted by the coinfusion of glucose, which induced insulin resistance. Importantly, the cerebral injections of AICAR, insulin, and glucose were associated with variations in the phosphorylation state of the AMP-activated kinase in the hypothalamus. In conclusion, our data showed for the first time that 1) the brain is sensitive to insulin and glucose for the regulation of muscle glycogen synthesis; and 2) the cerebral infusion of AICAR enhances insulin sensitivity. Although the above mechanisms are correlated with the regulation of AMP-activated kinase, the direct involvement of the enzyme in the mechanism remains to be demonstrated.
authors.affiliation: Unité Mixte de Recherche 5018, Centre National de la Recherche Scientifique-Paul Sabatier University and Institut Federatif de Recherche 31, Rangueil Hospital, L1 Building, 31403 Toulouse, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Perrin
authors.forename: Claude
authors.initials: C
authors.lastname: Knauf
authors.forename: Rémy
authors.initials: R
authors.lastname: Burcelin
mesh_terms: D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D005215:Fasting / Q000502:physiology; D005947:Glucose / Q000493:pharmacokinetics*; D006003:Glycogen / Q000096:biosynthesis; D006946:Hyperinsulinism / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects / Q000201:enzymology; D007276:Injections, Intraventricular; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012263:Ribonucleosides / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D009097:Multienzyme Complexes; D012263:Ribonucleosides; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D006003:Glycogen; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose