5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) effect on glucose production, but not energy metabolism, is independent of hepatic AMPK in vivo.

Hasenour CM, Ridley DE, Hughey CC, James FD, Donahue EP, Shearer J, Viollet B, Foretz M, Wasserman DH
J Biol Chem. 2014 289 (9): 5950-9

PMID: 24403081 · PMCID: PMC3937663 · DOI:10.1074/jbc.M113.528232

Metabolic stress, as well as several antidiabetic agents, increases hepatic nucleotide monophosphate (NMP) levels, activates AMP-activated protein kinase (AMPK), and suppresses glucose production. We tested the necessity of hepatic AMPK for the in vivo effects of an acute elevation in NMP on metabolism. 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR; 8 mg·kg(-1)·min(-1))-euglycemic clamps were performed to elicit an increase in NMP in wild type (α1α2(lox/lox)) and liver-specific AMPK knock-out mice (α1α2(lox/lox) + Albcre) in the presence of fixed glucose. Glucose kinetics were equivalent in 5-h fasted α1α2(lox/lox) and α1α2(lox/lox) + Albcre mice. AMPK was not required for AICAR-mediated suppression of glucose production and increased glucose disappearance. These results demonstrate that AMPK is unnecessary for normal 5-h fasting glucose kinetics and AICAR-mediated inhibition of glucose production. Moreover, plasma fatty acids and triglycerides also decreased independently of hepatic AMPK during AICAR administration. Although the glucoregulatory effects of AICAR were shown to be independent of AMPK, these studies provide in vivo support for the AMPK energy sensor paradigm. AICAR reduced hepatic energy charge by ∼20% in α1α2(lox/lox), which was exacerbated by ∼2-fold in α1α2(lox/lox) + Albcre. This corresponded to a ∼6-fold rise in AMP/ATP in α1α2(lox/lox) + Albcre. Consistent with the effects on adenine nucleotides, maximal mitochondrial respiration was ∼30% lower in α1α2(lox/lox) + Albcre than α1α2(lox/lox) livers. Mitochondrial oxidative phosphorylation efficiency was reduced by 25%. In summary, these results demonstrate that the NMP capacity to inhibit glucose production in vivo is independent of liver AMPK. In contrast, AMPK promotes mitochondrial function and protects against a more precipitous fall in ATP during AICAR administration.

MeSH Terms (14)

Aminoimidazole Carboxamide AMP-Activated Protein Kinases Animals Energy Metabolism Fatty Acids Glucose Hypoglycemic Agents Liver Mice Mice, Knockout Mitochondria, Liver Oxidative Phosphorylation Ribonucleotides Triglycerides

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