Hasenour 2014 J Biol Chem
| Hasenour CM, Ridley DE, Hughey CC, James FD, Donahue EP, Shearer J, Viollet B, Foretz M, Wasserman DH (2014) 5-Aminoimidazole-4-carboxamide-1-Ξ²-D-ribofuranoside (AICAR) effect on glucose production, but not energy metabolism, is independent of hepatic AMPK in vivo. J Biol Chem 289:5950-9. |
Hasenour CM, Ridley DE, Hughey CC, James FD, Donahue EP, Shearer J, Viollet B, Foretz M, Wasserman DH (2014) J Biol Chem
Abstract: Metabolic stress, as well as several antidiabetic agents, increase hepatic nucleotide monophosphate levels (NMP), activate AMP-activated protein kinase (AMPK), and suppress glucose production. We tested the necessity of hepatic AMPK for the in vivo effects of an acute elevation in NMP on metabolism. AICAR (8mgΒ·kg-1Β·min-1)-euglycemic clamps were performed to elicit an increase in NMP in wild-type (Ξ±1Ξ±2lox/lox) and liver-specific AMPK-knockout mice (Ξ±1Ξ±2lox/lox+Albcre) in the presence of fixed glucose. Glucose kinetics were equivalent in 5hr fasted (Basal) Ξ±1Ξ±2lox/lox and Ξ±1Ξ±2lox/lox+Albcre mice. AMPK was not required for AICAR-mediated suppression of glucose production and increased glucose clearance. These results demonstrate that AMPK is unnecessary for normal basal 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 (EC) by ~20% in Ξ±1Ξ±2lox/lox which was exacerbated by ~2-fold in Ξ±1Ξ±2lox/lox+Albcre. This corresponded to a ~6-fold rise in AMP/ATP in Ξ±1Ξ±2lox/lox+Albcre. Consistent with the effects on adenine nucleotides, maximal mitochondrial respiration was ~30% lower in Ξ±1Ξ±2lox/lox+Albcre than Ξ±1Ξ±2lox/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. β’ Keywords: AICAR, AMP, AMP kinase, AMP-activated kinase (AMPK), Energy metabolism, Fat metabolism, Liver metabolism, in vivo
β’ O2k-Network Lab: US TN Nashville Wasserman DH, CA Calgary Shearer J
Labels: MiParea: Respiration, Genetic knockout;overexpression
Organism: Mouse
Tissue;cell: Liver
Preparation: Isolated mitochondria
Regulation: ATP Coupling state: LEAK, OXPHOS, ET Pathway: N, ROX HRR: Oxygraph-2k
