| First Author | Hasenour CM | Year | 2014 |
| Journal | J Biol Chem | Volume | 289 |
| Issue | 9 | Pages | 5950-9 |
| PubMed ID | 24403081 | Mgi Jnum | J:209505 |
| Mgi Id | MGI:5568014 | Doi | 10.1074/jbc.M113.528232 |
| Citation | Hasenour CM, et al. (2014) 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) effect on glucose production, but not energy metabolism, is independent of hepatic AMPK in vivo. J Biol Chem 289(9):5950-9 |
| abstractText | 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-beta-D-ribofuranoside (AICAR; 8 mg.kg(-1).min(-1))-euglycemic clamps were performed to elicit an increase in NMP in wild type (alpha1alpha2(lox/lox)) and liver-specific AMPK knock-out mice (alpha1alpha2(lox/lox) + Albcre) in the presence of fixed glucose. Glucose kinetics were equivalent in 5-h fasted alpha1alpha2(lox/lox) and alpha1alpha2(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 approximately 20% in alpha1alpha2(lox/lox), which was exacerbated by approximately 2-fold in alpha1alpha2(lox/lox) + Albcre. This corresponded to a approximately 6-fold rise in AMP/ATP in alpha1alpha2(lox/lox) + Albcre. Consistent with the effects on adenine nucleotides, maximal mitochondrial respiration was approximately 30% lower in alpha1alpha2(lox/lox) + Albcre than alpha1alpha2(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. |
