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- Title
Hepatic Energy Status in Physiology and Diabetes in the C57BL/6J Mouse.
- Authors
Berglund, Eric D.; Donahue, E. P.; Lee-Young, Robert S.; Lustig, Daniel G.; James, Freyja D.; Camacho, Raul C.; Charron, Maureen J.; Wasserman, David H.
- Abstract
Adenine nucleotides define the cell energy status and sensitively regulate signaling pathways and enzymes that control nutrient flux. The liver plays a key role in energy metabolism as it is the site of energy producing and consuming pathways involved in not only cell, but whole-body metabolism. The aim was to assess in C57BL/6J mice (a) the role of adenine nucleotides during nutrient stress and diabetes, (b) whether adenine nucleotides potentially play a role in coordinating glucagun (GGN) action, and (c) whether changes in adenine nucleotides are consistent with a role in AMPK signaling. Hepatic energy charge (HEC) was calculated from adenine nucleotides [(ATP+0.5ADP)/ (ATP+ADP+AMP)] measured by HPLC. HEC decreased markedly from 0.72±0.02 in 5h fasted control mice to 0.22±0.01, 0.43±0.05, 0.20±0.02, and 0.33±0.22 in 5h fasted high-fat fed, 16h fasted, exercised, and streptozotocin-induced diabetic mice while the skeletal muscle energy charge (SEC) did not differ from the value in 5h fasted control mice (0.94±0.02). Elevated GGN is common to each of these conditions, thus we tested the role of this hormone using a novel phloridzin-glucose clamp technique (phlor-clamp). Wild type (WT) and GGN receptor knockout (KO) littermate mice were catheterized and infused with 10 ng/kg/min GGN (GGN) or saline (SAL) for 2h to in the conscious state while maintaining plasma glucose at basal (∼150 mg/dL). During the phlor-clamp, WT-GGN mice insulin and plasma glucose were unchanged despite increased GGN (51±8 to >1000 pg/mL) and HEC fell to 0.37±0.07. In WT-SAL, KO-SAL, and KO-GGN there were no changes in plasma glucose and insulin during the phlor-clamp and HEC was 0.66±0.02, 0.72±0.01, and 0.68±0.02. SEC was unaffected by GGN or genotype. AMPK activity increased 59% in WT-GGN compared to WT-SAL mice based on P-AMPK[Thr172]. In summary, (a) in contrast to muscle, liver experiences profound changes in energy status in response to nutrient stress and diabetes; (b) GGN receptor mediated processes play a role in regulation of adenine nucleotide metabolism; and (c) GGN potently activates AMPK in vivo and this may be secondary to changes in adenine nucleotides. The marked changes in energy status of the liver create a key role for adenine nucleotides in nutrient flux and should be considered in interpreting experiments designed to study liver.
- Subjects
ENERGY metabolism; LIVER cells; DIABETES; ADENINE nucleotides; LABORATORY mice; CELLULAR control mechanisms
- Publication
Diabetes, 2007, Vol 56, pA395
- ISSN
0012-1797
- Publication type
Article