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Hypothalamic AMPK activation blocks lipopolysaccharide inhibition of glucose production in mice liver

Author:
Santos, G.A., Moura, R.F., Vitorino, D.C., Roman, E.A.F.R., Torsoni, A.S., Velloso, L.A., Torsoni, M.A.
Source:
Molecular and Cellular Endocrinology 2013 v.381 pp. 88-96
ISSN:
0303-7207
Subject:
AMP-activated protein kinase, blood glucose, blood serum, dephosphorylation, endotoxemia, fasting, food intake, glucose, glycemic control, homeostasis, hypoglycemia, interleukin-1beta, lipopolysaccharides, liver, mice, patients, phosphorylation, survival rate, tumor necrosis factor-alpha
Abstract:
Endotoxic hypoglycaemia has an important role in the survival rates of septic patients. Previous studies have demonstrated that hypothalamic AMP-activated protein kinase (hyp-AMPK) activity is sufficient to modulate glucose homeostasis. However, the role of hyp-AMPK in hypoglycaemia associated with endotoxemia is unknown. The aims of this study were to examine hyp-AMPK dephosphorylation in lipopolysaccharide (LPS)-treated mice and to determine whether pharmacological hyp-AMPK activation could reduce the effects of endotoxemia on blood glucose levels. LPS-treated mice showed reduced food intake, diminished basal glycemia, increased serum TNF-α and IL-1β levels and increased hypothalamic p-TAK and TLR4/MyD88 association. These effects were accompanied by hyp-AMPK/ACC dephosphorylation. LPS-treated mice also showed diminished liver expression of PEPCK/G6Pase, reduction in p-FOXO1, p-AMPK, p-STAT3 and p-JNK level and glucose production. Pharmacological hyp-AMPK activation blocked the effects of LPS on the hyp-AMPK phosphorylation, liver PEPCK expression and glucose production. Furthermore, the effects of LPS were TLR4-dependent because hyp-AMPK phosphorylation, liver PEPCK expression and fasting glycemia were not affected in TLR4-mutant mice. These results suggest that hyp-AMPK activity may be an important pharmacological target to control glucose homeostasis during endotoxemia.
Agid:
1046713