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

Mol Cell Endocrinol. 2013 Dec 5;381(1-2):88-96. doi: 10.1016/j.mce.2013.07.018. Epub 2013 Jul 31.


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.

Keywords: AMPK; Glucose production; Hypothalamus; Lipopolysaccharide; Liver.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl-CoA Carboxylase / metabolism
  • Adenylate Kinase / metabolism*
  • Animals
  • Blood Glucose
  • Enzyme Activation
  • Gene Expression Regulation, Enzymologic
  • Glucagon / blood
  • Gluconeogenesis*
  • Hypothalamus / enzymology*
  • Hypothalamus / immunology
  • Interleukin-1beta / blood
  • Lipopolysaccharides / pharmacology*
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Transgenic
  • Phosphoenolpyruvate Carboxykinase (GTP) / genetics
  • Phosphoenolpyruvate Carboxykinase (GTP) / metabolism
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / blood


  • Blood Glucose
  • Interleukin-1beta
  • Lipopolysaccharides
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Glucagon
  • Adenylate Kinase
  • Phosphoenolpyruvate Carboxykinase (GTP)
  • Acetyl-CoA Carboxylase