title: Hypothalamic AMPK activation blocks lipopolysaccharide inhibition of glucose production in mice liver.
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.
authors.affiliation: Departamento de Medicina Interna, Faculdade de Ciências Médicas, Universidade Estadual de Campinas-UNICAMP, Campinas, São Paulo, Brazil.
authors.forename: G A
authors.initials: GA
authors.lastname: Santos
authors.forename: R F
authors.initials: RF
authors.lastname: Moura
authors.forename: D C
authors.initials: DC
authors.lastname: Vitorino
authors.forename: E A F R
authors.initials: EA
authors.lastname: Roman
authors.forename: A S
authors.initials: AS
authors.lastname: Torsoni
authors.forename: L A
authors.initials: LA
authors.lastname: Velloso
authors.forename: M A
authors.initials: MA
authors.lastname: Torsoni
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D005934:Glucagon / Q000097:blood; D005943:Gluconeogenesis; D007031:Hypothalamus / Q000201:enzymology* / Q000276:immunology; D053583:Interleukin-1beta / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D001786:Blood Glucose; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D005934:Glucagon; D000263:Adenylate Kinase; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D000103:Acetyl-CoA Carboxylase
keywords: AMPK; Glucose production; Hypothalamus; Lipopolysaccharide; Liver