SCH772984 ameliorates lipopolysaccharide-induced hypoglycemia in mice through reversing MEK/ERK/Foxo1-mediated gluconeogenesis suppression.

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  • Author(s): Wang Y;Wang Y; Qing S; Qing S; Yang J; Yang J; Qian D; Qian D
  • Source:
    Canadian journal of physiology and pharmacology [Can J Physiol Pharmacol] 2024 Jan 01; Vol. 102 (1), pp. 33-41. Date of Electronic Publication: 2023 Nov 09.
  • Publication Type:
    Journal Article
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Canadian Science Publishing Country of Publication: Canada NLM ID: 0372712 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1205-7541 (Electronic) Linking ISSN: 00084212 NLM ISO Abbreviation: Can J Physiol Pharmacol Subsets: MEDLINE
    • Publication Information:
      Publication: 2011- : Ottawa, ON : Canadian Science Publishing
      Original Publication: Ottawa, National Research Council of Canada.
    • Subject Terms:
      Gluconeogenesis* ; Hypoglycemia*/chemically induced ; Hypoglycemia*/drug therapy ; Hypoglycemia*/metabolism; Mice ; Animals ; Blood Glucose/metabolism ; Lipopolysaccharides/pharmacology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Liver ; Glucose/metabolism ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Mice, Inbred C57BL ; Forkhead Box Protein O1/metabolism ; Forkhead Box Protein O1/pharmacology
    • Abstract:
      Lipopolysaccharide (LPS) results in a lethal hypoglycemic response. However, the main molecular mechanism involved in LPS-induced glucose metabolism disorder is poorly understood. This study intends to investigate the signaling pathways involved in LPS-induced hypoglycemia and potential efficacy of extracellular signal-regulated kinase (ERK) inhibitor SCH772984. The effects of LPS and SCH772984 on gluconeogenesis, glucose absorption, and glycogenolysis were evaluated by pyruvate tolerance test, oral glucose tolerance test, and glucagon test, respectively. After a single intraperitoneal injection of 0.5 mg/kg LPS, the mice's blood glucose levels and gluconeogenesis ability were significantly lower than that of control group. Besides, mRNA and protein expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) decreased significantly after LPS treatment. LPS induced the phosphorylation of ERK1/2, MEK1/2 (mitogen-activated protein kinase), and Foxo1 while inhibited Foxo1 expression in the nucleus, indicating an important role of the MEK/ERK/Foxo1 signaling in the inhibition of gluconeogenesis by LPS. Furthermore, SCH772984 elevated blood glucose, increased the G6Pase and PEPCK expression, and inhibited pERK1/2 and pFoxo1 expression in LPS-induced mice. In summary, LPS inhibited gluconeogenesis and induced hypoglycemia through the MEK/ERK/Foxo1 signal pathway, and ERK inhibitor could effectively reverse decreased blood glucose in mice with LPS treatment. These findings provide a novel therapeutic target for LPS-induced hypoglycemia.
      Competing Interests: The authors declare that they have no conflict of interests.
    • Contributed Indexing:
      Keywords: MEK/ERK/Foxo1 signaling; SCH772984; gluconeogenesis; hypoglycemia; lipopolysaccharide
    • Accession Number:
      0 (Blood Glucose)
      0 (Lipopolysaccharides)
      EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
      0 (SCH772984)
      IY9XDZ35W2 (Glucose)
      EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
      0 (Foxo1 protein, mouse)
      0 (Forkhead Box Protein O1)
    • Publication Date:
      Date Created: 20231109 Date Completed: 20240103 Latest Revision: 20240103
    • Publication Date:
      20240103
    • Accession Number:
      10.1139/cjpp-2023-0133
    • Accession Number:
      37944129