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Suppressor of cytokine signalling-2 controls hepatic gluconeogenesis and hyperglycemia by modulating JAK2/STAT5

Xu Zhang1, Yuan Zhuang1, Tian Qin1

  • 1The Key Laboratory of Rare Metabolic Diseases, The Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 211166, China.

Metabolism: Clinical and Experimental
|July 1, 2021
PubMed

Insights

Suppressor of cytokine signaling-2 (SOCS2) regulates hepatic gluconeogenesis and glucose homeostasis. Metformin increases SOCS2, which inhibits glucose production, suggesting SOCS2 as a potential diabetes therapeutic target.

Area of Science:

  • Endocrinology
  • Metabolism
  • Molecular Biology

Background:

  • Hepatic gluconeogenesis is vital for blood glucose homeostasis.
  • Suppressor of cytokine signaling-2 (SOCS2) is a cytokine signaling inhibitor.
  • SOCS2 knockout mice resist high-fat diet-induced metabolic dysfunction, but its role in glucose metabolism is unclear.

Purpose of the Study:

  • To elucidate the mechanism by which SOCS2 regulates hepatic glucose homeostasis.
  • To investigate the role of SOCS2 in metformin's glucose-lowering effects.

Main Methods:

  • Studied SOCS2 expression in fasted and metformin-treated mice (C57BL/6J, db/db).
  • Utilized gain- and loss-of-function studies in hepatocytes and db/db mice.
  • Investigated the JAK2/STAT5 signaling pathway and SOCS2-JAK2-STAT5 interactions.

Main Results:

  • Hepatic SOCS2 expression decreased in fasted and db/db mice, but increased with metformin.
  • SOCS2 deficiency impaired metformin's ability to suppress gluconeogenesis.
  • SOCS2 regulates gluconeogenic gene expression and glucose output via JAK2/STAT5.
  • SOCS2 inactivates STAT5 by disrupting the JAK2-STAT5 interaction, reducing gluconeogenesis.

Conclusions:

  • SOCS2 plays a critical role in regulating hepatic gluconeogenesis.
  • Metformin's inhibition of gluconeogenesis is partly mediated by SOCS2 upregulation.
  • SOCS2 represents a potential therapeutic target for diabetes treatment.
Keywords:
DiabetesGluconeogenesisGluconeogenic enzymesMetforminSOCS2

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