Highlights
- •SOCS2 expression in liver is reduced in fasted or diabetic mice.
- •SOCS2 regulates hepatic gluconeogenesis via modulating JAK2/STAT5 Signalling pathway.
- •SOCS2 can be strongly induced by metformin treatment.
- •Ablation of SOCS2 attenuates suppressing effects of metformin on hepatic gluconeogenesis.
Abstract
Hepatic gluconeogenesis plays a crucial role in maintaining blood glucose homeostasis
in mammals. Globe knockout of suppressor of cytokine signalling-2 (SOCS2), a feedback
inhibitor of cytokine signalling, has been shown resistant to high-fat-diet (HFD)-induced
hepatic steatosis with impaired glucose tolerance in mice. However, the underlying
mechanism of SOCS2 regulates hepatic glucose homeostasis still undefined. In the present
study, we demonstrated that the hepatic SOCS2 expression is markedly reduced in fasted
C57BL/6 J mice or db/db mice. Moreover, hepatic SOCS2 expression levels are induced by metformin treatment.
Ablation of SOCS2 attenuates suppressing effects of metformin on gluconeogenesis in
hepatocytes. Gain- and loss-of-function studies indicated that SOCS2 regulates hepatic
gluconeogenic genes expression and glucose output by mediating JAK2/STAT5 signalling
pathway in db/db mice. Mechanistically, we observed that SOCS2 inactivates STAT5 by attenuating the
interaction between JAK2 and STAT5, which in turn reduces hepatic gluconeogenesis.
The present study reveals a critical role of SOCS2 in regulating hepatic gluconeogenesis.
The inhibitory effect of metformin on gluconeogenesis is mediated, at least in part,
by upregulating SOCS2 and therefore reducing hepatic gluconeogenic genes expression.
SOCS2 may represent a new therapeutic target for the treatment of diabetes.
Keywords
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Article info
Publication history
Published online: June 28, 2021
Accepted:
June 26,
2021
Received:
February 23,
2021
Identification
Copyright
© 2021 Elsevier Inc. All rights reserved.
