Suppressor of cytokine signalling-2 controls hepatic gluconeogenesis and hyperglycemia by modulating JAK2/STAT5 signalling pathway.
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.
Mesh Terms:
Animals, Blood Glucose, Cell Line, Cell Line, Tumor, Cytokines, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Diet, High-Fat, Disease Models, Animal, Fasting, Fatty Liver, Gluconeogenesis, HEK293 Cells, Hepatocytes, Humans, Hyperglycemia, Hypoglycemic Agents, Janus Kinase 2, Liver, Male, Metformin, Mice, Mice, Inbred C57BL, STAT5 Transcription Factor, Signal Transduction, Suppressor of Cytokine Signaling Proteins
Animals, Blood Glucose, Cell Line, Cell Line, Tumor, Cytokines, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Diet, High-Fat, Disease Models, Animal, Fasting, Fatty Liver, Gluconeogenesis, HEK293 Cells, Hepatocytes, Humans, Hyperglycemia, Hypoglycemic Agents, Janus Kinase 2, Liver, Male, Metformin, Mice, Mice, Inbred C57BL, STAT5 Transcription Factor, Signal Transduction, Suppressor of Cytokine Signaling Proteins
Metabolism
Date: Dec. 01, 2020
PubMed ID: 34197875
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