SCP4 Promotes Gluconeogenesis Through FoxO1/3a Dephosphorylation

Diabetes. 2018 Jan;67(1):46-57. doi: 10.2337/db17-0546. Epub 2017 Aug 29.


FoxO1 and FoxO3a (collectively FoxO1/3a) proteins regulate a wide array of cellular processes, including hepatic gluconeogenesis. Phosphorylation of FoxO1/3a is a key event that determines its subcellular location and transcriptional activity. During glucose synthesis, the activity of FoxO1/3a is negatively regulated by Akt-mediated phosphorylation, which leads to the cytoplasmic retention of FoxO1/3a. However, the nuclear phosphatase that directly regulates FoxO1/3a remains to be identified. In this study, we discovered a nuclear phosphatase, SCP4/CTDSPL2 (SCP4), that dephosphorylated FoxO1/3a and promoted FoxO1/3a transcription activity. We found that SCP4 enhanced the transcription of FoxO1/3a target genes encoding PEPCK1 and G6PC, key enzymes in hepatic gluconeogenesis. Ectopic expression of SCP4 increased, while knockdown of SCP4 inhibited, glucose production. Moreover, we demonstrated that gene ablation of SCP4 led to hypoglycemia in neonatal mice. Consistent with the positive role of SCP4 in gluconeogenesis, expression of SCP4 was regulated under pathophysiological conditions. SCP4 expression was induced by glucose deprivation in vitro and in vivo and was elevated in obese mice caused by genetic (Avy) and dietary (high-fat) changes. Thus, our findings provided experimental evidence that SCP4 regulates hepatic gluconeogenesis and could serve as a potential target for the prevention and treatment of diet-induced glucose intolerance and type 2 diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Forkhead Box Protein O1 / genetics
  • Forkhead Box Protein O1 / metabolism*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Gluconeogenesis / genetics
  • Gluconeogenesis / physiology
  • HEK293 Cells
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NIH 3T3 Cells
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation
  • Reverse Transcriptase Polymerase Chain Reaction


  • Blood Glucose
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • CTDSPL2 protein, mouse
  • Phosphoprotein Phosphatases