Cdc2-like kinase 2 is an insulin-regulated suppressor of hepatic gluconeogenesis

Cell Metab. 2010 Jan;11(1):23-34. doi: 10.1016/j.cmet.2009.11.006.

Abstract

Dynamic regulation of insulin signaling and metabolic gene expression is critical to nutrient homeostasis; dysregulation of these pathways is widely implicated in insulin resistance and other disease states. Though the metabolic effects of insulin are well established, the components linking insulin signal transduction to a metabolic response are not as well understood. Here, we show that Cdc2-like kinase 2 (Clk2) is an insulin-regulated suppressor of hepatic gluconeogenesis and glucose output. Clk2 protein levels and kinase activity are induced as part of the hepatic refeeding response by the insulin/Akt pathway. Clk2 directly phosphorylates the SR domain on PGC-1alpha, resulting in repression of gluconeogenic gene expression and hepatic glucose output. In addition, Clk2 is downregulated in db/db mice, and reintroduction of Clk2 largely corrects glycemia. Thus, we have identified a role for and regulation of the Clk2 kinase as a component of hepatic insulin signaling and glucose metabolism.

Publication types

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

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Blood Glucose / metabolism
  • Cells, Cultured
  • Eating
  • Gene Transfer Techniques
  • Gluconeogenesis*
  • Insulin / metabolism*
  • Liver / enzymology*
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Phosphorylation
  • Protein Stability
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • Trans-Activators / metabolism
  • Transcription Factors

Substances

  • Blood Glucose
  • Insulin
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Trans-Activators
  • Transcription Factors
  • Clk dual-specificity kinases
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt