TAp63 is a master transcriptional regulator of lipid and glucose metabolism

Cell Metab. 2012 Oct 3;16(4):511-25. doi: 10.1016/j.cmet.2012.09.006.

Abstract

TAp63 prevents premature aging, suggesting a link to genes that regulate longevity. Further characterization of TAp63-/- mice revealed that these mice develop obesity, insulin resistance, and glucose intolerance similar to those seen in mice lacking two key metabolic regulators, Silent information regulator T1 (Sirt1) and AMPK. While the roles of Sirt1 and AMPK in metabolism have been well studied, their upstream regulators are not well understood. We found that TAp63 is important in regulating energy metabolism by accumulating in response to metabolic stress and transcriptionally activating Sirt1, AMPKα2, and LKB1, resulting in increased fatty acid synthesis and decreased fatty acid oxidation. Moreover, we found that TAp63 lowers blood glucose levels in response to metformin. Restoration of Sirt1, AMPKα2, and LKB1 in TAp63-/- mice rescued some of the metabolic defects of the TAp63-/- mice. Our study defines a role for TAp63 in metabolism and weight control.

Publication types

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

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Cell Line
  • Energy Metabolism
  • Fatty Acids / biosynthesis
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Glucose / metabolism*
  • Lipid Metabolism / genetics*
  • Metformin / pharmacology
  • Mice
  • Mice, Knockout
  • Obesity / etiology
  • Obesity / metabolism
  • Phosphoproteins / deficiency
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction / drug effects
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • Trans-Activators / deficiency
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcriptional Activation / drug effects

Substances

  • Fatty Acids
  • Phosphoproteins
  • Trans-Activators
  • Trp63 protein, mouse
  • Metformin
  • AMPK alpha2 subunit, mouse
  • Protein Serine-Threonine Kinases
  • Stk11 protein, mouse
  • AMP-Activated Protein Kinases
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Glucose