Germline or inducible knockout of p300 or CBP in skeletal muscle does not alter insulin sensitivity

Am J Physiol Endocrinol Metab. 2019 Jun 1;316(6):E1024-E1035. doi: 10.1152/ajpendo.00497.2018. Epub 2019 Mar 19.


Akt is a critical mediator of insulin-stimulated glucose uptake in skeletal muscle. The acetyltransferases, E1A binding protein p300 (p300) and cAMP response element-binding protein binding protein (CBP) are phosphorylated and activated by Akt, and p300/CBP can acetylate and inactivate Akt, thus giving rise to a possible Akt-p300/CBP axis. Our objective was to determine the importance of p300 and CBP to skeletal muscle insulin sensitivity. We used Cre-LoxP methodology to generate mice with germline [muscle creatine kinase promoter (P-MCK and C-MCK)] or inducible [tamoxifen-activated, human skeletal actin promoter (P-iHSA and C-iHSA)] knockout of p300 or CBP. A subset of P-MCK and C-MCK mice were switched to a calorie-restriction diet (60% of ad libitum intake) or high-fat diet at 10 wk of age. For P-iHSA and C-iHSA mice, knockout was induced at 10 wk of age. At 13-15 wk of age, we measured whole-body energy expenditure, oral glucose tolerance, and/or ex vivo skeletal muscle insulin sensitivity. Although p300 and CBP protein abundance and mRNA expression were reduced 55%-90% in p300 and CBP knockout mice, there were no genotype differences in energy expenditure or fasting glucose and insulin concentrations. Moreover, neither loss of p300 or CBP impacted oral glucose tolerance or skeletal muscle insulin sensitivity, nor did their loss impact alterations in these parameters in response to a calorie restriction or high-fat diet. Muscle-specific loss of either p300 or CBP, be it germline or in adulthood, does not impact energy expenditure, glucose tolerance, or skeletal muscle insulin action.

Keywords: acetyltransferase; calorie restriction; glucose tolerance; high-fat; insulin sensitivity.

Publication types

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

MeSH terms

  • Animals
  • CREB-Binding Protein / genetics*
  • CREB-Binding Protein / metabolism
  • E1A-Associated p300 Protein / genetics*
  • E1A-Associated p300 Protein / metabolism
  • Energy Metabolism / genetics*
  • Gene Knockout Techniques / methods
  • Germ-Line Mutation
  • Glucose Tolerance Test
  • Insulin Resistance / genetics*
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / metabolism*
  • RNA, Messenger / metabolism


  • RNA, Messenger
  • CREB-Binding Protein
  • Crebbp protein, mouse
  • E1A-Associated p300 Protein
  • Ep300 protein, mouse