Cyclic AMP sensor EPAC proteins and energy homeostasis

Trends Endocrinol Metab. 2014 Feb;25(2):60-71. doi: 10.1016/j.tem.2013.10.004. Epub 2013 Nov 12.


The pleiotropic second-messenger cAMP plays a crucial role in mediating the effects of various hormones on metabolism. The major intracellular functions of cAMP are transduced by protein kinase A (PKA) and by exchange proteins directly activated by cAMP (EPACs). The latter act as guanine-nucleotide exchange factors for the RAS-like small G proteins Rap1 and Rap2. Although the role of PKA in regulating energy balance has been extensively studied, the impact of EPACs remains relatively enigmatic. This review summarizes recent genetic and pharmacological studies concerning EPAC involvement in glucose homeostasis and energy balance via the regulation of leptin and insulin signaling pathways. In addition, the development of small-molecule EPAC-specific modulators and their therapeutic potential for the treatment of diabetes and obesity are discussed.

Keywords: cAMP; energy balance; exchange protein directly activated by cAMP (EPAC); insulin secretion; leptin resistance.

Publication types

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

MeSH terms

  • Animals
  • Cyclic AMP / physiology*
  • Cyclic AMP-Dependent Protein Kinases / physiology
  • Energy Metabolism / physiology*
  • Glucose / metabolism
  • Guanine Nucleotide Exchange Factors / chemistry
  • Guanine Nucleotide Exchange Factors / metabolism
  • Guanine Nucleotide Exchange Factors / physiology*
  • Homeostasis / drug effects*
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Leptin / physiology
  • Models, Animal
  • STAT3 Transcription Factor / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins / physiology


  • Guanine Nucleotide Exchange Factors
  • Insulin
  • Leptin
  • RAPGEF3 protein, human
  • Rapgef4 protein, mouse
  • SOCS3 protein, human
  • STAT3 Transcription Factor
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Glucose