Cyclic AMP sensor EPAC proteins and energy homeostasis

• EPAC1 desensitizes leptin signaling in hypothalamus.
• EPAC2 facilitates GSIS in response to GLP-1 and obesity induced insulin resistance.
• Small molecule EPAC modulators have therapeutic potential for obesity and T2DM.

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.