Exchange protein directly activated by cAMP 1 plays an important role in β3-adrenergic induction of UCP1 in WAT and thermogenesis via regulating lipolysis

Abstract

Pharmaceutical enhancement of uncoupling protein1 (UCP1) and thermogenesis has drawn great interest to counteract obesity. Previously, the exchange protein directly activated by cAMP 1 (Epac1)-deficient mice showed less induction of beige cells with a significantly less UCP1 expression in white adipose tissue (WAT) and lower circulating free fatty acid (FFA) after chronic CL316,243 (a β3-adrenergic receptor agonist, CL, 1mg/kg/day for 10 days) administration, compared to that of wild type (wt) mice. To further study the role of Epac1 in β3-adrenergic induction of UCP1 and its function, energy expenditure and thermogenesis were determined. By indirect calorimetry, the Epac1-deficient mice showed slightly lower oxygen consumption from 9-16 hours after CL (1mg/kg) administration compared to that of wt mice. By using rectal thermometer, continuously lower rectal temperature within 30 min after the ninth dose of CL administration was observed in the Epac1-deficient mice relative to that of wt mice. These results suggest that in the absence of Epac1, increase of energy expenditure and thermogenesis induced by β3-adrenergic activation are compromised, which could be due to lower FFA and UCP1 induced by CL in the Epac1-deficent mice. To test whether the reduced FFA is due to compromised lipolysis, glycerol release from WAT explants was examined ex vivo. Interestingly, Epac1-deficient WAT explants showed impaired CL-stimulated glycerol release, indicating that absence of Epac1 diminishes β3-adrenergic receptor mediated lipolysis in WAT. In addition, Western blot showed that phosphorylation of hormone sensitive lipase at Ser660 by protein kinase A (PKA) was not different in Epac1-deficient WAT explants incubated with CL (10uM) for 10 min, compared to that of wt mice. Taken together, Epac1 plays an important role in β3-adrenergic induction of UCP1 in WAT and thermogenesis via mediating lipolysis independent of PKA.