Role of Exchange Protein Directly Activated by cAMP Isoform 1 in Energy Homeostasis

Cyclic AMP-mediated signaling pathways are important for maintaining metabolic homeostasis. The effects of cAMP are mediated mainly by protein kinase A (PKA) and the more recently discovered exchange protein directly activated by cAMP (Epac). Epac has two isoforms, the ubiquitously expressed Epac1 and the more tissue restricted Epac2. The biological functions of Epac1 have been revealed, including cardiac stress, chronic pain, cancer and infections. However, the roles of Epac1 in energy balance are relatively unclear. To investigate the integrated metabolic functions of Epac1 in leptin-mediated energy balance in vivo, we have generated floxed alleles for Epac1 and a global loss of function mutant for Epac1. Epac1 global deficiency mice are more resistant to high fat diet (HFD)-induced obesity, with reduced adiposity and enhanced glucose sensitivity. Although Epac1 knockout (KO) mice have significantly lower plasma leptin, an important hormone for controlling energy homeostasis, the leptin sensitivity in hypothalamus is greatly enhanced compared to wild-type (WT) littermates. These results demonstrate Epac1 plays an important role in regulating adiposity and energy balance.

To investigate if the apparent phenotypes of Epac1 KO mice are due to the loss of Epac1 functions specifically in the central nervous system or in peripheral adipose tissues, which is the dominant source for leptin production and secretion, we generated adipose tissue specific Epac1 knockout (AEKO) mice. Surprisingly, AEKO mice show more severe metabolic syndromes after being challenged by HFD, with increased average daily food intake, decreased energy expenditure and impaired glucose handling capability. Despite that AEKO mice on HFD display increased body weight; these mice have decreased circulating leptin levels as compared to the WT controls. In vivo and in vitro analyses further reveal that suppression of Epac1 decreases leptin mRNA expression and secretion via inhibiting CREB and Akt phosphorylation, respectively. Taken together, our results suggest that Epac1 plays an orexigenic role in central nervous system (CNS) while adipose Epac1 has an anorectic role. Deletion of Epac1 in CNS results in a more potent anorectic effect which overcomes the orexigenic effect of Epac1 deficiency in adipose tissue.