Enhanced Leptin Sensitivity, Reduced Adiposity, and Improved Glucose Homeostasis in Mice Lacking Exchange Protein Directly Activated by Cyclic AMP Isoform 1

Abstract

The prototypic second messenger cyclic AMP (cAMP) is essential for controlling cellular metabolism, including glucose and lipid homeostasis. In mammals, the majority of cAMP functions are mediated by cAMP-dependent protein kinase (PKA) and exchange proteins directly activated by cAMP (Epacs). To explore the physiological functions of Epac1, we generated Epac1 knockout mice. Here we report that Epac1 null mutants have reduced white adipose tissue and reduced plasma leptin levels but display heightened leptin sensitivity. Epac1-deficient mice are more resistant to high-fat diet-induced obesity, hyperleptinemia, and glucose intolerance. Furthermore, pharmacological inhibition of Epac by use of an Epac-specific inhibitor reduces plasma leptin levels in vivo and enhances leptin signaling in organotypic hypothalamic slices. Taken together, our results demonstrate that Epac1 plays an important role in regulating adiposity and energy balance.

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ACKNOWLEDGMENTS

We are in debt to Maki Wakamiya for help and advice on animal breeding and handling and to Ping Wu for access to a confocal microscope. We thank Ron Tilton for providing metabolic cages for the food intake study, Marxa Figueiredo for advice and assistance in isolating adipose stem cells, John Wang for advice and assistance in preparing organotypic brain slices, and Caterina M. Hernandez and Sarah Bullard for assistance in mouse stereotaxic surgery and glucose tolerance experiments. Animal behavior experiments were conducted in the Rodent In Vivo Assessment Core of the Center for Addiction Research at the University of Texas Medical Branch.

This work was supported in part by grants from the National Institutes of Health to Xiaodong Cheng (5R01GM066170), Ju Chen (P01 HL080101 and P01 HL46345), and Kathryn A. Cunningham (K05DA020087), as well as by institutional funds from the Department of Pharmacology and Toxicology and the Center of Addiction Research at the University of Texas Medical Branch.

We declare that we have no competing financial interests.