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  • br Conclusions br Declaration of interest br

    2020-01-19


    Conclusions
    Declaration of interest
    Acknowledgment
    This work was supported by an AIRC (Associazione Italiana Ricerca Cancro-Milan) Grant KFR062-2 to A.G.L, by Ricerca Funds by Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico (Grant No. 180/01) and by the ERA-NET “ERare” (Grant GOSAMPAC to A.S).
    EPAC proteins; new kids on the block cAMP is the prototypic second messenger discovered by Earl Sutherland and colleagues to play a key role in mediating the intracellular effects of hormones [1]. The deciphering of the cAMP signaling pathway is of major historical significance in biology and has led to scientific breakthroughs including the discoveries of cAMP-dependent protein kinase/protein kinase A (PKA), G proteins, and G protein-coupled receptors (GPCRs), for which Robert Lefkowitz and Brian Kobilka shared the latest Nobel Prize in Chemistry [2]. Since its initial discovery more than half a century ago, cAMP has been shown to play important roles in almost all aspects of biological functions, including metabolic regulation [3]. In mammals, with the exceptions of cyclic nucleotide-gated (CNG) ion channels in photoreceptor cells, olfactory sensory neurons, and hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels in cardiac sinoatrial node Senegenin and neurons [4], the major cellular functions of cAMP are mediated by two families of ubiquitously expressed intracellular sensors: the classic PKAs and the more recently discovered exchange proteins directly activated by cAMP (EPACs) 5, 6 (Box 1). The presence of two functionally different and highly coordinated sensors enables a more precise and cohesive control of intracellular cAMP signaling. Depending upon cellular context and their relative abundance, distribution, and localization, these two intracellular receptors may act independently, synergistically, or antagonistically in regulating a specific cellular function 7, 8. EPACs exist in mammals as two isoforms, EPAC1 and EPAC2, produced by independent genes (Box 1). Although EPAC1 is ubiquitously expressed, EPAC2 is predominantly expressed in the brain, liver, pancreas, and adrenal gland 5, 6. EPAC1 and EPAC2 act on the same immediate downstream effectors, small GTPases Rap1 and Rap2; however, their cellular functions are different due to their distinct tissue distribution and their abilities to form signalosomes at various cellular loci through interaction with specific cellular partners (reviewed in [9]). It is now well established that EPAC proteins are involved in numerous cAMP-mediated functions, and their roles in various diseases are increasingly appreciated 9, 10. To date, most functional analyses of EPAC1 and EPAC2 have been performed in vitro. However, the recent generation and use of EPAC1 and EPAC2 knockout mice has allowed the study of these proteins in vivo. These in vivo analyses confirm some of the earlier in vitro conclusions, but also reveal additional complexity and potential controversy. In this review we focus on the role of EPAC proteins in energy homeostasis and the development of obesity and diabetes, and discuss the potential of using small-molecule modulators targeting these proteins as an effective multi-mechanistic approach for the treatment of these chronic conditions.
    EPAC and leptin resistance Obesity is the result of a prolonged imbalance between energy intake and expenditure [11]. The identification of the leptin gene (ob) provided a breakthrough in our understanding of obesity at the molecular level [12]. Leptin, an appetite-suppressing hormone derived from adipose tissue, plays a key role in the central regulation of satiety and energy expenditure [13]. Leptin binds to and activates the ‘long form’ of leptin receptor (OB-Rb or LepRb), a single-transmembrane-domain cytokine receptor expressed in the central nervous system (CNS) and particularly the hypothalamus [14]. In the arcuate nucleus (Arc), OB-Rb is expressed on agouti-related protein (AgRP) and proopiomelanocortin (POMC) neurons which, upon activation, express and release orexigenic and anorexigenic neuropeptides, respectively. Leptin binding to OB-Rb activates intracellular signaling cascades including the janus kinase (JAK)/signal transducer and activators of transcription (STAT) 3 and phosphoinositide 3-kinase (PI3K) pathways 15, 16, 17. A hallmark of increased adiposity and obesity is high circulating leptin levels that results in compromised leptin signaling in the hypothalamus and leptin resistance. Leptin resistance manifests itself as lack of a reduction in food intake, defective leptin receptor signaling, and a reduction in the phosphorylation levels of STAT3, as well as changes in the release of orexigenic and anorexigenic peptides from AgRP and POMC neurons 18, 19.