cAMP mediated signaling pathways are important for maintaini
cAMP-mediated signaling pathways are important for maintaining metabolic homeostasis, and the effects of the glucagon/catecholamine–cAMP–PKA axis on energy balance have been well documented . For example, 78 7 receptor of the PKA 2β regulatory subunit (RIIβ) in mice leads to increased expression of uncoupling proteins in brown adipose tissue, which results in an elevated metabolic rate and body temperature, and a lean phenotype with diminished white adipose tissue. These mice are also resistant to diet-induced obesity (DIO) and fatty liver . By contrast, the involvement of EPAC protein in leptin signaling and energy balance was only revealed recently. Elmquist and colleagues demonstrate that leptin-mediated STAT3 phosphorylation is inhibited by cAMP-elevating agents such as forskolin and inhibitors of phosphodiesterase (PDE) enzymes that degrade cAMP . This inhibitory effect of cAMP is not affected by the non-selective PKA inhibitor H89, suggesting that it might be PKA-independent. By contrast, activation of EPAC using an EPAC-selective cAMP analog, 8-(4-chloro-phenylthio)-2′-O-methyladenosine-3′,5′-cyclic monophosphate (8-CPT-2′-O-Me-cAMP, also known as 007), blunts leptin signaling in the hypothalamus and impairs leptin-evoked depolarization of POMC neurons. Moreover, intracerebroventricular (ICV) infusion of 007 in mice blocked leptin-induced reduction of food intake . These results suggest that pharmacological activation of the cAMP–EPAC pathway in the hypothalamus leads to leptin resistance.
Yan et al. combined genetic and pharmacological approaches to determine which EPAC isoform modulates leptin action, and showed that EPAC1 plays a role in energy balance and leptin signaling in vivo. C57BL/6 EPAC1 knockout (EPAC1−/−) mice are more resistant to high-fat diet (HFD)-induced obesity, due to reduced food intake, and thus have reduced white adipose tissue and plasma leptin levels. However, they display heightened central leptin sensitivity as measured by STAT3 phosphorylation in the hypothalamus, and EPAC1−/− mice on a HFD are more glucose tolerant than wild type (WT) mice. Furthermore, pharmacological inhibition of EPAC1 by the EPAC-selective inhibitor ESI-09 resulted in reduced plasma leptin in vivo and enhanced leptin signaling in organotypic hypothalamic slices from WT mice . Collectively, these results are in agreement with the previous study using an EPAC-selective activator , and suggest that EPAC1 plays an important role in regulating adiposity and energy balance by modulating leptin signaling. Although mice on HFD have increased Rap-GTP levels in the hypothalamus , an indication of elevated EPAC signaling, studies that directly link EPAC hyperactivation in the hypothalamus to states of obesity or leptin resistance in humans are lacking.
EPAC and glucose homeostasis
Targeting EPAC for therapeutic intervention The studies reviewed here suggest that EPAC1 and EPAC2 play important roles in regulating leptin and insulin signaling, and represent attractive drug targets for the treatment of obesity and type 2 diabetes mellitus (T2DM). Small-molecule EPAC-selective modulators have been developed (Box 4) and can be further explored for their therapeutic potential 58, 59, 60, 61. Considering that EPAC1 and EPAC2 exert diverse and distinct functions, isoform-specific EPAC modulators, particularly EPAC1-specific inhibitors and EPAC2-specific activators, are most desirable for therapeutic purposes. Obesity and T2DM are chronic conditions that are intimately linked and are caused by dysfunction and dysregulation in crosstalk between multiple systems including the hypothalamus, liver, endocrine pancreas, skeletal muscle, and adipocytes (Figure 3). Hence, an evaluation of the therapeutic potential and possible drawbacks of specific small-molecule EPAC modulators must take into account their effects on individual organs as well as their potential impact on the feedback loops and pathways linking the aforementioned systems.