Yan et al combined genetic

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[23]. 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 [23]. Collectively, these results are in agreement with the previous study using an EPAC-selective activator [22], 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 [22], 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 cgk australia (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. Several studies have shown that, independently of body-weight control, the central actions of leptin improve glycemic control in obese diabetic rat and mouse models [62]. For instance, restoration of OB-Rb expression in OB-Rb-deficient mice, and in particular in POMC neurons, was sufficient to normalize blood glucose levels although had little impact on body weight 63, 64. The mechanisms by which leptin signaling in the CNS improves glucose homeostasis are not completely understood, but include sensitization to insulin signaling in the hypothalamus [65], and in liver through the vagus nerve [66], in addition to insulin-independent pathways [67]. These findings combined with previous reports showing that suppression of EPAC1 improves hypothalamic leptin sensitivity 22, 23, suggest that EPAC1 inhibitors might improve glycemic control in the context of obesity/diabetes and leptin/insulin resistance. In addition, because EPAC1−/− mice are resistant to DIO, pharmacologic inhibition of EPAC1 might lead to weight loss, which further enhances insulin sensitivity.