Epac2a-null mice exhibit obesity-prone nature more susceptible to leptin resistance

Abstract

Background:The exchange protein directly activated by cAMP (Epac), which is primarily involved in cAMP signaling, has been known to be essential for controlling body energy metabolism. Epac has two isoforms: Epac1 and Epac2. The function of Epac1 on obesity was unveiled using Epac1 knockout (KO) mice. However, the role of Epac2 in obesity remains unclear.Methods:To evaluate the role of Epac2 in obesity, we used Epac2a KO mice, which is dominantly expressed in neurons and endocrine tissues. Physiological factors related to obesity were analyzed: body weight, fat mass, food intake, plasma leptin and adiponectin levels, energy expenditure, glucose tolerance, and insulin and leptin resistance. To determine the mechanism of Epac2a, mice received exogenous leptin and then hypothalamic leptin signaling was analyzed.Results:Epac2a KO mice appeared to have normal glucose tolerance and insulin sensitivity until 12 weeks of age, but an early onset increase of plasma leptin levels and decrease of plasma adiponectin levels compared with wild-type mice. Acute leptin injection revealed impaired hypothalamic leptin signaling in KO mice. Consistently, KO mice fed a high-fat diet (HFD) were significantly obese, presenting greater food intake and lower energy expenditure. HFD-fed KO mice were also characterized by greater impairment of hypothalamic leptin signaling and by weaker leptin-induced decrease in food consumption compared with HFD-fed wild-type mice. In wild-type mice, acute exogenous leptin injection or chronic HFD feeding tended to induce hypothalamic Epac2a expression.Conclusions:Considering that HFD is an inducer of hypothalamic leptin resistance and that Epac2a functions in pancreatic beta cells during demands of greater work load, hypothalamic Epac2a may have a role in facilitating leptin signaling, at least in response to higher metabolic demands. Thus, our data indicate that Epac2a is critical for preventing obesity and thus Epac2a activators may be used to manage obesity and obesity-mediated metabolic disorders.

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

“…However, a recent study of EPAC2 Ϫ/Ϫ mice demonstrates whole-body deletion of EPAC2A induces an impaired hypothalamic leptin signaling, early-onset increases in plasma leptin levels, and decreases in plasma adiponectin levels. Moreover, EPAC2 null mice are more prone to HFD-induced obesity presumably due to increased food intake and lower energy expenditure compared with HFD-fed wild-type mice (454). These data suggest a protective role of EPAC2 against obesity.…”

“…Another possibility is that deletion of EPAC2A outside of the ␤-cell may offset the effect of increased incretin levels on GSIS after an oGTT. This proposed explanation is likely as a recent study demonstrates compared with wild-type counterparts, EPAC2A Ϫ/Ϫ mice have increased levels of plasma leptin (454), which can stimulate GLP-1 secretion from rodent and human intestinal L cells (26).…”

The Potential of a Novel Class of EPAC-Selective Agonists to Combat Cardiovascular Inflammation

“…A number of studies have suggested that EPAC-selective ligands may be useful for the future treatment of cardiac arrhythmia [ 38 ], obesity [ 39 , 40 ], diabetes [ 41 ], hypertension [ 42 ], cancer [ 43 ] and inflammatory pain [ 44 ]. Concerning inflammation, it has been suggested that selective EPAC regulators may be useful for the treatment of IL-8 driven lung inflammation associated with chronic obstructive pulmonary disorder (COPD), where EPAC2 appears to be pro-inflammatory, whereas EPAC1 suppresses lung remodelling [ 45 , 46 , 47 ].…”

β3 Adrenoceptor‐induced cholinergic inhibition in human and rat urinary bladders involves the exchange protein directly activated by cyclic AMP 1 favoring adenosine release

“…Positive identification of the β 2 ‐adrenoceptor was previously demonstrated using the same antibody in the mouse aorta (Moreira‐Rodrigues et al, ) and was further confirmed here using the rat aorta and the dentate gyrus of the human hippocampus (Figure S1). Regarding the EPAC2 antibody from Cell Signaling Tech, it was recently validated in the knockout mouse (Hwang et al, ). Moreover, both AAR‐016 and AAR‐017 antibodies detected major bands with apparent sizes around 44 kDa, which are compatible with the theoretical molecular masses of human and rat β 2 (~46 kDa) and β 3 (~43 kDa) adrenoceptors (Figure g).…”