Role of Exchange Protein Directly Activated by Cyclic AMP Isoform 1 in Energy Homeostasis: Regulation of Leptin Expression and Secretion in White Adipose Tissue

Abstract

h Epacs (exchange proteins directly activated by cyclic AMP [cAMP]) act as downstream effectors of cAMP and play important roles in energy balance and glucose homeostasis. While global deletion of Epac1 in mice leads to heightened leptin sensitivity in the hypothalamus and partial protection against high-fat diet (HFD)-induced obesity, the physiological functions of Epac1 in white adipose tissue (WAT) has not been explored. Here, we report that adipose tissue-specific Epac1 knockout (AEKO) mice are more prone to HFD-induced obesity, with increased food intake, reduced energy expenditure, and impaired glucose tolerance. Despite the fact that AEKO mice on HFD display increased body weight, these mice have decreased circulating leptin levels compared to their wild-type littermates. In vivo and in vitro analyses further reveal that suppression of Epac1 in WAT decreases leptin mRNA expression and secretion by inhibiting cAMP response element binding (CREB) protein and AKT phosphorylation, respectively. Taken together, our results demonstrate that Epac1 plays an important role in regulating energy balance and glucose homeostasis by promoting leptin expression and secretion in WAT.O besity has become a severe public health problem, and its prevalence has increased dramatically since the 1970s. In the United States, more than one-third of adults and approximately 17% of children are obese, defined as a body mass index (BMI) of 30 or above. It is projected that by 2030, more than 50% of the U.S. population will be obese (1). This dire outlook led the American Medical Association to officially recognize obesity as a disease. In addition to its direct health problems, obesity is also closely associated with other major human diseases, such as diabetes and cardiovascular diseases (2, 3). Despite its overwhelming prevalence and major health burdens, we know little about the molecular etiology of obesity and even less about its cures. At the physiology level, one major factor leading to the development of obesity is a chronic imbalance of energy homeostasis, which results in the accumulation of the excessive energy intake as fat in tissues, especially in adipocytes.Adipose tissue not only is the main reservoir for fat storage but also is an important endocrine organ that secrets various adiposederived hormones, called adipokines. As one of the most important and widely studied adipokines, leptin plays a critical role in energy balance, mainly by acting on receptors in the arcuate nucleus of the hypothalamus to suppress appetite and to increase energy expenditure (4, 5). While the circulating leptin level is proportional to the total body fat mass in rodents and human, in obese patients a reduced sensitivity to leptin leads to a failure in suppressing food intake despite increased fat stores and blood leptin levels. This apparent condition of leptin resistance is one major driver in developing obesity (6).Recent studies have implicated the involvement of Epac1 (exchange protein directly activated by cyclic AMP [cAMP])-mediated...

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity

“…However, in a similar study, Rapgef3 −/− mice develop severe obesity, increased respiratory exchange ratio and impaired glucose tolerance 33 . Adipose tissue-specific Rapgef3 knockout mice on a high-fat diet are also more prone to obesity, show increased food intake, reduced energy expenditure, impaired glucose tolerance, and reduced circulating leptin levels 72 . More research is needed to understand the consequences of RAPGEF3 manipulation.…”

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

“…These data suggest that EPAC1 plays an important role in regulating adiposity and energy balance by modulating leptin signaling. A subsequent report using WAT-specific knockout EPAC1 mice further reveals EPAC1 engaging dual roles in leptin signaling, promoting leptin expression and secretion in peripheral WAT and suppressing leptin signaling in the CNS (444). The regulatory effects of EPAC on leptin signaling in the hypothalamus is most likely mediated by the small GTPase Rap1, as loss of neuronal Rap1 also protects against diet-induced obesity, glucose imbalance, and insulin resistance in the periphery while enhancing leptin sensitivity in hypothalamus (489).…”

Inhibition of Epac1 suppresses mitochondrial fission and reduces neointima formation induced by vascular injury

“…Activation of Epac1 by cAMP further triggers down-stream RAS superfamily small GTPases, Rap1 and Rap2, which are critical for a wide variety of biological functions, ranging from cytoskeleton organization and intracellular trafficking to cell adhesion and junction789. Studies based on genetic Epac1 knockout mice have demonstrated that Epac1 contributes to leptin resistance1011, rickettsial infection12, chronic pain1314, stress induced phospholamban phosphorylation in cardiomyocytes15, Treg-mediated immune-suppression16, and cardiomyocyte hypertrophy17. However, the physiological roles of Epac1 in VSMC function and neointima formation remain controversial181920212223.…”