cAMP–PKA/EPAC signaling pathways: crucial regulators of lipid homeostasis

Adipose omeostasishomoeostasis is maintained through the precise coordination of lipogenesis, lipolysis, and adipocyte differentiation, with microenvironmental components dynamically regulating lipid metabolism. Even though the classical cAMP-PKA pathway has been well-characterized for its function in lipid metabolism by phosphorylating transcription factors and lipolytic enzymes, little is known about how it collaborates with elements of the adipose tissue microenvironment, such as immune cells and the vascular endothelium, especially in pathological situations like obesity. EPAC, a newly discovered cAMP effector, has shown new signalingsignallingsignalling signalling pathways in the immune and cardiovascular systems by activating small G proteins. However, there are important understanding gaps regarding its roles in adipose metabolism, namely adipocyte development, microenvironmental interaction, and the pathophysiology of metabolic diseases. By bringing together disparate studies on PKA and EPAC, this review provides the first comprehensive synthesis of the cAMP-PKA/EPAC dual signaling signalling signallingcins signalling network, filling in knowledge gaps. The reciprocal regulation between this signaling signalling signalling signalling network and the adipose microenvironment establishes a novel 'signaling-microenvironment-systemic metabolism' framework for understanding metabolic disorders, including obesity, diabetes, and hepatic steatosis. Pharmacological modulation of the PKA/EPAC signalingsignalling signalling signalling pathways may therefore represent a viable therapeutic approach for restoring adipose tissue homeostasis homoeostasis.