RAPGEF3, also known as the gene encoding exchange protein directly activated by cAMP isoform 1 (EPAC1), is a guanine nucleotide exchange factor for GTPases Rap1 and Rap2. EPAC1 is one of the cAMP sensors that mediate the intracellular functions of cAMP, playing a crucial role in various signaling pathways. It has been implicated in biological processes related to energy metabolism, pain response, and cellular adhesion, and thus is of great biological importance. Genetically engineered mouse models have been valuable for studying its functions [2].

In in vivo studies, selective pharmacological activation of EPAC1 (encoded by RAPGEF3) increases brown adipose tissue (BAT) mass and white fat browning, leading to higher energy expenditure and reduced diet-induced obesity. Loss of EPAC1 in PDGFRα-positive preadipocytes impedes BAT growth and worsens diet-induced obesity. Also, a coding variant of RAPGEF3 that is positively correlated with body mass index abolishes noradrenaline-induced proliferation of brown adipocytes [1]. In mice lacking Epac1 (Rapgef3), there is increased microvascular permeability, indicating that Epac1 exerts a tonic inhibition of in vivo basal microvascular permeability [3].

In conclusion, RAPGEF3-encoded EPAC1 is a key regulator in energy metabolism-related processes like BAT growth and beige adipogenesis, and also has a role in maintaining microvascular permeability. Studies using KO mouse models have provided important insights into its functions, especially in the context of obesity-related metabolic diseases and microvascular function regulation.

References:

1. Reverte-Salisa, Laia, Siddig, Sana, Hildebrand, Staffan, Krahmer, Natalie, Pfeifer, Alexander. 2024. EPAC1 enhances brown fat growth and beige adipogenesis. In Nature cell biology, 26, 113-123. doi:10.1038/s41556-023-01311-9. https://pubmed.ncbi.nlm.nih.gov/38195707/

2. Banerjee, Upasana, Cheng, Xiaodong. 2015. Exchange protein directly activated by cAMP encoded by the mammalian rapgef3 gene: Structure, function and therapeutics. In Gene, 570, 157-67. doi:10.1016/j.gene.2015.06.063. https://pubmed.ncbi.nlm.nih.gov/26119090/

3. Kopperud, R K, Rygh, C Brekke, Karlsen, T V, Reed, R K, Døskeland, S O. 2016. Increased microvascular permeability in mice lacking Epac1 (Rapgef3). In Acta physiologica (Oxford, England), 219, 441-452. doi:10.1111/apha.12697. https://pubmed.ncbi.nlm.nih.gov/27096875/