ESPE Yearbook of Paediatric Endocrinology

Brief Summary:This basic science study, using mice, cell models, and organoids, shows that the cAMP-binding protein EPAC1 is a central regulator of adaptive brown adipose tissue (BAT). EPAC1 specifically increases the number of thermogenic fat cells (brown and beige adipocytes), by promoting the differentiation and growth of brown adipocytes and the development of beige adipocytes through signaling pathways that enhance lipid metabolism and thermogenesis.

BAT plays a crucial role in promoting energy expenditure and enhancing cardiometabolic health by dissipating energy, primarily through a process known as non-shivering thermogenesis, which is facilitated by the uncoupling protein 1 (UCP1). An increase in BAT mass is positively correlated with leanness and a reduced risk of cardiovascular disease in adults. Besides brown fat cells, another type of thermogenic fat cell exists, known as beige cells; they are predominantly located in subcutaneous white adipose tissue (WAT). Similar to brown adipocytes, these beige cells can be induced through exposure to cold or pharmacological interventions, a process referred to as browning or beiging.

The study highlights exchange protein directly activated by cAMP isoform 1 (EPAC1) as a key regulator of adaptive BAT and beige adipogenesis, demonstrating that its pharmacological activation not only increases adipocyte cell mass but also promotes the browning of white fat, resulting in enhanced energy expenditure and reduced diet-induced obesity. EPAC1 specifically drives the proliferation of thermogenic fat cells without impacting white fat cells, and its absence in preadipocytes impairs BAT and beige adipogenesis, exacerbating obesity. Furthermore, activation of EPAC1 (encoded by the gene RAPGEF3 ) supports the proliferation and differentiation of human brown fat cells and organoids, while a coding variant of RAPGEF3, associated with body mass index, hinders norepinephrine-induced proliferation of brown fat cells.

Taken together, these findings suggest that EPAC1 could be a promising therapeutic target for treating obesity and related metabolic disorders by boosting the body’s natural fat-burning capabilities. The study also emphasizes the need for a deeper understanding of the molecular mechanisms governing BAT and beige adipogenesis, which could pave the way for innovative strategies to improve metabolic health.