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Reverte-Salisa, L.* ; Siddig, S.* ; Hildebrand, S.* ; Yao, X.* ; Zurkovic, J.* ; Jaeckstein, M.Y.* ; Heeren, J.* ; Lezoualc’h, F.* ; Krahmer, N. ; Pfeifer, A.*

EPAC1 enhances brown fat growth and beige adipogenesis.

Nat. Cell Biol. 26, 113–123 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
Brown adipose tissue (BAT) is a central thermogenic organ that enhances energy expenditure and cardiometabolic health. However, regulators that specifically increase the number of thermogenic adipocytes are still an unmet need. Here, we show that the cAMP-binding protein EPAC1 is a central regulator of adaptive BAT growth. In vivo, selective pharmacological activation of EPAC1 increases BAT mass and browning of white fat, leading to higher energy expenditure and reduced diet-induced obesity. Mechanistically, EPAC1 coordinates a network of regulators for proliferation specifically in thermogenic adipocytes, but not in white adipocytes. We pinpoint the effects of EPAC1 to PDGFRα-positive preadipocytes, and the loss of EPAC1 in these cells impedes BAT growth and worsens diet-induced obesity. Importantly, EPAC1 activation enhances the proliferation and differentiation of human brown adipocytes and human brown fat organoids. Notably, a coding variant of RAPGEF3 (encoding EPAC1) that is positively correlated with body mass index abolishes noradrenaline-induced proliferation of brown adipocytes. Thus, EPAC1 might be an attractive target to enhance thermogenic adipocyte number and energy expenditure to combat metabolic diseases.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Adipose-tissue; Camp; Identification; Thermogenesis; Adipocytes; Activation; Cells; White; Entry; Talk
ISSN (print) / ISBN 1465-7392
e-ISSN 1476-4679
Journal Nature Cell Biology
Quellenangaben Volume: 26, Issue: , Pages: 113–123 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place Heidelberger Platz 3, Berlin, 14197, Germany
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
Grants Deutsche Forschungsgemeinschaft (German Research Foundation)