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Eps15-homology domain containing protein 2 (EHD2) is a dynamin-related ATPase located at the neck of caveolae, but its physiological function has remained unclear. Here, we found that global genetic ablation of EHD2 in mice led to increased fat accumulation. This organismic phenotype was paralleled at the cellular level by increased lipid uptake via a caveolae-, dynamin- and CD36-dependent pathway, an elevated number of detached caveolae and higher caveolar mobility. Furthermore, EHD2 expression itself was down-regulated in the visceral fat of two obese mouse models and obese patients. Our data suggest that EHD2 controls a cell-autonomous, caveolae-dependent lipid uptake pathway and suggest that low EHD2 expression levels are linked to obesity.

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