EHD2-mediated restriction of caveolar dynamics regulates cellular lipid uptake

Abstract

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. We found that global genetic ablation of EHD2 in mice led to increased fat deposits in several organs. This organismic phenotype was paralleled at the cellular level by an increased lipid uptake via a CD36-dependent pathway, an elevated number of detached caveolae and higher caveolar mobility. Following a high fat diet, various enzymes involved in de novo fatty acid synthesis were down-regulated in EHD2 KO mice. Furthermore, EHD2 expression itself was down-regulated in the visceral fat of two obese mouse models and in diet-induced obesity. Thus, EHD2 controls a cell-autonomous, caveolae-dependent lipid uptake pathway, implicating a role of EHD2 in fat accumulation and obesity.