Adipose tissue dysfunction is an important determinant of obesity-associated, lipid-induced metabolic complications. Ceramides are well-known mediators of lipidinduced insulin resistance in peripheral organs such as muscle. DEGS1 is the desaturase catalyzing the last step in the main ceramide biosynthetic pathway. Functional suppression of DEGS1 activity results in substantial changes in ceramide species likely to affect fundamental biological functions such as oxidative stress, cell survival, and proliferation. Here, we show that degs1 expression is specifically decreased in the adipose tissue of obese patients and murine models of genetic and nutritional obesity. Moreover, loss-of-function experiments using pharmacological or genetic ablation of DEGS1 in preadipocytes prevented adipogenesis and decreased lipid accumulation. This was associated with elevated oxidative stress, cellular death, and blockage of the cell cycle. These effects were coupled with increased dihydroceramide content. Finally, we validated in vivo that pharmacological inhibition of DEGS1 impairs adipocyte differentiation. These data identify DEGS1 as a new potential target to restore adipose tissue function and prevent obesity-associated metabolic disturbances.Dysfunction of white adipose tissue (WAT) and impaired differentiation of new adipocytes may lead to lipid leakage and inappropriate accumulation of ectopic lipids in peripheral organs, causing lipotoxicity and the metabolic syndrome (1). The toxic effects of lipids are determined by both their quantity and their qualitative characteristics (2). Whereas it is well documented that specific species of sphingolipids and ceramides (Cers) mediate lipotoxicity in liver and muscle (3,4), the contribution of specific lipotoxic species to WAT dysfunction in the context of obesity is still not well defined. It is known that in rodent WAT, Cers increase in response to a high-fat diet (HFD) (5,6) concomitantly with the onset of insulin resistance (6). Lipid analysis of WAT from human obese subjects has produced

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