Adipose triglyceride lipase (ATGL) is rate-limiting in the mobilization of fatty acids from cellular triglyceride stores. This central role in lipolysis marks ATGL as interesting pharmacological target since deregulated fatty acid metabolism is closely linked to dyslipidemic and metabolic disorders. Here we report on the development and characterization of a small-molecule inhibitor of ATGL. Atglistatin is selective for ATGL and reduces fatty acid mobilization in vitro and in vivo. ATGL performs the first step in triacylglycerol (TG) catabolism generating diacylglycerol which is subsequently degraded by hormone-sensitive lipase (HSL) and monoglyceride lipase (MGL) into glycerol and fatty acids (FA).

Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are the major enzymes contributing to triacylglycerol (TG) breakdown in in vitro assays and in organ cultures of murine white adipose tissue (WAT).