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.

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Elevated circulating fatty acids (FAs) contribute to the development of obesity-associated metabolic complications such as insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). Hence, reducing adipose tissue lipolysis to diminish the mobilization of FAs and lower their respective plasma concentrations represents a potential treatment strategy to counteract obesity-associated disorders. Here we show that specific inhibition of adipose triglyceride lipase (Atgl) with the chemical inhibitor, Atglistatin, effectively reduces adipose tissue lipolysis, weight gain, IR and NAFLD in mice fed a high-fat diet. Importantly, even long-term treatment does not lead to lipid accumulation in ectopic tissues such as the skeletal muscle or heart. Thus, the severe cardiac steatosis and cardiomyopathy that is observed in genetic models of Atgl deficiency does not occur in Atglistatin-treated mice. Our data validate the pharmacological inhibition of Atgl as a potentially powerful therapeutic strategy to treat obesity and associated metabolic disorders.

The ability to deposit triacylglycerol (TG) within specifi c cellular organelles is an evolutionary conserved process present in virtually every mammalian cell and in most microorganisms ( 1-3 ). TG storage within lipid droplets (LDs) not only represents an energy reservoir, but is also an important source for the generation of membrane and signaling lipids ( 4 ). However, excessive accumulation of lipids is a hallmark of many metabolic disorders including obesity, hepatic steatosis, and cardiac steatosis ( 5-7 ). Apart from that, fatty acid (FA) esterifi cation and deposition within neutral lipids protect cells from the harmful excess of nonesterifi ed FAs also referred to as lipotoxicity ( 8,9 ). The LD surface is characterized by the presence of various hydrophobic proteins including members of the so-called PAT family ( 1, 10 ) (designation derived from perilipin, adipophilin, and tail-interacting protein of 47 kDa ) and neutral lipid hydrolases, which are involved in TG breakdown and the release of FAs and glycerol.

Monoglyerides (MGs) are short-lived, intermediary lipids deriving from the degradation of phospho- and neutral lipids, and monoglyceride lipase (MGL), also designated as monoacylglycerol lipase (MAGL), is the major enzyme catalyzing the hydrolysis of MGs into glycerol and fatty acids. This distinct function enables MGL to regulate a number of physiological and pathophysiological processes since both MGs and fatty acids can act as signaling lipids or precursors thereof. The most prominent MG species acting as signaling lipid is 2-arachidonoyl glycerol (2-AG) which is the most abundant endogenous agonist of cannabinoid receptors in the body. Importantly, recent observations demonstrate that 2-AG represents a quantitatively important source for arachidonic acid, the precursor of prostaglandins and other inflammatory mediators. Accordingly, MGL-mediated 2-AG degradation affects lipid signaling by cannabinoid receptor-dependent and independent mechanisms. Recent genetic and pharmacological studies gave important insights into MGL's role in (patho-)physiological processes, and the enzyme is now considered as a promising drug target for a number of disorders including cancer, neurodegenerative and inflammatory diseases. This review summarizes the basics of MG (2-AG) metabolism and provides an overview on the therapeutic potential of MGL.