Reporting in Science, Rudolf Zechner and colleagues describe the identification of a novel enzyme, adipose triglyceride lipase (ATGL), which catalyses the hydrolysis of triglycerides to diglycerides in mammalian adipose tissue. The discovery of this once elusive second lipase is an important step forward in the fight against obesity-related disorders.

Adipocytes, which make up the bulk of adipose tissue, have a typical morphology that is characterized by the presence of a large lipid droplet — a spherical organelle that contains abundant triglycerides. During periods of starvation, this repository of fat is mobilized by the catabolism of triglycerides to non-esterified fatty acids, which enter the circulation and provide cells with a source of energy. Until recently, researchers believed that hormone-sensitive lipase (HSL) was the sole rate-determining lipolytic enzyme in adipose tissue, but the phenotype of HSL-knockout mice changed this widely held view. These animals were not obese, and had accumulated diglycerides in adipocytes, which indicated that, even in the absence of HSL, as-yet-unidentified lipases efficiently degraded triglycerides to diglycerides.

Zechner and co-workers set out to find these enzymes by carrying out homology searches for murine and human proteins that were structurally similar to known lipases. One putative candidate, ATGL, was identified and, as both human and mouse adipose tissue express high levels of ATGL mRNA, it seemed as if this protein could well be the 'missing lipase'.

Zechner and his team expressed ATGL in a mammalian non-adipocyte cell line, and compared the in vitro activity and substrate specificity of ATGL with that of transfected HSL. Both proteins were enzymatically active but, whereas HSL showed a broad substrate specificity that included triglycerides, cholesterol esters and retinyl esters, ATGL activity was only directed towards triglycerides. Also, ATGL predominantly hydrolysed the first ester bond of triglyceride — which resulted in the conversion of triglycerides to diglycerides. Western-blot analysis and immunofluorescence microscopy confirmed that, in mouse adipocytes, adenovirus-encoded ATGL associated with the lipid droplet — the expected cellular location of a lipolytic enzyme. Furthermore, adipocytes that were infected with the adenoviral ATGL construct released larger amounts of glycerol and fatty acids compared with control cells. And the overexpression of ATGL caused an increase in diglyceride levels, which indicates that the enzyme has a physiological role in the catabolism of triglycerides.

In view of these results, the authors predict that lipids are mobilized in a two-step process: ATGL hydrolyses the first ester bond of triglycerides, which results in the formation of diglycerides that can then be broken down by HSL. As dysfunctional fatty-acid mobilization contributes to the metabolic defects that characterize type-2 diabetes, the addition of ATGL to the mammalian lipolytic repertoire might provide researchers with a novel target for the treatment of this disorder.