Metabolic lipases in lipid and energy metabolism

The focus of Rudolf Zechner`s research is lipid metabolism, which is a field of great clinical relevance because dysfunctions in this type of metabolism are associated with extremely common afflictions such as obesity, adult- onset diabetes and arteriosclerosis. Zechner concentrates mainly on those biochemical mechanisms which are involved in the mobilisation of lipids stored in cells. In 2002, Zechner and his team demonstrated that established textbook knowledge about lipid metabolism required revision. Mutant lines of mice lacking the only known enzyme for cellular lipid degradation (hormone-sensitive lipase) did not show any signs of adiposity, indicating that an unknown additional lipase must be involved. In 2004, Zechner`s team discovered this enzyme and named it Adipose Triglyceride Lipase (ATGL; Science, 2004). The ensuing characterisation of mutant mouse lines lacking ATGL enabled them to develop a completely new definition of fat degradation in mammals. The ATGL "knock-out" mice store large quantities of fat in various body tissues, thus clearly showing that ATGL catalyses the first step in fat degradation (Science, 2006). In their further work, Zechner`s group identified a co-activator of ATGL which is essential to the degradation of lipids in many cells (Cell Metabolism, 2006). The high relevance of this Graz-based research team`s discoveries was recently confirmed by the insight that mutations in the genes of ATGL or its co-activator can trigger severe disorders in human lipid metabolism ("neutral lipid storage disease"). In summary, Zechner`s team has not only redefined a pathway of lipid metabolism, but also provided the molecular basis for elucidating genetic disorders.

The research work supported by the Wittgenstein Award focused on the biochemistry, cell biology, and (patho)physiology of fat catabolism (lipolysis). On the basis of our discovery of adipose triglyceride hydrolase (ATGL) and the identification of its co-activator comparative gene identification-58 (CGI-58), we provided compelling evidence that the ATGL/CGI-58 complex initiates the degradation of fat not only in mice but in essentially all eukaryotic organisms including humans. Numerous studies on the biochemical function and regulation proved the essential role of ATGL/CGI-58 in neutral lipid metabolism in adipose and non-adipose tissues. More recently, we sought to understand how the breakdown of fat affects cell function and the pathogenesis of disease. We found a strong interaction between lipolysis and the regulation of cell signalling processes affecting nuclear receptor-, insulin-, and endocannabinoid-signalling. Changes in these processes due to dysregulated lipolysis lead to severe morbidity in mice and humans. For example, ATGL deficiency causes an often lethal cardiomyopathy due to defective nuclear receptor signalling in cardiomyocytes. On the other hand, ATGL deficiency improved insulin sensitivity and resistance to high fat diet-induced obesity.Unexpectedly, we also discovered that lipolysis was involved in the development of cancer- associated cachexia, which is characterized by an uncontrolled and irreversible loss of body weight, fat mass, and muscle mass in patients with cancer. The potential benefit of inhibiting lipolysis to prevent cancer-associated cachexia led us to develope specific small molecule inhibitors for the enzyme. Other important aspects of our work extended to the biochemical and physiological function of proteins and enzymes that are structurally related to ATGL, as well as the non-ATGL-dependent functions of CGI-58. Taken together, the Wittgenstein Award provided the financial support for sufficient personnel and infrastructure to perform internationally competitive research. The Award created opportunities for numerous fruitful collaborations, which in turn resulted in close to a hundred publications in journals with high visibility. The tremendous prestige of the Award had the additional benefit of motivating university administrations and other funding agencies to additionally support research the metabolism field in Graz, which can now considered an internationally recognized centre for lipid and metabolism research.