Development of Inhibitors for ATGL

White adipose tissue (WAT) functions as buffer for dietary lipids and stores excess energy in the form of triglycerides (TG). In periods of increased energy demand, WAT-TG stores are hydrolyzed and the body is provided with fuel in the form of free fatty acids (FFA). Adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase (MGL) are the major acylglycerol hydrolases in adipose tissue. ATGL removes the first fatty acid from the TG molecule and generates diglycerides (DG). The activity of ATGL is stimulated by the presence of the activator protein CGI-58 (comparative gene expression protein 58). HSL is the rate-limiting enzyme for the hydrolysis of DG. However, this enzyme is also capable of hydrolyzing TG and monoacylglycerol (MG). MGL performs the last step in TG hydrolysis leading to the liberation of free glycerol. TG hydrolysis as well as TG synthesis in adipose tissue has a major influence on systemic lipid metabolism and energy homeostasis. A dysregulation of these processes may result in metabolic disorders such as lipodystrophy, obesity, type 2 diabetes, and metabolic syndrome. Increased adipose tissue lipolysis, i.e. the release of fatty acids into the circulation, is linked to metabolic diseases such as insulin resistance and cachexia. Insulin resistance is a major risk factor for type 2 diabetes which is being recognized as global epidemic problem. According to the WHO, it was estimated that currently approximately 200 millions suffer from type 2 diabetes and the number of patients is rapidly increasing. Cachexia is frequently associated with cancer leading to severe depletion of adipose and muscle tissue. Cachexia is present in 63% of cancer patients and associated with a 20% increase in mortality. Experiments with mutant mice and observations in humans suggest that efficient lipolysis is dependent on the presence of ATGL activity. Thus, inhibition of ATGL could represent a strategy to medicate metabolic diseases which are associated with increased lipolysis. The objective of the current proposal is to develop inhibitors for ATGL. Additionally, we will investigate whether these inhibitors can counteract the development of insulin resistance and cachexia in mouse models for these metabolic diseases.

White adipose tissue (WAT) functions as buffer for dietary lipids and stores excess energy in the form of triglycerides (TG). In periods of increased energy demand, WAT-TG stores are hydrolyzed and the body is provided with fuel in the form of free fatty acids (FFA). Adipose triglyceride lipase (ATGL) is the most important enzyme in TG hydrolysis and therefore determines the rate of lipid degradation. Increased adipose tissue lipolysis, i.e. the release of fatty acids into the circulation, is linked to metabolic diseases such as insulin resistance and cachexia. Insulin resistance is a major risk factor for type 2 diabetes which is being recognized as global epidemic problem. According to the WHO, it was estimated that currently approximately 200 million suffer from type 2 diabetes and the number of patients is rapidly increasing. Cachexia is frequently associated with cancer leading to severe depletion of adipose and muscle tissue. Cachexia is present in 63% of cancer patients and associated with a 20% increase in mortality. Since increased lipolysis is linked to metabolic diseases, inhibition of ATGL could represent a strategy counteracting these diseases. In this project, we have developed a specific inhibitor of ATGL which reduces lipolysis in mice. Further experiments will reveal whether this inhibitor can improve insulin resistance and cancer-associated cachexia in mouse models of metabolic disease.