Ablation of adipose triglyceride lipase (ATGL) protects from cancer associated cachexia


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Suman Das1, Paul Vesely1, Silvia Schauer1, Guenter Haemmerle2, Clemens Diwoky3, Hannes Temmel1, Sandra Eder2, Robert Zimmermann2, Rudolf Zechner2, Gerald Hoefler1
1Institute for Pathology, Medical University of Graz, Graz, Austria,2Institute of Molecular Biosciences, University of graz, Graz, Austria,3Institute of Medical Engineering,Graz University of Technology, Graz, Austria

Background

Cachexia is one of the main syndrome(s) associated with cancer which deteriorates the medical and social well being of the patients. However its unknown causative mechanism(s) impedes the drug discovery process. It is characterized by progressive loss of body mass, resulting in severe depletion of both adipose tissue and skeletal muscle. The cachectic symptoms could be identified in more than 60 % of the cancer patients has been suggested to be responsible for at least 20% of cancer deaths. Through this project we identified the importance of lipases and lipotoxicity in the commencement as well as in the progression of tumour associated cachexia.

Method

Lewis lung carcinoma is used to develop tumour in wildtype, adipose triglyceride lipase (ATGL) knockout and hormone sensitive lipase (HSL) knockout mice and the resulting mice phenotypes were critically observed and evaluated objectively for the occurrence of cachexia and other related effects of cachexia and/or lipotoxicity.

Results

We could show sustained white adipose tissue (WAT) and skeletal muscle mass in ATGL ko mice after 21 days of tumour development while the wildtype tumour bearing mice lost ~90% WAT and ~40% skeletal muscle (m.gastocnemius). Also HSL ko mice showed reduced cachectic phenotype in comparison to wildtype. Thus we could de-lineate the importance of ATGL in the development of cachexia. Also we could identify the lipotoxic effect of tumour associated cachexia on other organs and/or organ systems especially heart. The importance of lipid metabolism and thus the specific role of ATGL in tumour development have also been analyzed during the project.

Conclusion

The results obtained during the project represent a completely new perspective of the age old syndrome. Also this project would help the scientific and medical community to analyze the hidden layers and players in cachexia syndrome in order to develop improved medication to effectively alleviate the syndrome.