ESPE Abstracts (2015) 84 P-3-845

RNAi as Tool to Study Molecular Mechanisms of Metabolic Adverse Reactions in Caenorhabditis Elegans

Manuela Hörnlea,b, Isabelle Hellwiga, Steve Hodgkinsonb & Wolfgang Kaschkaa

aZentrum Für Psychiatrie/Südwürttemberg, Weissenau, Germany; bUniversitätsklinikum Ulm, Ulm, Germany

Background: The introduction of second generation antipsychotic (SGA) drugs for the treatment of bipolar disorders has been associated with metabolic adverse reactions. Many studies cite significant weight gain as a common side effect, which is often attributed to dysfunction of glucose homeostasis and the development of dyslipidaemia. This in turn may trigger the early pathogenesis observed for example in type-2-diabetes. Factors controlling energy metabolism are largely conserved between mammals and the nematode Caenorhabditis elegans (C. elegans), thereby providing a powerful model to delineate the molecular pathways that lead to metabolic disorders.

Objective and hypotheses: Daf-3 is responsible for storage of fat.

Method: We established a tissue-specific molecular method (RNA Interference; RNAi) in our lab for controlled and cell type-specific silencing of protein synthesis in C. elegans. With this method it is possible to block protein synthesis in specific development stages of the worms. We used different C. elegans mutant strains which lack key regulator proteins of the Insulin- and TGF-β-signaling pathway to study the effects of their absence on tissue lipid accumulation and other metabolic disorders.

Results: Using GFP silencing we confirmed the suitability of the RNAi-method to study lipid metabolism at a single-cell-level. Further, studies in our lab have shown that treatment of C. elegans with olanzapine, a common antipsychotic drug resulted in significant weight gain just as in human patients. A regulatory protein DAF-3 is thought to be involved. Initial experiments indicate DAF-3 is necessary but not sufficient for this side effect.

Conclusion: C. elegans represents a powerful model-system for medical research. Molecular mechanisms leading to excessive storage of fat upon medication are very complex. At least two or more proteins operate in concert to cause this metabolic adverse reaction.

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