Intergenerational inheritance of high fat diet-induced cardiac lipotoxicity in Drosophila

Maria Clara Guida, Ryan Tyge Birse, Alessandra Dall’Agnese, Paula Coutinho Toto, Soda Balla Diop, Antonello Mai, Peter D. Adams, Pier Lorenzo Puri and Rolf Bodmer ()
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Maria Clara Guida: Sanford-Burnham-Prebys Medical Discovery Institute
Ryan Tyge Birse: Sanford-Burnham-Prebys Medical Discovery Institute
Alessandra Dall’Agnese: Sanford-Burnham-Prebys Medical Discovery Institute
Paula Coutinho Toto: Sanford-Burnham-Prebys Medical Discovery Institute
Soda Balla Diop: Sanford-Burnham-Prebys Medical Discovery Institute
Antonello Mai: Sapienza Università di Roma
Peter D. Adams: Sanford-Burnham-Prebys Medical Discovery Institute
Pier Lorenzo Puri: Sanford-Burnham-Prebys Medical Discovery Institute
Rolf Bodmer: Sanford-Burnham-Prebys Medical Discovery Institute

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Obesity is strongly correlated with lipotoxic cardiomyopathy, heart failure and thus mortality. The incidence of obesity has reached alarming proportions worldwide, and increasing evidence suggests that the parents’ nutritional status may predispose their offspring to lipotoxic cardiomyopathy. However, to date, mechanisms underlying intergenerational heart disease risks have yet to be elucidated. Here we report that cardiac dysfunction induced by high-fat-diet (HFD) persists for two subsequent generations in Drosophila and is associated with reduced expression of two key metabolic regulators, adipose triglyceride lipase (ATGL/bmm) and transcriptional cofactor PGC-1. We provide evidence that targeted expression of ATGL/bmm in the offspring of HFD-fed parents protects them, and the subsequent generation, from cardio-lipotoxicity. Furthermore, we find that intergenerational inheritance of lipotoxic cardiomyopathy correlates with elevated systemic H3K27 trimethylation. Lowering H3K27 trimethylation genetically or pharmacologically in the offspring of HFD-fed parents prevents cardiac pathology. This suggests that metabolic homeostasis is epigenetically regulated across generations.

Date: 2019
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DOI: 10.1038/s41467-018-08128-3

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