Paternal multigenerational exposure to an obesogenic diet drives epigenetic predisposition to metabolic diseases in mice

• Published in: eLife Vol. 10
• Main Authors: Raad, Georges, Serra, Fabrizio, Martin, Luc, Derieppe, Marie-Alix, Gilleron, Jérôme, Costa, Vera L, Pisani, Didier F, Amri, Ez-Zoubir, Trabucchi, Michele, Grandjean, Valerie
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 30.03.2021; eLife Sciences Publications Ltd; eLife Sciences Publication; eLife Sciences Publications, Ltd
• Subjects: Adipocytes; Biotechnology industry; Body fat; Body weight; Developmental Biology; Diet; DNA methylation; epigenetic; Epigenetic inheritance; Epigenetics; Families & family life; Fatty liver; Gene expression; Genotype & phenotype; Glucose metabolism; Heredity; inheritance; Life Sciences; Liver; Males; Metabolic disorders; Metabolism; Microinjection; Obesity; Overweight; Phenotypes; Physiological aspects; RNA; sperm; Zygotes; France; United States; mouse; inheritance; sperm; epigenetic; developmental biology; obesity
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.61736

Obesity is a growing societal scourge. Recent studies have uncovered that paternal excessive weight induced by an unbalanced diet affects the metabolic health of offspring. These reports mainly employed single-generation male exposure. However, the consequences of multigenerational unbalanced diet feeding on the metabolic health of progeny remain largely unknown. Here, we show that maintaining paternal Western diet feeding for five consecutive generations in mice induces an enhancement in fat mass and related metabolic diseases over generations. Strikingly, chow-diet-fed progenies from these multigenerational Western-diet-fed males develop a 'healthy' overweight phenotype characterized by normal glucose metabolism and without fatty liver that persists for four subsequent generations. Mechanistically, sperm RNA microinjection experiments into zygotes suggest that sperm RNAs are sufficient for establishment but not for long-term maintenance of epigenetic inheritance of metabolic pathologies. Progressive and permanent metabolic deregulation induced by successive paternal Western-diet-fed generations may contribute to the worldwide epidemic of metabolic diseases.