Abstract
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.
Highlights
Nongenetic inheritance of newly acquired phenotypes is a relatively new concept in biology whereby changes induced by specific environmental cues in parents can be transmitted to the generations (Chen et al, 2016; Fullston et al, 2013; Grandjean et al, 2016)
The increase in gWAT mass was positively correlated with total body weight (Figure 1—figure supplement 2E). It was associated with the hypertrophy of white adipocytes, with a median surface cell area of white adipocytes increasing from 1500 to 4000 mm2 from the first (WD1) to the fifth generation (WD5) and with a decreased calculated number of adipocytes in WD5 compared to the controls (Figure 1D–F)
Querying the WD1 and WD5 differentially expressed genes (DEGs) against the molecular signature database collection of curated gene pathway annotations revealed a specific WD5 enrichment in gene sets associated with CHEN_METABOLIC_SYNDROM_NETWORK and with genes potentially regulated by the methylation of lysine 4 (H3K4) and lysine 27 (H3K27) of histone H3 and by polycomb repressive complex 2 (PRC2) (Figure 1—source data 2; Liberzon, 2014)
Summary
Nongenetic inheritance of newly acquired phenotypes is a relatively new concept in biology whereby changes induced by specific environmental cues in parents (mothers and/or fathers) can be transmitted to the generations (Chen et al, 2016; Fullston et al, 2013; Grandjean et al, 2016). This process is evolutionarily conserved and has been described from worms to humans (Gapp et al, 2014; Portha et al, 2019; Remy, 2010; Skinner et al, 2015).
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