Obesity and Bariatric Surgery Drive Epigenetic Variation of Spermatozoa in Humans

Abstract

Obesity is a heritable disorder, with children of obese fathers at higher risk of developing obesity. Environmental factors epigenetically influence somatic tissues, but the contribution of these factors to the establishment of epigenetic patterns in human gametes is unknown. Here, we hypothesized that weight loss remodels the epigenetic signature of spermatozoa in human obesity. Comprehensive profiling of the epigenome of sperm from lean and obese men showed similar histone positioning, but small non-coding RNA expression and DNA methylation patterns were markedly different. In a separate cohort of morbidly obese men, surgery-induced weight loss was associated with a dramatic remodeling of sperm DNA methylation, notably at genetic locations implicated in the central control of appetite. Our data provide evidence that the epigenome of human spermatozoa dynamically changes under environmental pressure and offers insight into how obesity may propagate metabolic dysfunction to the next generation.

Adolescence and the next generation

“…Paternal obesity generates risks of metabolic disturbance and obesity in offspring through the gamete epigenome, but diet and exercise appear to modify these risks 62,63 . In humans, bariatric surgery reverses obesity-induced epigenetic changes in spermatozoa 64 . Whether these paternal processes are 'anticipatory adaptive responses' to a likely postnatal environment or have other functions is currently under debate [65][66][67] .…”

tRNA fragments: novel players in intergenerational inheritance

“…They conclude that diet-induced changes in tRNA fragments account for nutritioninduced transgenerational effects ( Figure 1). This conclusion might be of particular relevance to human pathophysiology, since a recent study observed alterations in germline non-coding RNA of obese men [13]. Interestingly, data from zygotic injection experiments of synthetic tRNA fragments lacking post transcriptional modifications suggest that these modifications are indispensible to induce transgeneratioanal effects [11] while Sharma's study [7] suggests functionality of unmodified tRNA fragments.…”

Sperm tsRNAs and acquired metabolic disorders

“…Deep sequencing of sperm from lean and obese men reveals that DNA methylation patterns are markedly different, and the methylation pattern is dynamically remodeled after bariatric surgery (Donkin et al 2016), indicating that human gametic epigenetic variation can be related to nutritional status. Changes in histone modification by mutation of histone methyltransferase SET-2 also correlate with the transgenerational effects of extended life span in worms (Rando 2016).…”

“…The expression level of sncRNAs such as microRNAs (miRNAs), piwiinteracting RNAs (piRNAs), tRNA fragments and small nuclear RNA fragments was reported to be altered in the sperm of obese men (Donkin et al 2016). Altered piRNA expression might coordinately modulate the expression of genes involved in behavior and food intake and could participate in predisposing the offspring to obesity (Donkin et al 2016).…”

“…The expression level of sncRNAs such as microRNAs (miRNAs), piwiinteracting RNAs (piRNAs), tRNA fragments and small nuclear RNA fragments was reported to be altered in the sperm of obese men (Donkin et al 2016). Altered piRNA expression might coordinately modulate the expression of genes involved in behavior and food intake and could participate in predisposing the offspring to obesity (Donkin et al 2016). In addition, deep sequencing analysis revealed that several miRNAs were upregulated and piRNAs were downregulated in the sperm of the traumatized mice (F 1 ), whereas these changes were not observed in F 2 mouse sperm (Gapp et al 2014).…”