Reversing paternal obesity before conception remodels sperm RNA and reduces metabolic risk in mouse offspring

A preprint posted to bioRxiv from researchers using outbred CD1 mice reports that the metabolic risk passed from obese fathers to their offspring can be substantially reduced if the father returns to a healthy diet and begins voluntary exercise before conception. The study, which has not yet been peer-reviewed, used a within-sire design — meaning the same male mice fathered offspring both during and after a period of high-fat diet exposure — allowing a direct comparison that controls for genetic background.

High-fat diet caused obesity, glucose intolerance, and insulin resistance in the father mice, along with extensive remodelling of sperm messenger RNA, long non-coding RNA, and small non-coding RNA profiles, as well as transcriptomic changes in metabolic tissues. When the same males were switched to a matched control diet and given access to voluntary exercise, sperm RNA profiles shifted back towards those seen in lean males, and offspring born after the reversal showed reduced metabolic dysfunction compared with offspring born during the obese period.

The findings add to a growing body of research on intergenerational epigenetic inheritance via the paternal germline, suggesting that sperm small non-coding RNAs and mRNAs may be one vehicle through which paternal metabolic state is communicated to offspring. As a preprint, these results have not been peer-reviewed and should be interpreted with appropriate caution.