Endocrine Abstracts

Several instances of RNA-mediated inheritance of phenotypic variation have been reported, among them metabolic disorders. We and others have observed that microinjection into naive fertilized mouse eggs of total sperm RNAs of obese and diabetic males maintained on high-fat diet induce the same pathological variation in the offspring. A role of noncoding RNAs is currently the prevailing hypothesis.

The sperm RNA content is complex. It depends on environmental conditions, but another level of variability is illustrated by the distinct pathological features reported by different groups, a variability that we tentatively attributed to the use of different inbred strains. We investigated the effect of different genotypes on the response to high-fat diet and its transgenerational maintenance. To that purpose, we maintained in the same housing and diet conditions mice of two inbred strains, C57BL/6 and Balb/c and B6/D2 F1 hybrids. From F0 males raised on high-fat diet we derived three generations by sexual mating (F0, F1 and F2) and two generations (G1 and G2) by microinjection into fertilized mouse eggs (Balb/c) of sperm RNAs of different founders. All mice other than the F0 males were maintained on a normal diet and followed for body weights and metabolic health up to 22 weeks. We observed very little difference among founders of the three genotypes fed on high fat diet. During this period strain dependant difference of gain of weight are observed. Variations in body weight were noticeable in the F1 and perpetuated to F2 generation (follow-up so far). Glucose and insulin tolerance tests evidenced a pathology prominent in founder animals and showed stronger differences in a strain dependent manner in generations F1 and F2. These results suggests that the initial signals that program offspring health are differentially perceived in the germ line of the different genotypes and start a genetic anticipation process. Furthermore, strain dependent phenotypic variations of the disease spectrum (GTT and ITT) are transferable by microinjection into fertilized eggs (Balb/c) of total sperm RNAs from C57/BL6, B6/D2 and Balb/c males. Together, these findings uncover a novel area of RNA-mediated epigenetic hereditary variation. Work is still in progress, up-dated results will be presented in the meeting.