A primate model to study epigenetic mechanisms involved in metabolism regulation in response to nutritional stress

The grey mouse lemur ( Microcebus murinus) is an arboreal primate originating from Madagascar, where it faces environmental conditions with strong contrasts between summer and winter seasons, in particular for food and water availability. Seasonal varia-tions result in adaptive response inducing energetic metabolism and behavioral changes that are fully reproducible in captivity. Characterized by its great phenotypic fiexibility, this primate appears as an interest­ ing mode!to evaluate the raies of epigenetic me-chanisms in modulating the adaptive responses to environmental modifications. In order to determine the impact of nutritional stress on epigenetic mechanisms, we submitted adult male mouse lemurs to either a control diet (CTL; ad libitum; N=6) or to an energetic challenge (CR; 40% calorie restriction; N=6) for 5 weeks, at the end of the winter season. Animals were then monitored for body mass, food intake, core temperature, metabolic performances and glucose tolerance. Liver biopsies were also performec\ before and after the experimental period, for both control and challenged animals. While calorie restriction had no major effect on body weight, core temperature· or metabolic performance, we observed an improvement of glucose tolerance in CR animals. We further investigated whether this result could be reflected at the epigenetic level. In a first approach, we focusecl on liver global DNA methylation. RNA and DNA were coextracted and DNA methylation measured by LUlMA (luminometric methylation as-say). Global liver DNA methylation was 65% ± 3% in Microcebus murinus. This level was not modified by the season and not affected by calorie restriction. Additional stuclies are needed to understand the molecular mechanisms that underlie the physiological changes displayed in response to environmental changes in the mouse lemur. A specific emphasis could be made on DNA methylation of gene promoters involved in lipid and glucose metabolism. This preliminary project challenges the role of epigenetic plasticity in adaptive processes and highlights the role that might play the mouse lemur as an animal model to decipher the mechanisms underlying phenotypic flexibility.