Unraveling Biochemical Pathways Affected by Mitochondrial Dysfunctions Using Metabolomic Approaches
We previously observed that female mice survived significantly longer than male mice under fasting conditions. To elucidate the mechanism underlying the sex different effect of fasting, we analyzed various events induced in male and female mice. Kinetic analysis revealed that fasting elicited hypothermia and decreased muscle weight more apparently in male than in female mice. The life-time of male was increased by administration of estradiol while that of female was decreased by ovariectomy. Although plasma levels of estradiol were below detectable levels in male mice, those in female were significantly high and remained unchanged for a fairly long time. Generation of ketone bodies was enhanced more markedly in female than in male animals. The increased generation of ketone bodies in female was strongly inhibited by ovariectomy while that in male animals was increased by administration of estradiol. Expression of uncoupling protein-1 (UCP-1) in brown adipose tissue increased markedly in female mice while it was low in male animals. These results suggest that estrogen is a major factor that increases the life-time of animals under fasting conditions by increasing fatty acid oxidation, ketone body production and heat generation that support the energy metabolism and homeostasis required for the survival of animals.