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New research has reported sex differences in how the livers of mice respond to short-term fasting. Although data exist showing that the liver is a sexually dimorphic organ, the reasons for this dimorphism were unclear until now.

In animals, a mutual interaction exists between liver activity and reproductive function. “In oviparous species, the liver is essential for ovarian functions because it provides the proteins for the maturation of the egg,” explain Adriana Maggi and Sara Della Torre. This feature has relevant functional consequences because it ensures that reproduction does not occur when food is scarce. “In mammals the liver can recognize when the female is cycling, pregnant or lactating and adjust its energy production accordingly,” adds Maggi.

The team were interested in investigating the mechanisms controlling the sexual dimorphism of the mammalian liver as males are not affected by changes in reproductive status. To do this, Adriana Maggi, Sara Della Torre and colleagues compared the metabolome and transcriptome of livers from adult mice in a condition of short-term fasting. “The mild starvation protocol was necessary to limit activation of the hepatic oestrogen receptor by dietary amino acids, a protocol that we adopted to maximize the sex differences due to physiological sex hormones,” explains Della Torre.

The finding … points to the possibility of selectively targeting this receptor for a novel generation of therapies for the post-menopause

The authors report that in response to short-term fasting, the livers of male mice stop producing energy storage molecules, while the livers of female mice make use of all available resources, including amino acids, to increase the available pool of lipids. Intriguingly, the authors found that the hepatic oestrogen receptor-α is integral to the adoption and maintenance of this sex-specific response to short-term fasting.

“The finding that in female mice the hepatic oestrogen receptor-α has a key role in the control of energy metabolism points to the possibility of selectively targeting this receptor for a novel generation of therapies for the post-menopause,” concludes Maggi.