ERALPHA: THE CROSSROAD BETWEEN METABOLIC FITNESS AND METABOLIC ILLNESS

Oestrogens are important regulators of energy homeostasis and lipid metabolism, acting both centrally and peripherally and, indeed, the impairment of oestrogen signalling is associated with the development of several metabolic diseases. The alpha isoform of the oestrogen receptor (ERα) is predominant in the liver and studies carried out in several laboratories, including ours, have shown that hepatic ERα exerts a major role in the control of lipid metabolism. Recently, we demonstrated the pivotal role played by oestrogens and ERα in female liver physiology. Indeed, our studies have shown that in female mammals hepatic ERα has a pivotal role in adapting energy metabolism to the needs of reproductive functions and that is transcriptionally regulated by estrogens and food intake. On the other hand in males, the expression of hepatic ERα is significantly lower than in females, yet its activity is highly regulated by food intake indicating that also in males hepatic ERα might have a role in the control of lipid metabolism. This led us to further investigate the activity of hepatic ERα in males and the aim of this study was to compare female and male liver metabolism and to unravel the role, if any, played by hepatic ERα in the regulation of energy metabolism in male mice. We performed this study in homeostatic conditions and in a stressed metabolic status, caused by the administration of an unbalanced diet. We analysed, with different techniques, key metabolic and inflammatory pathways in female and male control (SYN) and LERKO (Liver ERα knockout) mice fed with control diet (ND) or high fat diet (HFD) and the LERKO mouse model, generated by our lab, allowed us to single out the activity of hepatic ERα. This comprehensive study revealed that both metabolic and inflammatory pathways are different between females and males in homeostatic conditions and that the administration of HFD, per se or also in combination with the selective ablation of hepatic ERα, leads to different outcomes depending on sex. Moreover, the results of this work allowed us to identify the sex specific role of hepatic ERα in the regulation of liver metabolism and inflammation in normal or stressed metabolic conditions, and, interestingly, to highlight ERα possible opposite regulatory action in female and male metabolism. We believe that this is very relevant from both a pharmacological and a pathophysiological point of view. Indeed, the identification of a sex dependent regulatory action of ERα on metabolism would not only provide the conceptual bases for future therapeutic interventions, able to mimic the beneficial effect of oestrogens and ERα on metabolic parameters, but also further stress the necessity to consider sex as an essential biological variable in the design of personalized pharmacological therapies.