One of the consequences of sedentary lifestyle and consumption of a high-fat diet is Nonalcoholic Fatty Liver Disease (NAFLD), which affects approximately 30% of adults and up to 10% of children in developed countries. Interestingly, metabolic complications, such as insulin resistance and obesity, are less frequent in young women than in men of the same age or in postmenopausal women. In fact, reduced estrogen concentration during menopause is associated with increased visceral fat, metabolic diseases, insulin resistance, and T2DM. However, how estradiol is related to the development and progression of NAFLD remains unknown. Therefore, the general objective of this project was to study (in vivo) the effects of estrogen receptor alpha (ERα) ablation on hepatic energy metabolism. To this end, C57BL6 mice with ERα deletion specifically in the liver were generated using the Cre-Lox system (LERaKO). Sixth-week-old mice (Control and LERaKO mice) were fed a high-fat diet (HFD) with 45% fat. LERaKO mice displayed no difference in final body weight compared with control mice after four weeks of HFD feeding. A glucose tolerance test (GTT) was also performed after four weeks of HFD feeding. LERaKO mice displayed an increase in glucose intolerance by ~21% (P<0.05) compared with control mice, despite showing no difference in insulin secretion over the course of the GTT. Interestingly, we observed an increase in hepatic triglyceride (TAG) content by ~157% (P<0.05) in LERaKO mice compared with control mice and a decrease in plasma triglyceride concentration. We did not observe a significant difference in the expression of pro- and anti-inflammatory genes, but observed a significant increase in the expression of genes related to lipid synthesis and gluconeogenesis (P<0.05). Taken together, these data confirm the hypothesis that ERα plays a pivotal role in hepatic metabolism in mice, as liver-specific ERα ablation leads to glucose intolerance and hepatic steatosis.


F. Sucupira: None. L. Araujo: None. J. Camporez: None.


FAPESP (2021/02638-9)

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at