Metabolic effects of late-onset estradiol replacement in high-fat-fed ovariectomized mice

Decreased estrogen levels in postmenopausal women negatively impact metabolic health. It is known that estradiol (E2) replacement can reverse this condition. However, there is no consensus on whether the effects mediated by E2 depend on the starting time of E2 replacement after menopause. We aimed to investigate the effects of different onset E2 treatments on glucose tolerance and metabolic parameters in high-fat-fed ovariectomized mice.

Eight-week-old female C57BL/6J mice were divided into three groups: SHAM, OVX, and E2, to evaluate three different time points of E2 replacement after ovariectomy: early (after 4 weeks), intermediate (after 12 weeks), and late replacement (after 20 weeks). E2 groups received treatment through subcutaneous pellets.

E2 replacement improved the parameters analyzed independently of the time since ovariectomy, reducing body weight gain and fat mass, as well as increasing the percentage of lean mass. Glucose intolerance, fasting insulin, HOMA-IR, and cholesterol levels were also reduced after treatment with E2. In the liver, there was a decrease in triacylglycerol (TAG) deposition, with no difference in the expression of SREBP1 and ERα proteins. In the muscle, there was a decrease in TAG deposition. In periuterine adipose tissue, there was an increase in the expression of SREBP1, FASN, and SCD, with no difference in the expression of ERα.

Our findings reinforce the critical role of E2 in regulating both glucose and lipid metabolism and indicate that E2 action on metabolic health was not dependent on time since ovariectomy for the parameters analyzed.