The role of estrogen receptor beta DNA binding domain in mediating adipose tissue and systemic metabolic effects of exercise in ovariectomized mice

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Estradiol protects women from various cardiovascular and metabolic diseases, a protection which is lost with menopause when estradiol levels drop. Estrogen receptor beta (ERb), one of the two major estrogen receptors in the body, acts via genomic and non-genomic signaling pathways to affect many metabolic functions, including mitochondrial biogenesis and respiration. This study explores the effect of the non-genomic pathway of ERb on adipocyte mitochondria and insulin resistance by assessing the influence of ovariectomy, a model of menopause, and exercise in mice lacking the ERb DNA-binding domain (DBD). Specifically, 21 wild-type (WT) mice and 20 ERb DBD-knockout (KO) were all fed high-fat diet, ovariectomized, and randomized into sedentary and exercise groups. The exercise groups were provided a running wheel for eight weeks. Unexpectedly, exercise increased fasting insulin and surrogate measures of insulin resistance in the KO group, and exercised KO mice showed increased gene expression of mitochondrial gene cytochrome c oxidase subunit 4. Importantly, uncoupling protein 1 (UCP1) protein expression, a marker of adipocyte browning, increased with exercise only in the WT, indicating that the ERb DBD is required for exercise-induced browning in ovariectomized female mice. The increased insulin resistance observed in the exercised KO mice may be related to the lack of UCP1 upregulation in response to exercise, but the mechanism requires further investigation.Includes bibliographical references