Crosstalk between the muscular estrogen receptor α and BDNF/TrkB signaling alleviates metabolic syndrome via 7,8-dihydroxyflavone in female mice

Objective: 7,8-Dihydroxyflavone (7,8-DHF), a small molecular mimetic of brain-derived neurotrophic factor (BDNF), alleviates high-fat diet-induced obesity in female mice in a sex-specific manner by activating muscular tropomyosin-related kinase B (TrkB). However, the underlying molecular mechanism for this sex difference is unknown. Moreover, muscular estrogen receptor α (ERα) plays a critical role in metabolic diseases. Impaired ERα action is often accompanied by metabolic syndrome (MetS) in postmenopausal women. This study investigated whether muscular ERα is involved in the metabolic effects of 7,8-DHF. Methods: For the in vivo studies, 72 female C57BL/6J mice were given a low-fat diet or high-fat diet, and both received daily intragastric administration of vehicle or 7,8-DHF for 24 weeks. The hypothalamic-pituitary-ovarian (HPO) axis function was assessed by investigating typical sex-related serum hormones and the ovarian reserve. Indicators of menopausal MetS, including lipid metabolism, insulin sensitivity, bone density, and serum inflammatory cytokines, were also evaluated. The expression levels of ERα and other relevant signaling molecules were also examined. In vitro, the molecular mechanism involved in the interplay of ERα and TrkB receptors was verified in differentiated C2C12 myotubes using several inhibitors and a lentivirus short hairpin RNA-knockdown strategy. Results: Long-term oral administration of 7,8-DHF acted as a protective factor for the female HPO axis function, protecting against ovarian failure, earlier menopause, and sex hormone disorders, which was paralleled by the alleviation of MetS coupled with the production of ERα-rich, TrkB-activated, and uncoupling protein 1 (UCP1) high thermogenic skeletal muscle tissues. 7,8-DHF-stimulated transactivation of ERα at serine 118 (S118) and tyrosine 537 (Y537), which was crucial to activate the BDNF/TrkB signaling cascades. In turn, activation of BDNF/TrkB signaling was also required for the ligand-independent activation of ERα, especially at the Y537 phosphorylation site. In addition, Src family kinases played a core role in the interplay of ERα and TrkB, synergistically activating the signaling pathways related to energy metabolism. Conclusions: These findings revealed a novel role of 7,8-DHF in protecting the function of the female HPO axis and activating tissue-specific ERα, which improves our understanding of this sex difference in 7,8-DHF-mediated maintenance of metabolic homeostasis and provides new therapeutic strategies for managing MetS in women.