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

Zhao, Zhenlei; Gu, Yanpei; Han, Jianxin; Jia, Yingxian; Ye, Keqiang; Zhang, Ying

doi:10.1016/j.molmet.2020.101149

Cited by 22 publications

(10 citation statements)

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“…Recently, we found that 7,8-DHF at the dose of 10 mg/kg•BW resulted in a marked increase in bone mineral density (BMD) irrespective of dietary conditions in female mice (Z. Zhao et al, 2021). Inspired by the studies above, we wonder if 7,8-DHF could serve as a regulator on bone remodeling and exert antiosteoporosis effects.…”

Section: Introductionmentioning

confidence: 99%

“…It has been shown that BDNF could promote osteoblast differentiation, migration, and fracture healing ( Kilian et al, 2014 ; Liu et al, 2018 ; Zhang et al, 2020 ; Zhang et al, 2017 ). Recently, we found that 7,8-DHF at the dose of 10 mg/kg·BW resulted in a marked increase in bone mineral density (BMD) irrespective of dietary conditions in female mice ( Zhao et al, 2021 ). Inspired by the studies above, we wonder if 7,8-DHF could serve as a regulator on bone remodeling and exert antiosteoporosis effects.…”

Section: Introductionmentioning

confidence: 99%

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7,8-Dihydroxyflavone modulates bone formation and resorption and ameliorates ovariectomy-induced osteoporosis

Zhao

Han

et al. 2021

eLife

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Imbalances in bone formation and resorption cause osteoporosis. Mounting evidence supports that brain-derived neurotrophic factor (BDNF) implicates in this process. 7,8-dihydroxyflavone (7,8-DHF), a plant-derived small molecular TrkB agonist, mimics the functions of BDNF. We show that both BDNF and 7,8-DHF promoted the proliferation, osteogenic differentiation and mineralization of MC3T3-E1 cells. These effects might be attributed to the activation of the Wnt/β-catenin signaling pathway as the expression of cyclin D1, phosphorylated-glycogen synthase kinase-3β (p-GSK3β), β-catenin, Runx2, Osterix and osteoprotegerin (OPG) were all significantly up-regulated. Knockdown of β-catenin restrained the up-regulation of Runx2 and Osterix stimulated by 7,8-DHF. In particular, blocking TrkB by its specific inhibitor K252a suppressed 7,8-DHF-induced osteoblastic proliferation, differentiation and expression of osteoblastogenic genes. Moreover, BDNF and 7,8-DHF repressed osteoclastic differentiation of RAW264.7 cells. The transcription factor c-fos and osteoclastic genes such as tartrate-resistant acid phosphatase (TRAP), matrix metalloprotein-9 (MMP-9), Adamts5 were inhibited by 7,8-DHF. More importantly, 7,8-DHF attenuated bone loss, improved trabecular microarchitecture, tibial biomechanical properties and bone biochemical indexes in an ovariectomy (OVX) rat model. The current work highlights the dual regulatory effects that 7,8-DHF exerts on bone remodeling.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

7,8-Dihydroxyflavone modulates bone formation and resorption and ameliorates ovariectomy-induced osteoporosis

Zhao

Han

et al. 2021

eLife

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“…6 ). Remarkably, we have recently reported that 7,8-DHF decreases follicle stimulatory hormone (FSH) production, resulting in increased serum estradiol in female mice treated with HFD 45 . Previously, it has been reported that FSH triggers bone loss and anti-FSH increased bone density without altering estrogen concentrations 46 , 47 .…”

Section: Discussionmentioning

confidence: 99%

A TrkB agonist prodrug prevents bone loss via inhibiting asparagine endopeptidase and increasing osteoprotegerin

et al. 2022

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Brain-derived neurotrophic factor (BDNF) and its tropomyosin-related kinase B receptor (TrkB) are expressed in human osteoblasts and mediate fracture healing. BDNF/TrkB signaling activates Akt that phosphorylates and inhibits asparagine endopeptidase (AEP), which regulates the differentiation fate of human bone marrow stromal cells (hBMSC) and is altered in postmenopausal osteoporosis. Here we show that R13, a small molecular TrkB receptor agonist prodrug, inhibits AEP and promotes bone formation. Though both receptor activator of nuclear factor kappa-Β ligand (RANK-L) and osteoprotegerin (OPG) induced by ovariectomy (OVX) remain comparable between WT and BDNF+/− mice, R13 treatment significantly elevates OPG in both mice without altering RANKL, blocking trabecular bone loss. Strikingly, both R13 and anti-RANK-L exhibit equivalent therapeutic efficacy. Moreover, OVX increases RANK-L and OPG in WT and AEP KO mice with RANK-L/OPG ratio lower in the latter than the former, attenuating bone turnover. 7,8-DHF, released from R13, activates TrkB and its downstream effector CREB, which is critical for OPG augmentation. Consequently, 7,8-DHF represses C/EBPβ/AEP pathway, inhibiting RANK-L-induced RAW264.7 osteoclastogenesis. Therefore, our findings support that R13 exerts its therapeutic efficacy toward osteoporosis via inhibiting AEP and escalating OPG.

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“…The metabolic effects of DHF were recently reported to be impacted by interactions between estrogen receptor-α (ERα) and the TrkB receptor in female mice ( 111 ). Specifically, DHF stimulated transactivation of ERα at Serine and Tyrosine residues, while TrkB signaling was reported to mediate ligand-independent activation of ERα.…”

Section: Discussionmentioning

confidence: 99%

Metabolic protection by the dietary flavonoid 7,8-dihydroxyflavone requires an intact gut microbiome

Sharma

Silva²,

Pfreundschuh³

et al. 2022

Front. Nutr.

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Background7,8-dihydroxyflavone (DHF) is a naturally occurring flavonoid found in Godmania, Tridax, and Primula species that confers protection against high-fat diet (HFD) induced metabolic pathologies selectively in female mice. We have previously reported that this metabolic protection is associated with early and stable remodeling of the intestinal microbiome, evident in female but not male DHF-supplemented mice. Early changes in the gut microbiome in female DHF-fed mice were highly predictive of subsequent metabolic protection, suggesting a causative association between the gut microbiome and the metabolic effects of DHF.ObjectiveTo investigate a causal association between the gut microbiome and the metabolic effects of DHF using a model of antibiotic-induced gut microbiome ablation.Materials and methodsAge-matched male and female C57Bl6/J mice were given ad libitum access to HFD and drinking water containing vehicle or DHF for 12 weeks. For antibiotic (Abx) treatment, female mice were given drinking water containing a cocktail of antibiotics for 2 weeks prior to HFD feeding and throughout the feeding period. Metabolic phenotyping consisted of longitudinal assessments of body weights, body composition, food, and water intake, as well as measurement of energy expenditure, glucose tolerance, and plasma and hepatic lipids. Protein markers mediating the cellular effects of DHF were assessed in brown adipose tissue (BAT) and skeletal muscle.ResultsMetabolic protection conferred by DHF in female HFD-fed mice was only apparent in the presence of an intact gut microbiome. Abx-treated mice were not protected from HFD-induced obesity by DHF administration. Further, tissue activation of the tropomyosin-related kinase receptor B (TrkB) receptor, which has been attributed to the biological activity of DHF, was lost upon gut microbiome ablation, indicating a requirement for microbial “activation” of DHF for its systemic effects. In addition, we report for the first time that DHF supplementation significantly activates TrkB in BAT of female, but not male, mice uncovering a novel target tissue of DHF. DHF supplementation also increased uncoupling protein 1 (UCP1) and AMP-activated protein kinase (AMPK) protein in BAT, consistent with protection from diet-induced obesity.ConclusionThese results establish for the first time a requirement for the gut microbiome in mediating the metabolic effects of DHF in female mice and uncover a novel target tissue that may mediate these sexually-dimorphic protective effects.

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

Cited by 22 publications

References 85 publications

7,8-Dihydroxyflavone modulates bone formation and resorption and ameliorates ovariectomy-induced osteoporosis

7,8-Dihydroxyflavone modulates bone formation and resorption and ameliorates ovariectomy-induced osteoporosis

A TrkB agonist prodrug prevents bone loss via inhibiting asparagine endopeptidase and increasing osteoprotegerin

Metabolic protection by the dietary flavonoid 7,8-dihydroxyflavone requires an intact gut microbiome

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