6-7-dihydroxyflavone and Metabolic-Syndrome

Prolonged Endoplasmic Reticulum Stress (ERS) is involved in the pathogenesis of metabolic syndrome, including type-2 diabetes mellitus, cardiovascular diseases, atherosclerosis, obesity, and fatty liver disease. There have been significant efforts to discover molecules to treat ERS and/or to ameliorate associate symptoms. In this study, we investigated the effect of 7,8-Dihydroxyflavone (7,8-DHF) on ERS in liver and pancreas tissues in a cafeteria (CAF) diet induced metabolic syndrome model.. Male C57BL/6 mice were fed CAF diet for 16 weeks and 7,8-DHF was administered intraperitoneally (5 mg/kg/day) for last four weeks. 78-kDa glucose-regulated protein (GRP78) and C/EBP homologous protein (CHOP) in liver and pancreas tissues, insulin and interleukin-1β (IL-1β) in serum were analyzed by ELISA method and serum biochemistry parameters were analyzed with autoanalyzer. GRP78 and CHOP gene expression levels were determined by qRT-PCR. In addition, histopathological analyzes were performed on liver and pancreas tissues.. Findings revealed that CAF diet caused metabolic abnormalities, insulin resistance and inflammation in serum and triggered ERS in pancreas and liver tissues. 7,8-DHF treatment significantly reduced metabolic abnormalities by reducing serum biochemical parameters, HOMO-IR and IL-1β levels. qRT-PCR and ELISA results indicated that 7,8-DHF treatment down-regulated GRP78 and CHOP expression and protein levels in the liver and GRP78 expression in pancreas. Efficiency of 7,8-DHF in these tissues was also demonstrated by histopathological tests.. In conclusion, CAF diet-induced metabolic syndrome model, 7,8-DHF suppressed ERS and ERS-induced metabolic disorders in both liver and pancreas. Therefore, 7,8-DHF may potentially be a novel therapeutic compound to ameliorate ERS and related metabolic symptoms.

Topics: Animals; Apoptosis; Diet, High-Fat; Endoplasmic Reticulum Stress; Flavones; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL

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.. 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.. 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.. 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.

Topics: Animals; Brain-Derived Neurotrophic Factor; Diet, High-Fat; Energy Metabolism; Estrogen Receptor alpha; Female; Flavones; Glucose; Homeostasis; Inflammation; Liver; Membrane Glycoproteins; Menopause; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Obesity; Ovary; Protein-Tyrosine Kinases; Signal Transduction; Transcriptome