Sharma Priyanka, Silva Camila, Pfreundschuh Sarah, Ye Hong, Sampath Harini
Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, United States.
Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition, and Health, Rutgers University, New Brunswick, NJ, United States.
Front Nutr. 2022 Aug 17;9:987956. doi: 10.3389/fnut.2022.987956. eCollection 2022.
7,8-dihydroxyflavone (DHF) is a naturally occurring flavonoid found in , , and 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.
To investigate a causal association between the gut microbiome and the metabolic effects of DHF using a model of antibiotic-induced gut microbiome ablation.
Age-matched male and female C57Bl6/J mice were given 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.
Metabolic 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.
These 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.
7,8 - 二羟基黄酮（DHF）是一种天然存在的黄酮类化合物，在[具体植物1]、[具体植物2]和[具体植物3]物种中被发现，它能选择性地保护雌性小鼠免受高脂饮食（HFD）诱导的代谢疾病影响。我们之前报道过，这种代谢保护作用与肠道微生物群的早期和稳定重塑有关，这在补充了DHF的雌性小鼠中明显，而在雄性小鼠中则不然。喂食DHF的雌性小鼠肠道微生物群的早期变化高度预测了随后的代谢保护作用，这表明肠道微生物群与DHF的代谢效应之间存在因果关系。
使用抗生素诱导的肠道微生物群消融模型，研究肠道微生物群与DHF代谢效应之间的因果关系。
将年龄匹配的雄性和雌性C57Bl6/J小鼠给予高脂饮食，并提供含有载体或DHF的饮用水，持续12周。对于抗生素（Abx）治疗，雌性小鼠在高脂饮食喂养前2周及整个喂养期间给予含有抗生素混合物的饮用水。代谢表型分析包括对体重、身体组成、食物和水摄入量的纵向评估，以及能量消耗、葡萄糖耐量、血浆和肝脏脂质的测量。在棕色脂肪组织（BAT）和骨骼肌中评估介导DHF细胞效应的蛋白质标志物。
DHF对喂食高脂饮食的雌性小鼠的代谢保护作用仅在肠道微生物群完整的情况下才明显。用抗生素处理的小鼠通过给予DHF并不能免受高脂饮食诱导的肥胖影响。此外，原肌球蛋白相关激酶受体B（TrkB）受体的组织激活作用（这已归因于DHF的生物活性）在肠道微生物群消融后丧失，这表明DHF的全身效应需要微生物对其进行“激活”。此外，我们首次报道，补充DHF能显著激活雌性小鼠（而非雄性小鼠）BAT中的TrkB，揭示了DHF的一个新的靶组织。补充DHF还增加了BAT中解偶联蛋白1（UCP1）和AMP激活的蛋白激酶（AMPK）的蛋白水平，这与预防饮食诱导的肥胖一致。
这些结果首次证实了肠道微生物群在介导DHF对雌性小鼠代谢效应中的必要性，并揭示了一个可能介导这些性别差异保护作用的新靶组织。
