Aryl hydrocarbon receptor deficiency protects mice from diet-induced adiposity and metabolic disorders through increased energy expenditure.
Aryl hydrocarbon receptor deficiency protects mice from diet-induced adiposity and metabolic disorders through increased energy expenditure.
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DOI：
10.1038/ijo.2015.63
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发表时间：
2015-08
期刊：
影响因子：
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通讯作者：
Tischkau SA
中科院分区：
文献类型：
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作者：
Xu CX;Wang C;Zhang ZM;Jaeger CD;Krager SL;Bottum KM;Liu J;Liao DF;Tischkau SA
肥胖和糖尿病的流行正在加剧。高热量/高脂肪食物是这些全球性健康问题的主要原因，但高脂肪饮食诱导肥胖的分子机制仍未被充分了解。芳香烃受体（AhR）是一种作为外源性物质传感器的转录因子，介导环境毒物诱导的肥胖、胰岛素抵抗和糖尿病的发展。AhR还影响脂质代谢和饮食诱导的肥胖。研究了AhR缺失对饮食诱导的肥胖、肝脂肪变性和胰岛素抵抗的影响。
雄性野生型（WT）、AhR基因敲除（AhR - / -）和AhR杂合子（AhR + / -）小鼠分别喂食正常饲料（NCD，10%的热量来自脂肪）或高脂肪饲料（HFD，60%的热量来自脂肪）长达14周。评估了肥胖程度、脂肪和肝脏的形态、胰岛素信号传导、代谢参数和基因图谱。
AhR缺失可防止高脂肪饮食诱导的肥胖、肝脂肪变性、胰岛素抵抗和炎症。此外，AhR缺失可维持主要代谢组织中的胰岛素信号传导。与野生型相比，这些保护作用源于AhR缺失小鼠更高的能量消耗。棕色脂肪组织中产热基因解偶联蛋白1（Ucp1）以及肌肉中线粒体β - 氧化基因的转录水平在AhR - / -和AhR + / -小鼠中显著高于野生型。
这项工作证明了AhR在高脂肪饮食暴露下对体重调节、肝脏脂肪沉积、胰岛素敏感性和能量消耗具有生理相关的功能，表明AhR信号传导可能被开发为治疗肥胖和代谢紊乱的潜在治疗靶点。
Epidemics of obesity and diabetes are escalating. High-calorie/high-fat food is a major cause for these global health issues, but molecular mechanisms underlying high-fat, diet-induced obesity are still not well understood. The aryl hydrocarbon receptor (AhR), a transcription factor that acts as a xenobiotic sensor, mediates environmental toxicant-induced obesity, insulin resistance and development of diabetes. AhR also influences lipid metabolism and diet-induced obesity. The effects of AhR deficiency on diet-induced obesity, hepatic steatosis and insulin resistance were examined. : Male wild type (WT), AhR null (AhR−/−) and AhR heterozygote (AhR+/−) mice were fed a normal chow diet (NCD, 10% kcal from fat) or a high-fat diet (HFD, 60% kcal from fat) for up to 14 weeks. Adiposity, adipose and liver morphology, insulin signaling, metabolic parameters and gene profiles were assessed. AhR deficiency protected against HFD-induced obesity, hepatic steatosis, insulin resistance and inflammation. Moreover, AhR deficiency preserved insulin signaling in major metabolic tissues. These protective effects result from a higher energy expenditure in AhR-deficient mice compared to WT. Levels of transcript for both the thermogenic gene, uncoupling protein 1 (Ucp1), in brown adipose tissue and mitochondrial β-oxidation genes in muscle were significantly higher in AhR−/− and AhR+/− mice compared to WT. This work documents a physiologically relevant function for AhR in regulation of body weight, hepatic fat deposition, insulin sensitivity and energy expenditure under HFD exposure, suggesting that AhR signaling may be developed as a potential therapeutic target for treatment of obesity and metabolic disorders.