Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)/Université Paul Sabatier (UPS), Université Toulouse 3, Toulouse, France.
Service de Diabétologie, Maladies Métaboliques et Nutrition, Centre Hospitalier Universitaire (CHU) de Toulouse, Toulouse, France.
Front Endocrinol (Lausanne). 2023 Jul 17;14:1215947. doi: 10.3389/fendo.2023.1215947. eCollection 2023.
Estrogen Receptor α (ERα) is a significant modulator of energy balance and lipid/glucose metabolisms. Beyond the classical nuclear actions of the receptor, rapid activation of intracellular signaling pathways is mediated by a sub-fraction of ERα localized to the plasma membrane, known as Membrane Initiated Steroid Signaling (MISS). However, whether membrane ERα is involved in the protective metabolic actions of endogenous estrogens in conditions of nutritional challenge, and thus contributes to sex differences in the susceptibility to metabolic diseases, remains to be clarified.
Male and female mice, harboring a point mutation which results in the abolition of membrane localization and MISS-related effects of the receptor, and their wild-type littermates () were maintained on a normal chow diet (NCD) or fed a high-fat diet (HFD). Body weight gain, body composition and glucose tolerance were monitored. Insulin sensitivity and energy balance regulation were further investigated in HFD-fed female mice.
genotype had no influence on body weight gain, adipose tissue accumulation and glucose tolerance in NCD-fed mice of both sexes followed up to 7 months of age, nor male mice fed a HFD for 12 weeks. In contrast, compared to WT-ERα littermates, HFD-fed female mice exhibited: 1) accelerated fat mass accumulation, liver steatosis and impaired glucose tolerance; 2) whole-body insulin resistance, assessed by hyperinsulinemic-euglycemic clamps, and altered insulin-induced signaling in skeletal muscle and liver; 3) significant decrease in energy expenditure associated with histological and functional abnormalities of brown adipose tissue and a defect in thermogenesis regulation in response to cold exposure.
Besides the well-characterized role of ERα nuclear actions, membrane-initiated ERα extra-nuclear signaling contributes to female, but not to male, protection against HFD-induced obesity and associated metabolic disorders in mouse.
雌激素受体 α（ERα）是能量平衡和脂质/葡萄糖代谢的重要调节剂。除了受体的经典核作用外，细胞内信号通路的快速激活还由位于质膜上的 ERα 的亚部分介导，称为膜起始甾体信号（MISS）。然而，在营养挑战条件下，膜 ERα 是否参与内源性雌激素的保护代谢作用，从而导致代谢疾病易感性的性别差异，仍有待阐明。
雄性和雌性 小鼠，携带导致受体膜定位和与 MISS 相关的作用丧失的点突变，及其野生型同窝仔（）维持在正常饮食（NCD）或高脂肪饮食（HFD）中。监测体重增加、身体成分和葡萄糖耐量。进一步研究 HFD 喂养的雌性小鼠的胰岛素敏感性和能量平衡调节。
基因型对 7 个月龄以下的 NCD 喂养的雌雄小鼠的体重增加、脂肪组织积累和葡萄糖耐量没有影响，也对 HFD 喂养 12 周的雄性小鼠没有影响。相比之下，与 WT-ERα 同窝仔相比，HFD 喂养的 雌性小鼠表现出：1）加速脂肪量积累、肝脂肪变性和葡萄糖耐量受损；2）全身胰岛素抵抗，通过高胰岛素正葡萄糖钳夹评估，以及改变骨骼肌和肝脏中的胰岛素诱导信号；3）能量消耗显著减少，与棕色脂肪组织的组织学和功能异常以及冷暴露时的产热调节缺陷相关。
除了 ERα 核作用的特征作用外，膜起始的 ERα 核外信号有助于雌性而非雄性小鼠对 HFD 诱导的肥胖和相关代谢紊乱的保护。
