Van Sinderen Michelle L, Steinberg Gregory R, Jørgensen Sebastian B, Honeyman Jane, Chow Jenny D, Herridge Kerrie A, Winship Amy L, Dimitriadis Evdokia, Jones Margaret E E, Simpson Evan R, Boon Wah Chin
MIMR-PHI Institute of Medical Research, Clayton Vic 3180 Australia; Dept of Anatomy and Developmental Biology, Monash University, Clayton Vic 3800, Australia.
St Vincent's Institute of Medical Research and Dept of Medicine, University of Melbourne, Fitzroy, Vic 3065, Australia.
PLoS One. 2015 Aug 28;10(8):e0136143. doi: 10.1371/journal.pone.0136143. eCollection 2015.
The maintenance of glucose homeostasis within the body is crucial for constant and precise performance of energy balance and is sustained by a number of peripheral organs. Estrogens are known to play a role in the maintenance of glucose homeostasis. Aromatase knockout (ArKO) mice are estrogen-deficient and display symptoms of dysregulated glucose metabolism. We aim to investigate the effects of estrogen ablation and exogenous estrogen administration on glucose homeostasis regulation. Six month-old female wildtype, ArKO, and 17β-estradiol (E2) treated ArKO mice were subjected to whole body tolerance tests, serum examination of estrogen, glucose and insulin, ex-vivo muscle glucose uptake, and insulin signaling pathway analyses. Female ArKO mice display increased body weight, gonadal (omental) adiposity, hyperinsulinemia, and liver triglycerides, which were ameliorated upon estrogen treatment. Tolerance tests revealed that estrogen-deficient ArKO mice were pyruvate intolerant hence reflecting dysregulated hepatic gluconeogenesis. Analyses of skeletal muscle, liver, and adipose tissues supported a hepatic-based glucose dysregulation, with a down-regulation of Akt phosphorylation (a key insulin signaling pathway molecule) in the ArKO liver, which was improved with E2 treatment. Concurrently, estrogen treatment lowered ArKO serum leptin and adiponectin levels and increased inflammatory adipokines such as tumour necrosis factor alpha (TNFα) and interleukin 6 (IL6). Furthermore, estrogen deficiency resulted in the infiltration of CD45 macrophages into gonadal adipose tissues, which cannot be reversed by E2 treatment. This study describes the effects of estrogens on glucose homeostasis in female ArKO mice and highlights a primary phenotype of hepatic glucose dysregulation and a parallel estrogen modified adipokine profile.
体内葡萄糖稳态的维持对于能量平衡的持续精确运作至关重要，并且由多个外周器官来维持。已知雌激素在葡萄糖稳态的维持中发挥作用。芳香化酶敲除（ArKO）小鼠缺乏雌激素，并表现出葡萄糖代谢失调的症状。我们旨在研究雌激素缺失和外源性雌激素给药对葡萄糖稳态调节的影响。对6月龄的雌性野生型、ArKO和经17β-雌二醇（E2）处理的ArKO小鼠进行了全身耐受性试验、雌激素、葡萄糖和胰岛素的血清检测、离体肌肉葡萄糖摄取以及胰岛素信号通路分析。雌性ArKO小鼠体重增加、性腺（网膜）肥胖、高胰岛素血症和肝脏甘油三酯增加，雌激素治疗后这些症状有所改善。耐受性试验表明，缺乏雌激素的ArKO小鼠对丙酮酸不耐受，因此反映出肝脏糖异生失调。对骨骼肌、肝脏和脂肪组织的分析支持基于肝脏的葡萄糖失调，ArKO肝脏中Akt磷酸化（一种关键的胰岛素信号通路分子）下调，E2治疗后有所改善。同时，雌激素治疗降低了ArKO血清瘦素和脂联素水平，并增加了炎性脂肪因子，如肿瘤坏死因子α（TNFα）和白细胞介素6（IL6）。此外，雌激素缺乏导致CD45巨噬细胞浸润到性腺脂肪组织中，E2治疗无法逆转这种情况。本研究描述了雌激素对雌性ArKO小鼠葡萄糖稳态的影响，并突出了肝脏葡萄糖失调的主要表型以及平行的雌激素修饰的脂肪因子谱。
