Riant Elodie, Waget Aurélie, Cogo Haude, Arnal Jean-François, Burcelin Rémy, Gourdy Pierre
Institut National de la Santé et de la Recherche Médicale Unité 858, Institut de Médecine Moléculaire de Rangueil, Boite Postale 84225, 31432 Toulouse Cedex 4, France.
Endocrinology. 2009 May;150(5):2109-17. doi: 10.1210/en.2008-0971. Epub 2009 Jan 22.
Although corroborating data indicate that estrogens influence glucose metabolism through the activation of the estrogen receptor alpha (ERalpha), it has not been established whether this pathway could represent an effective therapeutic target to fight against metabolic disturbances induced by a high-fat diet (HFD). To this end, we first evaluated the influence of chronic 17beta-estradiol (E2) administration in wild-type ovariectomized mice submitted to either a normal chow diet or a HFD. Whereas only a modest effect was observed in normal chow diet-fed mice, E2 administration exerted a protective effect against HFD-induced glucose intolerance, and this beneficial action was abolished in ERalpha-deficient mice. Furthermore, E2 treatment reduced HFD-induced insulin resistance by 50% during hyperinsulinemic euglycemic clamp studies and improved insulin signaling (Akt phosphorylation) in insulin-stimulated skeletal muscles. Unexpectedly, we found that E2 treatment enhanced cytokine (IL-6, TNF-alpha) and plasminogen activator inhibitor-1 mRNA expression induced by HFD in the liver and visceral adipose tissue. Interestingly, although the proinflammatory effect of E2 was abolished in visceral adipose tissue from chimeric mice grafted with bone marrow cells from ERalpha-deficient mice, the beneficial effect of the hormone on glucose tolerance was not altered, suggesting that the metabolic and inflammatory effects of estrogens can be dissociated. Eventually comparison of sham-operated with ovariectomized HFD-fed mice demonstrated that endogenous estrogens levels are sufficient to exert a full protective effect against insulin resistance and glucose intolerance. In conclusion, the regulation of the ERalpha pathway could represent an effective strategy to reduce the impact of high-fat diet-induced type 2 diabetes.
尽管确证数据表明雌激素通过激活雌激素受体α（ERα）影响葡萄糖代谢，但尚未确定该途径是否可作为对抗高脂饮食（HFD）诱导的代谢紊乱的有效治疗靶点。为此，我们首先评估了对接受正常饲料或高脂饮食的野生型卵巢切除小鼠长期给予17β-雌二醇（E2）的影响。在喂食正常饲料的小鼠中仅观察到适度的效果，而给予E2对高脂饮食诱导的葡萄糖不耐受具有保护作用，且这种有益作用在ERα缺陷小鼠中消失。此外，在高胰岛素正常血糖钳夹研究期间，E2治疗使高脂饮食诱导的胰岛素抵抗降低了50%，并改善了胰岛素刺激的骨骼肌中的胰岛素信号传导（Akt磷酸化）。出乎意料的是，我们发现E2治疗增强了高脂饮食在肝脏和内脏脂肪组织中诱导的细胞因子（IL-6、TNF-α）和纤溶酶原激活物抑制剂-1 mRNA表达。有趣的是，尽管在移植了来自ERα缺陷小鼠骨髓细胞的嵌合小鼠的内脏脂肪组织中E2的促炎作用消失了，但该激素对葡萄糖耐量的有益作用并未改变，这表明雌激素的代谢和炎症作用可以分离。最终，对假手术小鼠与卵巢切除的高脂饮食喂养小鼠的比较表明，内源性雌激素水平足以对胰岛素抵抗和葡萄糖不耐受发挥充分的保护作用。总之，调节ERα途径可能是减轻高脂饮食诱导的2型糖尿病影响的有效策略。
