Estrogen exerts its action through the binding to two major receptors, estrogen receptor (ER)α and β. Recently, the beneficial role of selective ERβ activation in the regulation of metabolic homeostasis in obesity has been demonstrated, but its importance is still controversial. However, no data are available regarding possible gender differences in response to pharmaceutical activation of ERβ. Male mice were fed a control diet (CD) or a high fat diet (HFD) before being treated with the ERβ selective ligand, 4-(2-(3-5-dimethylisoxazol-4-yl)-1H-indol-3yl)phenol (DIP) in the same conditions as in our recently published paper in female mice. Magnetic resonance imaging and spectroscopy were performed repeatedly in vivo after 6 weeks of diet and after 2 weeks of DIP. Adipose tissue distribution and hepatic triglycerides composition were quantified. HFD-treated males showed a feminization of their fat distribution towards more subcutaneous fat depots and increase total fat content and visceral adipose tissue showed clear browning sites after DIP. Hepatic lipid composition was modified by DIP, with less saturated and more unsaturated lipids and an improved insulin sensitivity. Finally, brown adipose tissue size expended after DIP, due to an increase of the size of the lipid droplets. Our data demonstrate that selective activation of ERβ exerts a tissue-specific and sex-dependent response to metabolic adaptation to overfeeding. Most importantly, together with our previously published results in females, the current findings support the concept that sex should be considered in the future development of obesity-moderating drugs.

中文翻译：

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选择性雌激素受体（ER）β的激活可引起脂肪量的重新分布，并改变肥胖雄性小鼠的肝甘油三酸酯组成。

雌激素通过与两个主要受体雌激素受体（ER）α和β结合而发挥作用。最近，已经证明选择性ERβ活化在肥胖症代谢稳态中的调节作用中的有益作用，但是其重要性仍存在争议。但是，尚无有关响应ERβ药物活化的可能性别差异的数据。在用ERβ选择性配体4-（2-（3-5-二甲基异恶唑-4-基）-1H-吲哚-3yl）治疗之前，给雄性小鼠喂食对照饮食（CD）或高脂饮食（HFD）。苯酚（DIP）的条件与我们最近在雌性小鼠中发表的论文相同。饮食6周和DIP 2周后，在体内重复进行磁共振成像和光谱学检查。量化脂肪组织分布和肝甘油三酯组成。经HFD处理的男性显示出其脂肪分布向更多皮下脂肪库的女性化，并增加了总脂肪含量，内脏脂肪组织在DIP后显示出清晰的褐变部位。肝脂质组成通过DIP修饰，具有更少的饱和脂质和更多的不饱和脂质，并改善了胰岛素敏感性。最后，由于脂质小滴的大小增加，棕色脂肪组织的大小在DIP后增加。我们的数据表明，ERβ的选择性激活对过度摄食的代谢适应产生组织特异性和性别依赖性反应。最重要的是，与我们先前发表的关于女性的研究结果一起，当前的发现支持了在肥胖控制药物的未来开发中应考虑性别的观念。