Anti-inflammatory effects of oestrogen mediate the sexual dimorphic response to lipid-induced insulin resistance
Anti-inflammatory effects of oestrogen mediate the sexual dimorphic response to lipid-induced insulin resistance
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DOI：
10.1113/jp277270
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发表时间：
2019-08-01
影响因子：
5.5
通讯作者：
Shulman, Gerald, I
中科院分区：
文献类型：
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作者：
Camporez, Joao Paulo;Lyu, Kun;Shulman, Gerald, I
要点在人类和啮齿动物研究中，雌激素已被证明在代谢稳态和胰岛素敏感性调节中发挥着重要作用。与同龄男性相比，绝经前女性的胰岛素敏感性更高，而这些女性中与代谢相关的心血管疾病和 2 型糖尿病的发生率较低。用雌二醇治疗的雌性和雄性小鼠都可以免受肥胖引起的胰岛素抵抗。对肥胖引起的胰岛素抵抗的保护与肝脏和骨骼肌中异位脂质含量的减少有关。这些结果与胰岛素刺激对白色脂肪组织脂肪分解的抑制增加和炎症减少有关。在人类和啮齿动物研究中，雌激素已被证明在调节代谢稳态和胰岛素敏感性中发挥着重要作用。总体而言，女性可以免受肥胖引起的胰岛素抵抗；然而，负责这种保护的机制尚不清楚。因此，本工作的目的是评估与雄性小鼠相比，雌性小鼠免受肥胖引起的胰岛素抵抗的潜在机制。我们研究了年龄匹配或体重匹配条件下的雄性和雌性小鼠。他们被喂食高脂肪饮食 (HFD) 或普通食物 4 周。我们还研究了用雌二醇或媒介物治疗的 HFD 雄性小鼠。与 HFD 雄性小鼠相比，用雌二醇治疗的 HFD 雌性和 HFD 雄性小鼠均表现出全身胰岛素敏感性增加，与异位肝脏和肌肉脂质含量减少相关。这些小鼠异位脂质含量的减少与胰岛素刺激的白色脂肪组织（WAT）脂解作用的抑制增加有关。用雌二醇治疗的 HFD 雌性和 HFD 雄性小鼠也表现出 WAT 炎症的显着减少，表现为血浆和脂肪组织肿瘤坏死因子 α 和白细胞介素 6 浓度的降低。综上所述，这些数据支持这样的假设：由于雌二醇介导的 WAT 炎症减少，HFD 雌性小鼠免受肥胖诱导的胰岛素抵抗，从而改善胰岛素介导的 WAT 脂解抑制，并减少肝脏和骨骼肌中的异位脂质含量。
Key pointsOestrogen has been shown to play an important role in the regulation of metabolic homeostasis and insulin sensitivity in both human and rodent studies. Insulin sensitivity is greater in premenopausal women compared with age-matched men, and metabolism-related cardiovascular diseases and type 2 diabetes are less frequent in these same women. Both female and male mice treated with oestradiol are protected against obesity-induced insulin resistance. The protection against obesity-induced insulin resistance is associated with reduced ectopic lipid content in liver and skeletal muscle. These results were associated with increased insulin-stimulated suppression of white adipose tissue lipolysis and reduced inflammation. Oestrogen has been shown to play an important role in the regulation of metabolic homeostasis and insulin sensitivity in both human and rodent studies. Overall, females are protected against obesity-induced insulin resistance; yet, the mechanisms responsible for this protection are not well understood. Therefore, the aim of the present work was to evaluate the underlying mechanism(s) by which female mice are protected against obesity-induced insulin resistance compared with male mice. We studied male and female mice in age-matched or body weight-matched conditions. They were fed a high-fat diet (HFD) or regular chow for 4 weeks. We also studied HFD male mice treated with oestradiol or vehicle. Both HFD female and HFD male mice treated with oestradiol displayed increased whole-body insulin sensitivity, associated with reduction in ectopic hepatic and muscle lipid content compared to HFD male mice. Reductions in ectopic lipid content in these mice were associated with increased insulin-stimulated suppression of white adipose tissue (WAT) lipolysis. Both HFD female and HFD male mice treated with oestradiol also displayed striking reductions in WAT inflammation, represented by reductions in plasma and adipose tissue tumour necrosis factor alpha and interleukin 6 concentrations. Taken together these data support the hypothesis that HFD female mice are protected from obesity-induced insulin resistance due to oestradiol-mediated reductions in WAT inflammation, leading to improved insulin-mediated suppression of WAT lipolysis and reduced ectopic lipid content in liver and skeletal muscle.