Diet-Induced Obesity Elicits Macrophage Infiltration and Reduction in Spine Density in the Hypothalami of Male but Not Female Mice.
Diet-Induced Obesity Elicits Macrophage Infiltration and Reduction in Spine Density in the Hypothalami of Male but Not Female Mice.
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DOI：
10.3389/fimmu.2018.01992
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发表时间：
2018
影响因子：
7.3
通讯作者：
Coss D
中科院分区：
文献类型：
--
作者：
Lainez NM;Jonak CR;Nair MG;Ethell IM;Wilson EH;Carson MJ;Coss D
肥胖症的日益流行已成为公众关注的重大问题。C57 BL/6 J小鼠在喂食高脂饮食（HFD）时易于发生饮食诱导的肥胖（DIO），并发展慢性炎症和代谢综合征，使它们成为分析肥胖诱发病理学机制的良好模型。DIO小鼠在炎症和下丘脑功能方面对HFD的反应表现出深刻的性别差异。首先，我们确定男性容易DIO，而女性则有抵抗力。另一方面，卵巢切除的女性易受DIO的影响，这意味着卵巢激素的保护。雄性动物（而非雌性动物）下丘脑神经肽表达出现变化。令人惊讶的是，卵巢切除的女性仍然抵抗神经内分泌的变化，表明卵巢激素不是必要的保护。其次，肥胖小鼠在DIO诱导的炎症中表现出性别差异。在雄性动物的下丘脑中观察到小胶质细胞活化和外周巨噬细胞浸润，而无论是否存在卵巢激素，雌性动物均免受炎性细胞因子增加的影响，并且未表现出小胶质细胞形态学变化或单核细胞衍生的巨噬细胞浸润。引人注目的是，抗炎细胞因子IL-10在女性的下丘脑中增加，而不是男性。第三，本研究提出了一个潜在的机制，肥胖引起的损害下丘脑功能，肥胖男性表现出降低水平的突触蛋白在下丘脑和更少的刺在GnRH神经元，位于该地区表现出巨噬细胞浸润。我们的研究表明，炎症诱导的突触重塑可能是下丘脑损伤的原因，下丘脑损伤可能导致促性腺激素激素、睾酮和精子数量水平降低，我们观察到这一点，并与肥胖人群中的观察结果相对应。两者合计，我们的数据涉及神经免疫机制的性别特异性差异的肥胖引起的下丘脑功能的损害与生殖和生育的潜在后果。
Increasing prevalence in obesity has become a significant public concern. C57BL/6J mice are prone to diet-induced obesity (DIO) when fed high-fat diet (HFD), and develop chronic inflammation and metabolic syndrome, making them a good model to analyze mechanisms whereby obesity elicits pathologies. DIO mice demonstrated profound sex differences in response to HFD with respect to inflammation and hypothalamic function. First, we determined that males are prone to DIO, while females are resistant. Ovariectomized females, on the other hand, are susceptible to DIO, implying protection by ovarian hormones. Males, but not females, exhibit changes in hypothalamic neuropeptide expression. Surprisingly, ovariectomized females remain resistant to neuroendocrine changes, showing that ovarian hormones are not necessary for protection. Second, obese mice exhibit sex differences in DIO-induced inflammation. Microglial activation and peripheral macrophage infiltration is seen in the hypothalami of males, while females are protected from the increase in inflammatory cytokines and do not exhibit microglia morphology changes nor monocyte-derived macrophage infiltration, regardless of the presence of ovarian hormones. Strikingly, the anti-inflammatory cytokine IL-10 is increased in the hypothalami of females but not males. Third, this study posits a potential mechanism of obesity-induced impairment of hypothalamic function whereby obese males exhibit reduced levels of synaptic proteins in the hypothalamus and fewer spines in GnRH neurons, located in the areas exhibiting macrophage infiltration. Our studies suggest that inflammation-induced synaptic remodeling is potentially responsible for hypothalamic impairment that may contribute to diminished levels of gonadotropin hormones, testosterone, and sperm numbers, which we observe and corresponds to the observations in obese humans. Taken together, our data implicate neuro-immune mechanisms underlying sex-specific differences in obesity-induced impairment of the hypothalamic function with potential consequences for reproduction and fertility.
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影响因子：
4.3
作者：
Agustí A;García-Pardo MP;López-Almela I;Campillo I;Maes M;Romaní-Pérez M;Sanz Y
通讯作者：
Sanz Y
DOI：
10.1038/nri3071
发表时间：
2011-10-10
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
16.6
作者：
Dorfman MD;Krull JE;Douglass JD;Fasnacht R;Lara-Lince F;Meek TH;Shi X;Damian V;Nguyen HT;Matsen ME;Morton GJ;Thaler JP
通讯作者：
Thaler JP
影响因子：
64.8
作者：
Ebert, Daniel H.;Greenberg, Michael E.
通讯作者：
Greenberg, Michael E.
DOI：
10.1016/s0140-6736(16)30054-x
发表时间：
2016-04-02
期刊：
Lancet (London, England)
影响因子：
--
作者：
NCD Risk Factor Collaboration (NCD-RisC)
通讯作者：
NCD Risk Factor Collaboration (NCD-RisC)