A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity.
A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity.
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DOI：
10.1038/ni.3728
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发表时间：
2017-06
影响因子：
30.5
通讯作者：
Chavakis T
中科院分区：
文献类型：
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作者：
Chung KJ;Chatzigeorgiou A;Economopoulou M;Garcia-Martin R;Alexaki VI;Mitroulis I;Nati M;Gebler J;Ziemssen T;Goelz SE;Phieler J;Lim JH;Karalis KP;Papayannopoulou T;Blüher M;Hajishengallis G;Chavakis T
在肥胖症中，白色脂肪组织（AT）炎症与米色脂肪生成减少相关，米色脂肪生成是由表达解偶联蛋白-1（UCP 1）的米色脂肪细胞介导的产热和能量耗散功能。在这里，我们剖析了肥胖症中米色脂肪形成的炎症驱动的抑制机制，其需要分别由α4整合素及其反受体VCAM-1介导的巨噬细胞和脂肪细胞之间的直接粘附相互作用，其表达在肥胖症中上调。这种粘附相互作用促进并伴随着调节巨噬细胞中的炎症活化和脂肪细胞中ERK依赖的UCP 1下调。小鼠体内α4整联蛋白的遗传或药理学失活导致UCP 1表达升高和肥胖症皮下AT的米色脂肪形成。我们的研究结果，建立在小鼠和人类系统，揭示了一个自我维持的周期炎症驱动的损害米色脂肪形成肥胖。
In obesity, white adipose tissue (AT) inflammation is associated with reduced beige adipogenesis, a thermogenic and energy-dissipating function mediated by uncoupling protein-1 (UCP1)-expressing beige adipocytes. Here, we dissected an inflammation-driven inhibitory mechanism of beige adipogenesis in obesity that required direct adhesive interactions between macrophages and adipocytes mediated, respectively, by α4 integrin and its counter-receptor VCAM-1, the expression of which was upregulated in obesity. This adhesive interaction reciprocally and concomitantly modulated inflammatory activation in macrophages and Erk–dependent downregulation of UCP1 in adipocytes. Genetic or pharmacologic inactivation of α4 integrin in mice resulted in elevated UCP1 expression and beige adipogenesis of the subcutaneous AT in obesity. Our findings, established in both mouse and human systems, reveal a self-sustained cycle of inflammation-driven impairment of beige adipogenesis in obesity.