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首页> 外文期刊>EBioMedicine >Peripheral Neuropathy and Hindlimb Paralysis in a Mouse Model of Adipocyte-Specific Knockout of Lkb1
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Peripheral Neuropathy and Hindlimb Paralysis in a Mouse Model of Adipocyte-Specific Knockout of Lkb1

机译：Lkb1的脂肪细胞特异性基因敲除小鼠模型中的周围神经病变和后肢瘫痪。

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Brown adipose tissues (BAT) burn lipids to generate heat through uncoupled respiration, thus representing a powerful target to counteract lipid accumulation and obesity. The tumor suppressor liver kinase b1 (Lkb1) is a key regulator of cellular energy metabolism; and adipocyte-specific knockout of Lkb1 (Ad-Lkb1 KO) leads to the expansion of BAT, improvements in systemic metabolism and resistance to obesity in young mice. Here we report the unexpected finding that the Ad-Lkb1 KO mice develop hindlimb paralysis at mid-age. Gene expression analyses indicate that Lkb1 KO upregulates the expression of inflammatory cytokines in interscapular BAT and epineurial brown adipocytes surrounding the sciatic nerve. This is followed by peripheral neuropathy characterized by infiltration of macrophages into the sciatic nerve, axon degeneration, reduced nerve conductance, and hindlimb paralysis. Mechanistically, Lkb1 KO reduces AMPK phosphorylation and amplifies mammalian target-of-rapamycin (mTOR)-dependent inflammatory signaling specifically in BAT but not WAT. Importantly, pharmacological or genetic inhibition of mTOR ameliorates inflammation and prevents paralysis. These results demonstrate that BAT inflammation is linked to peripheral neuropathy.
机译：棕色脂肪组织（BAT）燃烧脂质以通过不耦合的呼吸产生热量，因此是抵抗脂质堆积和肥胖的有力靶标。抑癌肝激酶b1（Lkb1）是细胞能量代谢的关键调节因子; Lkb1（Ad-Lkb1 KO）的脂肪细胞特异性敲除会导致BAT的扩增，系统代谢的改善以及对年轻小鼠的肥胖抵抗力。在这里，我们报告了意想不到的发现，即Ad-Lkb1 KO小鼠在中年出现后肢麻痹。基因表达分析表明，Lkb1 KO上调肩s间BAT和坐骨神经周围的肾上腺棕色脂肪细胞中炎性细胞因子的表达。其次是周围神经病变，其特征在于巨噬细胞浸入坐骨神经，轴突变性，神经传导降低和后肢麻痹。从机制上讲，Lkb1 KO降低了AMPK磷酸化并放大了哺乳动物雷帕霉素靶标（mTOR）依赖性炎症信号，特别是在BAT中而不在WAT中。重要的是，mTOR的药理或遗传抑制作用可改善炎症并预防麻痹。这些结果表明，BAT炎症与周围神经病变有关。

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