Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, PR China.
Group of Chronic Disease and Environmental Genomics, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, PR China.
Free Radic Biol Med. 2021 Mar;165:289-298. doi: 10.1016/j.freeradbiomed.2021.01.043. Epub 2021 Feb 3.
Nuclear factor-erythroid 2-related factor 1 (NFE2L1) is a key transcription factor that regulates cellular adaptive responses to various stresses. Our previous studies revealed that adult adipocyte-specific Nfe2l1-knockout [Nfe2l1(f)-KO] mice show adipocyte hypertrophy and severe adipose inflammation, which can be worsened by rosiglitazone, a peroxisome proliferator-activated receptor γ agonist. To further assess the crucial roles of NFE2L1 in adipocytes, we investigated the effect of CL316243, a β3 adrenergic agonist that promotes lipolysis via a post-translational mechanism, on adipose inflammation in juvenile Nfe2l1(f)-KO mice. In contrast to adult mice, 4-week-old juvenile Nfe2l1(f)-KO mice displayed a normal fat distribution but reduced fasting plasma glycerol levels and elevated adipocyte hypertrophy and macrophage infiltration in inguinal and gonadal WAT. In addition, Nfe2l1(f)-KO mice had decreased expression of multiple lipolytic genes and reduced lipolytic activity in WAT. While 7 days of CL316243 treatment showed no significant effect on adipose inflammation in Nfe2l1-Floxed control mice, the same treatment dramatically alleviated macrophage infiltration and mRNA expression of inflammation and pyroptosis-related genes in WAT of Nfe2l1(f)-KO mice. Together with previous findings in adult mice, the current study highlights that NFE2L1 plays a fundamental regulatory role in lipolytic gene expression and thus might be an important target to improve adipose plasticity and lipid homeostasis.
核因子红细胞 2 相关因子 1 (NFE2L1) 是一种关键的转录因子，调节细胞对各种应激的适应性反应。我们之前的研究表明，成年脂肪细胞特异性 Nfe2l1 敲除 [Nfe2l1(f)-KO] 小鼠表现出脂肪细胞肥大和严重的脂肪炎症，这种情况可以被过氧化物酶体增殖物激活受体 γ 激动剂罗格列酮进一步加重。为了进一步评估 NFE2L1 在脂肪细胞中的关键作用，我们研究了 CL316243（一种β3 肾上腺素能激动剂）对幼年 Nfe2l1(f)-KO 小鼠脂肪炎症的影响，CL316243 通过翻译后机制促进脂肪分解。与成年小鼠不同，4 周龄的幼年 Nfe2l1(f)-KO 小鼠表现出正常的脂肪分布，但空腹血浆甘油水平降低，腹股沟和性腺白色脂肪组织中的脂肪细胞肥大和巨噬细胞浸润增加。此外，Nfe2l1(f)-KO 小鼠的多个脂肪分解基因表达降低，脂肪组织的脂肪分解活性降低。虽然 7 天的 CL316243 处理对 Nfe2l1-Floxed 对照小鼠的脂肪炎症没有显著影响，但相同的处理显著减轻了 Nfe2l1(f)-KO 小鼠白色脂肪组织中巨噬细胞浸润和炎症及细胞焦亡相关基因的 mRNA 表达。结合之前在成年小鼠中的发现，本研究强调了 NFE2L1 在脂肪分解基因表达中发挥着基本的调节作用，因此可能是改善脂肪组织可塑性和脂质平衡的重要靶点。
