Xing Chun, Jiang Duo, Liu Yang, Tang Qiqun, Huang Haiyan
Key Laboratory of Metabolism and Molecular Medicine, The Ministry of Education, Department of Biochemistry and Molecular Biology, Fudan University School of Basic Medical Sciences, Shanghai 200032, PR China.
Genes Dis. 2020 Oct 10;9(1):140-150. doi: 10.1016/j.gendis.2020.10.001. eCollection 2022 Jan.
Accumulating evidence from both animal and human studies suggests that activation of beige fat increases cellular energy expenditure, ultimately reducing adiposity. Here, we report the central role of adipocyte-derived lysyl oxidase (Lox) in the formation of thermogenic beige fat. Mice exposed to cold or a β3 agonist showed drastically lower Lox expression in thermogenically activated beige fat. Importantly, inhibition of Lox activity with BAPN stimulated biogenesis of beige fat in inguinal white adipose tissue (iWAT) under housing conditions and potentiated cold-induced adaptive thermogenesis and beiging in both iWAT and epididymal white adipose tissue (eWAT). Notably, white adipocytes with Lox repression undergo transdifferentiation into beige adipocytes which can be suppressed by tumor necrosis factor-α (TNFα) via ERK activation. This work provides new insight into the molecular control to expand beige fat by Lox inhibition and suggest the potential for utilizing inhibitor of Lox to treat the emerging epidemics of obesity and diabetes.
来自动物和人体研究的越来越多的证据表明，米色脂肪的激活会增加细胞能量消耗，最终减少肥胖。在此，我们报告脂肪细胞衍生的赖氨酰氧化酶（Lox）在产热米色脂肪形成中的核心作用。暴露于寒冷环境或β3激动剂的小鼠在产热激活的米色脂肪中Lox表达大幅降低。重要的是，用β-氨基丙腈（BAPN）抑制Lox活性可刺激在正常饲养条件下腹股沟白色脂肪组织（iWAT）中米色脂肪的生成，并增强iWAT和附睾白色脂肪组织（eWAT）中冷诱导的适应性产热和米色化。值得注意的是，Lox表达受抑制的白色脂肪细胞会转分化为米色脂肪细胞，而肿瘤坏死因子-α（TNFα）可通过激活细胞外信号调节激酶（ERK）来抑制这种转分化。这项工作为通过抑制Lox来扩展米色脂肪的分子调控提供了新的见解，并提示了利用Lox抑制剂治疗肥胖和糖尿病等新出现的流行病的潜力。
