Theobromine suppresses adipogenesis through enhancement of CCAAT-enhancer-binding protein β degradation by adenosine receptor A1
Theobromine suppresses adipogenesis through enhancement of CCAAT-enhancer-binding protein β degradation by adenosine receptor A1
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DOI：
10.1016/j.bbamcr.2017.09.017
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发表时间：
2017-12-01
影响因子：
5.1
通讯作者：
Ashida, Hitoshi
中科院分区：
文献类型：
--
作者：
Mitani, Takakazu;Watanabe, Shun;Ashida, Hitoshi
可可碱是一种从可可豆中提取的甲基黄嘌呤，据报道具有多种促进健康的特性，但可可碱对脂肪细胞分化和脂肪形成的影响的分子机制尚不清楚。本研究旨在阐明可可碱体内外抗脂肪作用的分子机制。给4周龄的ICR小鼠注射可可碱（0.1 g/kg），连续7天。可可碱可以减轻小鼠身体和附睾脂肪组织重量的增加，并抑制小鼠脂肪组织中脂肪生成相关基因的表达。在3T3-L1前脂肪细胞中，可可碱通过泛素-蛋白酶体途径引起C/EBP β蛋白的降解。拉下实验表明，可可碱选择性地与腺苷受体A1（AR1）相互作用，AR1的下调抑制了可可碱诱导的C/ESPfi降解。可可碱增加了C/EBP β '在Lys133上的聚合。小泛素样修饰物（SUMO）特异性蛋白酶2 （SENP2）基因的表达被可可碱抑制，该基因编码去氧化酶。体内敲除研究表明，小鼠体内AR1敲除会减弱可可碱在年轻小鼠体内的抗脂肪生成作用。可可碱通过增加脂酰化抑制脂肪细胞分化和诱导C/EBPP降解。此外，AR1信号的抑制对可可碱诱导的C/EBP β降解很重要。
Theobromine, a methylxanthine derived from cacao beans, reportedly has various health-promoting properties but molecular mechanism by which effects of theobromine on adipocyte differentiation and adipogenesis remains unclear. In this study, we aimed to clarify the molecular mechanisms of the anti-adipogenic effect of theobromine in vitro and in vivo. ICR mice (4 week-old) were administered with theobromine (0.1 g/kg) for 7 days. Theobromine administration attenuated gains in body and epididymal adipose tissue weights in mice and suppressed expression of adipogenic-associated genes in mouse adipose tissue. In 3T3-L1 preadipocytes, theobromine caused degradation of C/EBP beta protein by the ubiquitin-proteasome pathway. Pull down assay showed that theobromine selectively interacts with adenosine receptor A1(AR1), and AR1 knockdown inhibited theobromine-induced C/ESPfi degradation. Theobromine increased sumoylation of C/EBP beta' at Lys133. Expression of the small ubiquitin-like modifier (SUMO)-specific protease 2 (SENP2) gene, coding for a desumoylation enzyme, was suppressed by theobromine. In vivo knockdown studies showed that AR1 knockdown in mice attenuated the anti-adipogenic effects of theobromine in younger mice. Theobromine suppresses adipocyte differentiation and induced C/EBPP degradation by increasing its sumoylation. Furthermore, the inhibition of AR1 signaling is important for theobromine-induced C/EBP beta degradation.