Lipolytic Effects of 3-Iodothyronamine (T1AM) and a Novel Thyronamine-Like Analog SG-2 through the AMPK Pathway
Lipolytic Effects of 3-Iodothyronamine (T1AM) and a Novel Thyronamine-Like Analog SG-2 through the AMPK Pathway
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DOI：
10.3390/ijms20164054
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发表时间：
2019-08-02
影响因子：
5.6
通讯作者：
Assadi-Porter, Fariba M.
中科院分区：
文献类型：
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作者：
Rogowski, Michael;Bellusci, Lorenza;Assadi-Porter, Fariba M.
3-碘甲腺原氨酸（T1 AM）及其合成类似物SG-2正在迅速成为细胞代谢重编程的有前途的驱动因素。我们最近的研究表明，在肥胖小鼠中，亚慢性低剂量T1 AM治疗增加了脂解，与独立于食物消耗的显著体重减轻相关。T1 AM的脂解作用的具体细胞机制及其作用位点仍然未知。首先，为了研究T1 AM进入细胞的机制，我们通过将其与罗丹明（TRITC）缀合来合成T1 AM的荧光标记版本（FL-T1 AM），并分析其在3 T3-L1小鼠脂肪细胞中的细胞摄取和定位。使用共聚焦显微镜的细胞成像显示FL-T1 AM快速细胞间摄取进入线粒体，而不定位于成熟脂肪细胞的脂滴或细胞核。用T1 AM和SG-2处理3 T3-L1脂肪细胞导致脂质积累减少，后者显示出比T1 AM显著更高的效力（分别为10 μ M对20 μ M）。我们进一步研究了T1 AM和SG-2对肝HepG 2细胞的影响。在用T1 AM或SG-2处理的HepG 2细胞中观察到脂质积累的显著减少，这是由于脂解活性增加。这通过培养基中甘油的积累和AMPK/ACC信号通路的激活得到证实。
3-Iodothyronamine (T1AM) and its synthetic analog SG-2 are rapidly emerging as promising drivers of cellular metabolic reprogramming. Our recent research indicates that in obese mice a sub-chronic low dose T1AM treatment increased lipolysis, associated with significant weight loss independent of food consumption. The specific cellular mechanism of T1AM's lipolytic effect and its site of action remains unknown. First, to study the mechanism used by T1AM to gain entry into cells, we synthesized a fluoro-labeled version of T1AM (FL-T1AM) by conjugating it to rhodamine (TRITC) and analyzed its cellular uptake and localization in 3T3-L1 mouse adipocytes. Cell imaging using confocal microscopy revealed a rapid intercellular uptake of FL-T1AM into mitochondria without localization to the lipid droplet or nucleus of mature adipocytes. Treatment of 3T3-L1 adipocytes with T1AM and SG-2 resulted in decreased lipid accumulation, the latter showing a significantly higher potency than T1AM (10 mu M vs. 20 mu M, respectively). We further examined the effects of T1AM and SG-2 on liver HepG2 cells. A significant decrease in lipid accumulation was observed in HepG2 cells treated with T1AM or SG-2, due to increased lipolytic activity. This was confirmed by accumulation of glycerol in the culture media and through activation of the AMPK/ACC signaling pathways.