Kim Dae Whan, Kim Beom Sue, Kwon Hee-Seok, Kim Chan Gil, Lee Han-Woong, Choi Woong Hwan, Kim Chul Geun
The Department of Life Science and the Research Institute for Natural Sciences, College of Natural Sciences Hanyang University, Seoul 133-791, Korea.
Exp Mol Med. 2003 Dec 31;35(6):518-26. doi: 10.1038/emm.2003.67.
Adipose tissue is an important endocrine regulator of glucose metabolism and energy homeostasis. Researches have focused on this tissue not only as a target for pharmacotherapy of obesity and insulin resistance but also as an endocrine tissue with leptin secretion and high insulin sensitivity. Brown adipose tissue (BAT) additionally plays a unique role in thermoregulation through the mitochondrial uncoupling protein 1 (UCP1), which uncouples oxidative phosphorylation. As a genetic tissue ablation model of BAT, we made transgenic mice expressing herpes simplex virus thymidine kinase (HSV-TK) driven by the brown adipocyte- specific UCP1 minimal regulatory element. The HSV-TK transgene was expressed specifically in BAT and more than 35% increase of apoptosis was induced by ganciclovir (GCV) treatment. Nevertheless, the expression level was not high enough to induce BAT ablation in GCV-treated adult mice. Importantly, however, we found that brown adipocytes in the periphery of interscapular BAT were transformed into white adipocyte-like unilocular cells. These cells express white adipocyte-specific leptin protein but are different in the ultrastructure of mitochondria from classical white adipocytes. Our data indicates that atrophy of BAT causes transformation into white adipocyte-like cells in the adult mouse and also suggests that further molecular understanding of adipocyte plasticity using our transgenic mouse model might be beneficial for the development of anti-obesity/anti-diabetic therapies.
脂肪组织是葡萄糖代谢和能量稳态的重要内分泌调节因子。研究不仅将该组织视为肥胖症和胰岛素抵抗药物治疗的靶点，还将其视为具有瘦素分泌和高胰岛素敏感性的内分泌组织。棕色脂肪组织（BAT）通过线粒体解偶联蛋白1（UCP1）在体温调节中发挥独特作用，UCP1可使氧化磷酸化解偶联。作为BAT的基因组织消融模型，我们构建了由棕色脂肪细胞特异性UCP1最小调控元件驱动表达单纯疱疹病毒胸苷激酶（HSV-TK）的转基因小鼠。HSV-TK转基因在BAT中特异性表达，更昔洛韦（GCV）处理可诱导超过35%的细胞凋亡。然而，其表达水平不足以在GCV处理的成年小鼠中诱导BAT消融。然而，重要的是，我们发现肩胛间BAT周边的棕色脂肪细胞转变为白色脂肪细胞样的单泡细胞。这些细胞表达白色脂肪细胞特异性瘦素蛋白，但线粒体超微结构与经典白色脂肪细胞不同。我们的数据表明，BAT萎缩会导致成年小鼠转变为白色脂肪细胞样细胞，也表明利用我们的转基因小鼠模型进一步从分子层面理解脂肪细胞可塑性可能有助于抗肥胖/抗糖尿病疗法的开发。
