PDF(Pubmed)
Abstract：
Adipose dysfunction in lipodystrophic SEIPIN deficiency is associated with multiple metabolic disorders and increased risks of developing cardiovascular diseases, such as atherosclerosis, cardiac hypertrophy, and heart failure. Recently, adipose transplantation has been found to correct adipose dysfunction and metabolic disorders in lipodystrophic Seipin knockout mice; however, whether adipose transplantation could improve lipodystrophy-associated cardiovascular consequences is still unclear. Here, we aimed to explore the effects of adipose transplantation on lipodystrophy-associated metabolic cardiovascular diseases in Seipin knockout mice crossed into atherosclerosis-prone apolipoprotein E (Apoe) knockout background. At 2 months of age, lipodystrophic Seipin/Apoe double knockout mice and nonlipodystrophic Apoe knockout controls were subjected to adipose transplantation or sham operation. Seven months later, mice were euthanized. Our data showed that although adipose transplantation had no significant impact on endogenous adipose atrophy or gene expression, it remarkably increased plasma leptin but not adiponectin concentration in Seipin/Apoe double knockout mice. This led to significantly reduced hyperlipidemia, hepatic steatosis, and insulin resistance in Seipin/Apoe double knockout mice. Consequently, atherosclerosis burden, intraplaque macrophage infiltration, and aortic inflammatory gene expression were all attenuated in Seipin/Apoe double knockout mice with adipose transplantation. However, adipocyte morphology, macrophage infiltration, or fibrosis of the perivascular adipose tissue was not altered in Seipin/Apoe double knockout mice with adipose transplantation, followed by no significant improvement of vasoconstriction or relaxation. In conclusion, we demonstrate that adipose transplantation could alleviate lipodystrophy-associated metabolic disorders and atherosclerosis but has an almost null impact on perivascular adipose abnormality or vascular dysfunction in lipodystrophic Seipin/Apoe double knockout mice.NEW & NOTEWORTHY Adipose transplantation (AT) reverses multiply metabolic derangements in lipodystrophy, but whether it could improve lipodystrophy-related cardiovascular consequences is unknown. Here, using Seipin/Apoe double knockout mice as a lipodystrophy disease model, we showed that AT partially restored adipose functionality, which translated into significantly reduced atherosclerosis. However, AT was incapable of reversing perivascular adipose abnormality or vascular dysfunction. The current study provides preliminary experimental evidence on the therapeutic potential of AT on lipodystrophy-related metabolic cardiovascular diseases.
摘要：
脂肪营养不良的SEIPIN缺乏症的脂肪功能障碍与多种代谢紊乱和发生心血管疾病的风险增加有关，比如动脉粥样硬化，心脏肥大,和心力衰竭。最近,已经发现脂肪移植可以纠正脂肪营养不良的Seipin基因敲除小鼠的脂肪功能障碍和代谢紊乱;然而,脂肪移植是否能改善脂肪营养不良相关的心血管后果尚不清楚.这里,我们旨在探讨脂肪移植对Seipin基因敲除小鼠脂肪代谢障碍相关代谢性心血管疾病的影响,该基因敲除小鼠的动脉粥样硬化易发载脂蛋白E(Apoe)基因敲除背景.在2个月大的时候，脂肪营养不良的Seipin/Apoe双敲除小鼠和非脂肪营养不良的Apoe敲除对照进行脂肪移植或假手术。七个月后,对小鼠实施安乐死。我们的数据表明，尽管脂肪移植对内源性脂肪萎缩或基因表达没有显著影响，它显着增加了Seipin/Apoe双基因敲除小鼠的血浆瘦素浓度，而不是脂联素浓度。这导致高脂血症显著减少，肝脂肪变性,Seipin/Apoe双基因敲除小鼠的胰岛素抵抗。因此,动脉粥样硬化负担，斑块内巨噬细胞浸润，Seipin/Apoe双基因敲除小鼠脂肪移植后，主动脉炎症基因表达均减弱。然而,脂肪细胞形态学,巨噬细胞浸润，或血管周围脂肪组织的纤维化在Seipin/Apoe双敲除小鼠脂肪移植中没有改变，随后血管收缩或舒张无明显改善。总之,我们证明,脂肪移植可减轻脂肪营养不良相关的代谢紊乱和动脉粥样硬化,但对脂肪营养不良Seipin/Apoe双基因敲除小鼠的血管周围脂肪异常或血管功能障碍几乎没有影响.新的和注意脂肪移植（AT）逆转了脂肪营养不良中的多重代谢紊乱，但它是否能改善与脂肪营养不良相关的心血管后果尚不清楚。这里,使用Seipin/Apoe双基因敲除小鼠作为脂肪营养不良疾病模型，我们发现AT部分恢复了脂肪功能,转化为显著减少的动脉粥样硬化。然而,AT不能逆转血管周围脂肪异常或血管功能障碍。目前的研究为AT对脂肪营养不良相关的代谢性心血管疾病的治疗潜力提供了初步的实验证据。
