Adipose specific disruption of seipin causes early-onset generalised lipodystrophy and altered fuel utilisation without severe metabolic disease.
Adipose specific disruption of seipin causes early-onset generalised lipodystrophy and altered fuel utilisation without severe metabolic disease.
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DOI：
10.1016/j.molmet.2018.01.019
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发表时间：
2018-04
影响因子：
8.1
通讯作者：
Rochford JJ
中科院分区：
文献类型：
--
作者：
Mcilroy GD;Suchacki K;Roelofs AJ;Yang W;Fu Y;Bai B;Wallace RJ;De Bari C;Cawthorn WP;Han W;Delibegović M;Rochford JJ
BSCL 2基因突变破坏蛋白质seipin，导致最严重的先天性全身性脂肪营养不良（CGL）。受影响的个体表现出白色脂肪组织（WAT）几乎完全丧失并患有代谢疾病。Seipin对于培养物中的脂肪细胞发育至关重要，并且具有Bscl 2生殖系破坏的小鼠概括了BSCL 2破坏在人类中的作用。在这里，我们检查了体内发育中的脂肪细胞中特异性Bscl 2的丢失是否足以阻止脂肪组织发育并引起先天性BSCL 2破坏所观察到的所有特征。我们使用脂肪特异性Adiponectin-Cre系生成并表征了一种新的发育中脂肪细胞Bscl 2缺陷的小鼠模型（Ad-B2（−/−））。我们证明，Ad-B2（-/-）小鼠表现出早发性脂肪营养不良，与先天性Bscl 2缺失小鼠和CGL 2患者相同。然而，葡萄糖耐受不良、胰岛素抵抗和严重的肝脂肪变性并不明显。食物摄入和能量消耗没有变化，但Ad-B2（−/−）小鼠表现出显着改变的底物利用率。我们还发现了不同的影响，具体的脂肪库之间的seipin损失揭示了新的见解，其不同的特点。当喂食高脂肪饮食时，Ad-B2（−/−）小鼠完全不能增加脂肪量，但仍保持葡萄糖耐受性。我们的研究结果表明，在发育中的脂肪细胞中特异性地破坏Bscl 2足以引起在BSCL 2突变患者中观察到的早发性全身性脂肪营养不良。然而，这种脂肪量的显著减少不会引起在Bscl 2敲除小鼠中观察到的明显代谢功能障碍，即使在高脂肪饮食挑战之后。只有在发育中的脂肪细胞中的Seipin损失驱动严重的早发性脂肪营养不良。这导致代谢底物的使用显著改变。我们发现发育差异之间的特点差的脂肪库。尽管脂肪量严重减少，但小鼠未显示明显的代谢疾病。
Mutations to the BSCL2 gene disrupt the protein seipin and cause the most severe form of congenital generalised lipodystrophy (CGL). Affected individuals exhibit a near complete loss of white adipose tissue (WAT) and suffer from metabolic disease. Seipin is critical for adipocyte development in culture and mice with germline disruption to Bscl2 recapitulate the effects of BSCL2 disruption in humans. Here we examined whether loss of Bscl2 specifically in developing adipocytes in vivo is sufficient to prevent adipose tissue development and cause all features observed with congenital BSCL2 disruption. We generated and characterised a novel mouse model of Bscl2 deficiency in developing adipocytes (Ad-B2(−/−)) using the adipose-specific Adiponectin-Cre line. We demonstrate that Ad-B2(−/−) mice display early onset lipodystrophy, in common with congenital Bscl2 null mice and CGL2 patients. However, glucose intolerance, insulin resistance, and severe hepatic steatosis are not apparent. Food intake and energy expenditure are unchanged, but Ad-B2(−/−) mice exhibit significantly altered substrate utilisation. We also find differential effects of seipin loss between specific adipose depots revealing new insights regarding their varied characteristics. When fed a high-fat diet, Ad-B2(−/−) mice entirely fail to expand adipose mass but remain glucose tolerant. Our findings demonstrate that disruption of Bscl2 specifically in developing adipocytes is sufficient to cause the early-onset generalised lipodystrophy observed in patients with mutations in BSCL2. However, this significant reduction in adipose mass does not cause the overt metabolic dysfunction seen in Bscl2 knockout mice, even following a high-fat diet challenge. Seipin loss only in developing adipocytes drives severe early-onset lipodystrophy. This leads to significantly altered use of metabolic substrates. We uncover developmental differences between poorly characterised adipose depots. Despite severely reduced adipose mass mice do not show overt metabolic disease.
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影响因子：
4.9
作者：
Ioan-Facsinay A;Kloppenburg M
通讯作者：
Kloppenburg M
影响因子：
2.9
作者：
Binns D;Lee S;Hilton CL;Jiang QX;Goodman JM
通讯作者：
Goodman JM
影响因子：
5.8
作者：
Kim, C. A.;Delepine, Marc;Magre, Jocelyne
通讯作者：
Magre, Jocelyne
影响因子：
7.7
作者：
Joubert, Michael;Jagu, Benoit;Prieur, Xavier
通讯作者：
Prieur, Xavier
DOI：
10.1073/pnas.2536828100
发表时间：
2003-12-23
影响因子：
11.1
作者：
He, WM;Barak, Y;Evans, RM
通讯作者：
Evans, RM