Cox Aaron R, Chernis Natasha, Kim Kang Ho, Masschelin Peter M, Saha Pradip K, Briley Shawn M, Sharp Robert, Li Xin, Felix Jessica B, Sun Zheng, Moore David D, Pangas Stephanie A, Hartig Sean M
Division of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, TX, USA; Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Mol Metab. 2021 Jun;48:101221. doi: 10.1016/j.molmet.2021.101221. Epub 2021 Mar 24.
White adipose tissue (WAT) expansion regulates energy balance and overall metabolic homeostasis. The absence or loss of WAT occurring through lipodystrophy and lipoatrophy contributes to the development of hepatic steatosis and insulin resistance. We previously demonstrated that sole small ubiquitin-like modifier (SUMO) E2-conjugating enzyme Ube2i represses human adipocyte differentiation. The role of Ube2i during WAT development remains unknown.
To determine how Ube2i impacts body composition and energy balance, we generated adipocyte-specific Ube2i knockout mice (Ube2i). CRISPR/Cas9 gene editing inserted loxP sites flanking exons 3 and 4 at the Ube2i locus. Subsequent genetic crosses to Adipoq-Cre transgenic mice allowed deletion of Ube2i in white and brown adipocytes. We measured multiple metabolic endpoints that describe energy balance and carbohydrate metabolism in Ube2i and littermate controls during postnatal growth.
Surprisingly, Ube2i mice developed hyperinsulinemia and hepatic steatosis. Global energy balance defects emerged from dysfunctional WAT marked by pronounced local inflammation, loss of serum adipokines, hepatomegaly, and near absence of major adipose tissue depots. We observed progressive lipoatrophy that commences in the early adolescent period.
Our results demonstrate that Ube2i expression in mature adipocytes allows WAT expansion during postnatal growth. Deletion of Ube2i in fat cells compromises and diminishes adipocyte function that induces WAT inflammation and ectopic lipid accumulation in the liver. Our findings reveal an indispensable role for Ube2i during white adipocyte expansion and endocrine control of energy balance.
白色脂肪组织（WAT）扩张调节能量平衡和整体代谢稳态。通过脂肪营养不良和脂肪萎缩导致的WAT缺失或丧失会促进肝脂肪变性和胰岛素抵抗的发展。我们之前证明，唯一的小泛素样修饰物（SUMO）E2缀合酶Ube2i可抑制人类脂肪细胞分化。Ube2i在WAT发育过程中的作用尚不清楚。
为了确定Ube2i如何影响身体组成和能量平衡，我们构建了脂肪细胞特异性Ube2i基因敲除小鼠（Ube2i）。CRISPR/Cas9基因编辑在Ube2i基因座的外显子3和4两侧插入了loxP位点。随后与Adipoq-Cre转基因小鼠进行基因杂交，使得白色和棕色脂肪细胞中的Ube2i被敲除。我们测量了出生后生长期间Ube2i小鼠和同窝对照小鼠中描述能量平衡和碳水化合物代谢的多个代谢终点指标。
令人惊讶的是，Ube2i小鼠出现了高胰岛素血症和肝脂肪变性。由明显的局部炎症、血清脂肪因子丧失、肝肿大以及主要脂肪组织库几乎缺失所标记的功能失调的WAT导致了整体能量平衡缺陷。我们观察到在青春期早期开始出现进行性脂肪萎缩。
我们的结果表明，成熟脂肪细胞中Ube2i的表达可使出生后生长期间WAT扩张。脂肪细胞中Ube2i的缺失损害并削弱了脂肪细胞功能，从而诱导WAT炎症和肝脏中的异位脂质积累。我们的研究结果揭示了Ube2i在白色脂肪细胞扩张和能量平衡的内分泌控制中不可或缺的作用。
