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Human CIDEC transgene improves lipid metabolism and protects against high-fat diet-induced glucose intolerance in mice
Journal of Biological Chemistry ( IF 5.5 ) Pub Date : 2022-08-11 , DOI: 10.1016/j.jbc.2022.102347
Abhishek Gupta 1 , Bijinu Balakrishnan 1 , Shakun Karki 2 , Mark Slayton 1 , Sukanta Jash 3 , Sayani Banerjee 3 , Tan Hooi Min Grahn 4 , Srikarthika Jambunathan 5 , Sarah Disney 1 , Hebaallaha Hussein 1 , Dong Kong 6 , Bradford B Lowell 7 , Purushothaman Natarajan 8 , Umesh K Reddy 8 , Noyan Gokce 2 , Vishva M Sharma 1 , Vishwajeet Puri 1
Affiliation  

Cell death-inducing DNA fragmentation factor-like effector C (CIDEC) expression in adipose tissue positively correlates with insulin sensitivity in obese humans. Further, E186X, a single-nucleotide CIDEC variant is associated with lipodystrophy, hypertriglyceridemia, and insulin resistance. To establish the unknown mechanistic link between CIDEC and maintenance of systemic glucose homeostasis, we generated transgenic mouse models expressing CIDEC (Ad-CIDECtg) and CIDEC E186X variant (Ad-CIDECmut) transgene specifically in the adipose tissue. We found that Ad-CIDECtg but not Ad-CIDECmut mice were protected against high-fat diet (HFD)-induced glucose intolerance. Furthermore, we revealed the role of CIDEC in lipid metabolism using transcriptomics and lipidomics. Serum triglycerides, cholesterol, and low-density lipoproteins were lower in HFD-fed Ad-CIDECtg mice compared to their littermate controls. Mechanistically, we demonstrated that CIDEC regulates the enzymatic activity of adipose triglyceride lipase via interacting with its activator, CGI-58, to reduce free fatty acid release and lipotoxicity. In addition, we confirmed that CIDEC is indeed a vital regulator of lipolysis in adipose tissue of obese humans and treatment with recombinant CIDEC decreased triglyceride breakdown in visceral human adipose tissue. Our study unravels a central pathway whereby adipocyte-specific CIDEC plays a pivotal role in regulating adipose lipid-metabolism and whole-body glucose homeostasis. In summary, our findings identify human CIDEC as a potential ‘drug’ or a ‘druggable’ target to reverse obesity-induced lipotoxicity and glucose intolerance.



中文翻译:

人类 CIDEC 转基因可改善脂质代谢并保护小鼠免受高脂饮食诱导的葡萄糖耐受不良

脂肪组织中细胞死亡诱导 DNA 片段化因子样效应子 C (CIDEC) 的表达与肥胖人类的胰岛素敏感性呈正相关。此外,单核苷酸 CIDEC 变体 E186X 与脂肪营养不良、高甘油三酯血症和胰岛素抵抗有关。为了建立 CIDEC 与维持全身葡萄糖稳态之间未知的机制联系,我们生成了在脂肪组织中特异性表达 CIDEC (Ad-CIDECtg) 和 CIDEC E186X 变体 (Ad-CIDECmut) 转基因的转基因小鼠模型。我们发现 Ad-CIDECtg 而不是 Ad-CIDECmut 小鼠可以免受高脂饮食 (HFD) 诱导的葡萄糖耐受不良。此外,我们使用转录组学和脂质组学揭示了 CIDEC 在脂质代谢中的作用。血清甘油三酯、胆固醇、与同窝对照组相比,HFD 喂养的 Ad-CIDECtg 小鼠的低密度脂蛋白和低密度脂蛋白较低。从机制上讲,我们证明 CIDEC 通过与其激活剂 CGI-58 相互作用来调节脂肪甘油三酯脂肪酶的酶活性,以减少游离脂肪酸的释放和脂毒性。此外,我们证实 CIDEC 确实是肥胖人类脂肪组织中脂肪分解的重要调节剂,重组 CIDEC 治疗可减少人内脏脂肪组织中甘油三酯的分解。我们的研究揭示了一个中心途径,即脂肪细胞特异性 CIDEC 在调节脂肪脂质代谢和全身葡萄糖稳态中起关键作用。总之,我们的研究结果将人类 CIDEC 确定为一种潜在的“药物”或“可成药”的目标,以逆转肥胖引起的脂毒性和葡萄糖耐受不良。

更新日期:2022-08-12
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