Department of Biomedical Sciences and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA.
Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA.
J Biol Chem. 2022 Sep;298(9):102347. doi: 10.1016/j.jbc.2022.102347. Epub 2022 Aug 11.
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-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 high-fat diet-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.
脂肪组织中细胞死亡诱导 DNA 片段化因子样效应物 C（CIDEC）的表达与肥胖人群的胰岛素敏感性呈正相关。此外，E186X 是 CIDEC 的一种单核苷酸变异，与脂肪营养不良、高三酰甘油血症和胰岛素抵抗有关。为了确定 CIDEC 与维持全身葡萄糖稳态之间未知的机制联系，我们生成了特异性在脂肪组织中表达 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 小鼠能够防止高脂肪饮食诱导的葡萄糖不耐受。此外，我们通过转录组学和脂质组学揭示了 CIDEC 在脂质代谢中的作用。与同窝对照相比，高脂肪饮食喂养的 Ad-CIDECtg 小鼠的血清三酰甘油、胆固醇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，从而减少游离脂肪酸的释放和脂毒性。此外，我们证实 CIDEC 确实是肥胖人群脂肪组织脂肪分解的重要调节剂，重组 CIDEC 处理可减少内脏人脂肪组织中甘油三酯的分解。我们的研究揭示了一条中心途径，即脂肪细胞特异性 CIDEC 在调节脂肪代谢和全身葡萄糖稳态中发挥关键作用。总之，我们的发现确定了人类 CIDEC 是一种潜在的“药物”或“可成药”靶点，可以逆转肥胖引起的脂毒性和葡萄糖不耐受。
