Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan.
Genes Cells. 2022 Mar;27(3):202-213. doi: 10.1111/gtc.12920. Epub 2022 Jan 24.
Thermogenic brown and beige adipocytes express uncoupling protein 1 (UCP1) and stimulate energy metabolism, protecting against obesity and metabolic diseases such as type 2 diabetes and hyperlipidemia. Cellular repressor of E1A-stimulated genes 1 (CREG1) can stimulate thermogenic fat formation, induce UCP1, and reduce diet-induced obesity (DIO) in mice at normal room temperature. In this study, we investigated the effect of CREG1 administration and the importance of UCP1 in DIO inhibition under thermoneutral conditions at 30°C, which attenuate thermogenic fat formation. Interestingly, subcutaneous administration of recombinant CREG1 protein via an osmotic pump in C57BL/6J mice for four weeks increased UCP1 expression in interscapular brown adipose tissue (IBAT), inhibited visceral white fat hypertrophy with partial browning, and reduced DIO compared to that in PBS-treated mice. The mRNA expression of energy metabolism-related genes was significantly increased in the IBAT of CREG1-treated mice compared to that in PBS-treated mice. In contrast, adipocyte-specific overexpression of CREG1 failed to improve DIO in UCP1-knockout mice at thermoneutrality. Our results indicate the therapeutic potential of CREG1 administration for obesity under thermogenic fat-attenuating conditions and highlight the indispensable role of UCP1 in the DIO-inhibitory effect of CREG1.
产热棕色和米色脂肪细胞表达解偶联蛋白 1（UCP1），并刺激能量代谢，可预防肥胖和代谢疾病，如 2 型糖尿病和高脂血症。E1A 刺激基因的细胞抑制剂 1（CREG1）可以刺激产热脂肪形成，诱导 UCP1，并减少正常室温下（22℃）饮食诱导的肥胖（DIO）。在这项研究中，我们研究了在 30°C 的热中性条件下给予 CREG1 治疗的效果以及 UCP1 在抑制 DIO 中的重要性，因为热中性条件会减弱产热脂肪形成。有趣的是，通过渗透泵向 C57BL/6J 小鼠皮下给药重组 CREG1 蛋白持续四周，可增加肩胛间棕色脂肪组织（IBAT）中 UCP1 的表达，部分棕色化抑制内脏白色脂肪肥大，并降低 DIO，与 PBS 处理的小鼠相比。与 PBS 处理的小鼠相比，CREG1 处理的小鼠 IBAT 中与能量代谢相关的基因的 mRNA 表达显著增加。相比之下，在热中性条件下，UCP1 敲除小鼠脂肪细胞特异性过表达 CREG1 未能改善 DIO。我们的研究结果表明，在产热脂肪减弱的情况下，给予 CREG1 治疗肥胖具有治疗潜力，并强调了 UCP1 在 CREG1 抑制 DIO 中的不可或缺作用。
