Brown and brown-like beige/brite adipocytes dissipate energy and have been proposed as therapeutic targets to combat metabolic disorders. However, the therapeutic effects of cell-based therapy in humans remain unclear. Here, we created human brown-like (HUMBLE) cells by engineering human white preadipocytes using CRISPR-Cas9–SAM–gRNA to activate endogenous uncoupling protein 1 expression. Obese mice that received HUMBLE cell transplants showed a sustained improvement in glucose tolerance and insulin sensitivity, as well as increased energy expenditure. Mechanistically, increased arginine/nitric oxide (NO) metabolism in HUMBLE adipocytes promoted the production of NO that was carried by S-nitrosothiols and nitrite in red blood cells to activate endogenous brown fat and improved glucose homeostasis in recipient animals. Together, these data demonstrate the utility of using CRISPR-Cas9 technology to engineer human white adipocytes to display brown fat-like phenotypes and may open up cell-based therapeutic opportunities to combat obesity and diabetes.

棕色和类似褐色的米色/棕褐色脂肪细胞会耗散能量，并已被提议作为对抗代谢紊乱的治疗靶标。然而，基于细胞的疗法在人类中的治疗效果仍不清楚。在这里，我们通过使用CRISPR-Cas9–SAM–gRNA激活内源解偶联蛋白1的表达，通过工程化人类白色前脂肪细胞，创建了人类褐色样（HUMBLE）细胞。接受HUMBLE细胞移植的肥胖小鼠显示出葡萄糖耐量和胰岛素敏感性的持续改善，以及增加的能量消耗。从机理上讲，HUMBLE脂肪细胞中精氨酸/一氧化氮（NO）代谢的增加促进了S携带的NO的产生。红细胞中的亚硝基硫醇和亚硝酸盐激活内源性棕色脂肪并改善受体动物体内的葡萄糖稳态。总之，这些数据证明了使用CRISPR-Cas9技术改造人类白色脂肪细胞以显示棕色脂肪样表型的实用性，并可能为对抗肥胖和糖尿病的细胞治疗方法提供了机会。