Obesity is a major risk factor for liver and cardiovascular diseases. However, obesity-driven mechanisms that contribute to the pathogenesis of multiple organ diseases are still obscure and treatment is inadequate. We hypothesized that increased , glucose-6-phosphate dehydrogenase (G6PD), the key rate-limiting enzyme in the pentose shunt, is critical in evoking metabolic reprogramming in multiple organs and is a significant contributor to the pathogenesis of liver and cardiovascular diseases. G6PD is induced by a carbohydrate-rich diet and insulin. Long-term (8 months) high-fat diet (HFD) feeding increased body weight and elicited metabolic reprogramming in visceral fat, liver, and aorta, of the wild-type rats. In addition, HFD increased inflammatory chemokines in visceral fat. Interestingly, CRISPR-edited loss-of-function Mediterranean G6PD variant (G6PD) rats, which mimic human polymorphism, moderated HFD-induced weight gain and metabolic reprogramming in visceral fat, liver, and aorta. The G6PD variant prevented HFD-induced CCL7 and adipocyte hypertrophy. Furthermore, the G6PD variant increased – a gene encoding circadian clock-related protein that suppresses obesity associated with Prader-Willi syndrome – and reduced HFD-induced non-alcoholic fatty liver. Additionally, the G6PD variant reduced aging-induced aortic stiffening. Our findings suggest G6PD is a regulator of HFD-induced obesity, adipocyte hypertrophy, and fatty liver.

中文翻译：

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功能丧失的 G6PD 变异可调节雄性大鼠高脂饮食诱导的肥胖、脂肪细胞肥大和脂肪肝


肥胖是肝脏和心血管疾病的主要危险因素。然而，导致多器官疾病发病机制的肥胖驱动机制仍不清楚，且治疗不足。我们假设，葡萄糖-6-磷酸脱氢酶（G6PD）（戊糖分流中的关键限速酶）的增加对于引起多个器官的代谢重编程至关重要，并且是肝脏和心血管疾病发病机制的重要因素。 G6PD 是由富含碳水化合物的饮食和胰岛素诱导的。长期（8 个月）高脂肪饮食 (HFD) 喂养会增加野生型大鼠的体重，并引发内脏脂肪、肝脏和主动脉的代谢重编程。此外，高脂饮食还会增加内脏脂肪中的炎症趋化因子。有趣的是，经过 CRISPR 编辑的功能丧失的地中海 G6PD 变体 (G6PD) 大鼠模仿人类多态性，可调节 HFD 诱导的体重增加以及内脏脂肪、肝脏和主动脉的代谢重编程。 G6PD 变体可阻止 HFD 诱导的 CCL7 和脂肪细胞肥大。此外，G6PD 变体（一种编码生物钟相关蛋白的基因，可抑制与普瑞德威利综合征相关的肥胖）增加，并减少了 HFD 诱发的非酒精性脂肪肝。此外，G6PD 变体还减少了衰老引起的主动脉硬化。我们的研究结果表明，G6PD 是 HFD 引起的肥胖、脂肪细胞肥大和脂肪肝的调节因子。