Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue.

代谢可塑性是生物系统使其代谢表型适应不同环境压力源的能力。我们使用全身和组织特异性表型、功能、蛋白质组学、代谢组学和转录组学方法来系统地评估饮食诱导的肥胖小鼠在综合营养和运动干预后的代谢可塑性。尽管大多数肥胖和营养过剩相关的病理特征已成功恢复，但我们观察到内脏白色脂肪组织存在高度代谢功能障碍，其特征是线粒体形态和功能异常。尽管有两次连续的治疗干预和明显的全球健康表型，肥胖引发了内脏脂肪组织中的一连串事件，从线粒体代谢和蛋白质静力改变发展到广泛的细胞应激，这会损害其生物合成和回收能力。在人类中，减肥手术后的体重减轻在内脏脂肪组织中显示出转录特征，类似于我们的肥胖逆转小鼠模型。总体而言，我们的数据表明，肥胖会引发持久的代谢指纹，从而导致内脏脂肪组织中代谢可塑性的逐渐破坏。