Reducing body weight to improve metabolic health and related comorbidities is a primary goal in treating obesity^1,2. However, maintaining weight loss is a considerable challenge, especially as the body seems to retain an obesogenic memory that defends against body weight changes^3,4. Overcoming this barrier for long-term treatment success is difficult because the molecular mechanisms underpinning this phenomenon remain largely unknown. Here, by using single-nucleus RNA sequencing, we show that both human and mouse adipose tissues retain cellular transcriptional changes after appreciable weight loss. Furthermore, we find persistent obesity-induced alterations in the epigenome of mouse adipocytes that negatively affect their function and response to metabolic stimuli. Mice carrying this obesogenic memory show accelerated rebound weight gain, and the epigenetic memory can explain future transcriptional deregulation in adipocytes in response to further high-fat diet feeding. In summary, our findings indicate the existence of an obesogenic memory, largely on the basis of stable epigenetic changes, in mouse adipocytes and probably other cell types. These changes seem to prime cells for pathological responses in an obesogenic environment, contributing to the problematic ‘yo-yo’ effect often seen with dieting. Targeting these changes in the future could improve long-term weight management and health outcomes.

减轻体重以改善代谢健康和相关合并症是治疗肥胖症的主要目标^1,2。然而，保持体重减轻是一个相当大的挑战，尤其是因为身体似乎保留了防御体重变化的致肥胖记忆^3,4。克服这一障碍以实现长期治疗成功是困难的，因为支撑这种现象的分子机制在很大程度上仍然未知。在这里，通过使用单核 RNA 测序，我们表明人类和小鼠脂肪组织在体重明显减轻后都保留了细胞转录变化。此外，我们发现小鼠脂肪细胞表观基因组的持续肥胖诱导改变会对其功能和对代谢刺激的反应产生负面影响。携带这种致肥胖记忆的小鼠表现出加速的反弹体重增加，表观遗传记忆可以解释脂肪细胞未来响应进一步高脂肪饮食喂养的转录失调。总之，我们的研究结果表明，小鼠脂肪细胞和可能的其他细胞类型中存在致肥胖记忆，这主要是基于稳定的表观遗传变化。这些变化似乎为细胞在致肥胖环境中的病理反应做好准备，导致了节食中常见的有问题的“溜溜球”效应。在未来针对这些变化可以改善长期体重管理和健康结果。