Adipose tissue retains an epigenetic memory of obesity after weight loss

Affiliations

• Laboratory of Nutrition and Metabolic Epigenetics, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
• Biomedicine Programme, Life Science Zurich Graduate School, Zurich, Switzerland
• Functional Genomics Center Zurich, ETH Zurich and University Zurich, Zurich, Switzerland
• Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
• Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
• Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG), Helmholtz Zentrum München, University of Leipzig and University Hospital Leipzig, Leipzig, Germany
• Medical Department III – Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany

PMID:    DOI: 10.1038/s41586-024-08165-7

Abstract

Reducing body weight to improve metabolic health and related comorbidities is a primary goal in treating obesity. However, maintaining weight loss is a considerable challenge, especially as the body seems to retain an obesogenic memory that defends against body weight changes. 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.

减少体重以改善代谢健康和相关的合并症是治疗肥胖的主要目标。然而，维持体重减轻是一项巨大的挑战，尤其是因为身体似乎保留了一种肥胖记忆，阻碍体重的改变。克服这一长期治疗成功的障碍非常困难，因为支撑这种现象的分子机制仍然在很大程度上未知。在这项研究中，通过单核RNA测序，我们发现在人类和小鼠的脂肪组织中，即使在显著减重后，细胞的转录变化依然存在。此外，我们还发现，小鼠脂肪细胞中肥胖诱导的表观基因组改变具有持久性，这些改变对脂肪细胞的功能及其对代谢刺激的响应产生负面影响。具有这种肥胖记忆的小鼠表现出加速的体重反弹，而这种表观遗传记忆可以解释脂肪细胞在再次高脂饮食喂养时的未来转录失调。总之，我们的研究结果表明，小鼠脂肪细胞中存在一种基于稳定表观遗传变化的肥胖记忆，并且可能在其他细胞类型中也存在。这些变化似乎使细胞在肥胖环境中对病理性反应做好准备，这可能是节食时常见的“反复回弹”现象的原因。未来针对这些变化的治疗可能有助于改善长期体重管理和健康结果。

关键词：减肥，表观遗传，司美格鲁肽，替尔泊肽，佰乐博，佰乐博生物