Study

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 appears 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-nuclei RNA-sequencing, we show that both human and mouse adipose tissue retain cellular transcriptional changes after appreciable weight loss. Furthermore, we find persistent obesity-induced alterations in the mouse adipocyte epigenome, negatively affecting 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 based on stable epigenetic changes, in mouse adipocytes, and likely other cell types. These changes appear 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.

If you use data or generate plots from the apps for publications please cite: Hinte et al.

Code for data analysis can be found here: GitHub

Mouse snRNAseq data and epigenetic data can be accessed at GEO: GSE236580

Contact information: Ferdinand von Meyenn () or visit us at https://epigenetics.ethz.ch/

Human snRNAseq

We collected omental and/or subcutaneous adipose tissue biopsies from people living with obesity (T0) undergoing bariatric surgery. Two years post surgery we collected omental and/or subcutaneous biopsies from the same individuals. All individuals lost at least 25% of BMI and were not diabetic. Biopsies from lean individuals were collected in the same studies. These studies were MTSS and LTSS from Germany and NEFA from Sweden. Tissues were used for snRNAseq. snRNAseq data from each cohort and time point can be explored here: hsAT_memory. Results from cell type specific differential gene expression analysis can be explored here: DEGs in human AT

Mouse snRNAseq

We collected epididymal adipose tissue from mice at different time points. 6-week-old male mice were fed a high-fat diet (HFD; 60% kcal from fat) or low-fat chow diet (10% kcal from fat) for 12 (H and C) or 25 weeks (HH and CC_l). Subsequently, we switched the diet to a standard chow diet (HC, CC_s, HHC, CCC), leading to weight normalization within 4-8 weeks. Tissues were used for snRNAseq. snRNAseq data from each time point can be explored here: mmAT_memory. Results from cell type specific differential gene expression analysis can be explored here: DEGs in mouse AT

Epigenetic Analysis of Mouse Adipocytes

AdipoERCre x NuTRAP mice were gavaged with tamoxifen at age of 4-5 weeks. After a two week wash out period HFD was started. These 6-week-old male mice were fed a high-fat diet (HFD; 60% kcal from fat) or low-fat chow diet (10% kcal from fat) for 12 (H and C) or 25 weeks (HH and CC_l). Subsequently, we switched the diet to a standard chow diet (HC, CC_s, HHC, CCC), leading to weight normalization within 4-8 weeks. We collected epididymal adipose tissue from mice at different time points and isolated nuclei from labelled adipocytes for CUT&Tag and ATAC-seq. We profiled H3K4me3, H3K4me1, H3K27me3 and H3K27ac. The results of differential enrichment analysis for promoters and enhancers can be explored here: Epigenetics_AT_Memory