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. 2024 Dec;636(8042):457-465.
doi: 10.1038/s41586-024-08165-7. Epub 2024 Nov 18.

Adipose tissue retains an epigenetic memory of obesity after weight loss

Laura C Hinte #  1   2 , Daniel Castellano-Castillo #  1   3 , Adhideb Ghosh  1   4   5 , Kate Melrose  1   2 , Emanuel Gasser  1 , Falko Noé  1   4   5 , Lucas Massier  6   7 , Hua Dong  5   8 , Wenfei Sun  5   9 , Anne Hoffmann  7 , Christian Wolfrum  5 , Mikael Rydén  6 , Niklas Mejhert  6 , Matthias Blüher  7   10 , Ferdinand von Meyenn  11
Affiliations

Adipose tissue retains an epigenetic memory of obesity after weight loss

Laura C Hinte et al. Nature. 2024 Dec.

Abstract

Reducing body weight to improve metabolic health and related comorbidities is a primary goal in treating obesity1,2. However, maintaining weight loss is a considerable challenge, especially as the body seems to retain an obesogenic memory that defends against body weight changes3,4. 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.

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Conflict of interest statement

Competing interests: M.B. received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer-Ingelhiem, Lilly, Novo Nordisk and Sanofi. M.R. received honoraria as a consultant and speaker from AstraZeneca, Boehringer-Ingelheim, Lilly, Novo Nordisk and Sanofi. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Human AT retains cellular transcriptional changes after BaS-induced WL.
a, omAT and scAT biopsies were collected from people living with obesity during BaS (T0) and 2 yr post-surgery (T1). Only individuals that had lost at least 25% of BMI compared with T0 were included. omAT and scAT biopsies were collected from healthy weight/lean individuals from the same studies (MTSS, LTSS and NEFA). b, Sex, age, starting BMI and BMI loss of lean donors and donors with obesity. c, Uniform manifold approximation and projection (UMAP) of 22,742 nuclei representing omAT pools from lean subjects (n = 5; 2 males, 3 females) and paired omAT from T0 and T1 (n = 5 each; 2 males, 3 females) from LTSS. d, Proportion of retained transcriptional changes in highly abundant cell types of LTSS omAT. e, UMAP of 15,347 nuclei representing scAT pools from lean subjects (n = 5; 2 males, 3 females) and paired scAT from T0 and T1 (n = 5 each; 2 males, 3 females) from LTSS. f, Proportion of retained transcriptional changes in highly abundant cell types of LTSS scAT. g, Proportion of retained transcriptional changes in integrated omAT adipocytes of LTSS and MTSS omAT. h, Normalized expression of selected memory DEGs in omAT adipocytes. i, Proportion of retained transcriptional changes in integrated omAT adipocytes of LTSS and NEFA scAT. j, Normalized expression of selected memory DEGs in scAT adipocytes. Wilcoxon rank-sum test with adjusted P < 0.01 by the Bonferroni correction method, and log2 fold change (log2FC) > ±0.5 was used for DEG identification in d, f, g, h, i and j. DCs, dendritic cells; EndoCs, endothelial cells; EndoACs, arteriolar EndoCs; EndoSCs, stalk EndoCs; EndoVCs, venular EndoCs; LECs, lymphatic EndoCs; FAPs, fibro-adipogenic progenitors; Macro, macrophages; MastCs, mast cells; MesoCs, mesothelial cells; NeurCs, neuronal-like cells; SMCs, (vascular) smooth muscle cells; NA, not applicable; m/f, male/female. Credit: a, Copyright 2017—Simplemaps.com (https://simplemaps.com/resources/svg-maps). Source Data
Fig. 2
Fig. 2. Transcriptional changes persist WL induced (partial) remodelling of epiAT.
a, Experimental setup of the WL study. b,c, 18-week-old (b) or 31-week-old (c) diet-induced obesity or age-matched control male mice were fed chow diet for 8 weeks. Body weight (n = 20 each; data from two experiments). d, UMAP of 48,046 nuclei representing integrated epiAT pools (n = 5 pooled mice each) from C, CC, CCC, H, HC, HH and HHC mice. e, Relative abundance of cell types/clusters per condition. f, Relative abundance of macrophage subclusters per condition as percentage of total macrophages. g,h, Proportion of retained upregulated (g) or downregulated (h) transcriptional changes in different cell types. i, Normalized expression of selected DEGs in adipocytes across all conditions that did not restore expression profile (left), restored only in HC adipocytes (middle) or restored expression profile (right) (Wilcoxon rank-sum test, adjusted P < 0.05 by the Bonferroni correction method; FC > ±0.5). Significance for b and c was calculated using unpaired, multiple t-tests with Benjamini, Krieger and Yekutieli post-hoc test for multiple comparisons. ***FDR < 0.001, ****FDR < 0.0001. Exact P values are in the Source Data. EpiCs, epithelial cells; FDR, false discovery rate; FIPs, fibro-inflammatory progenitors; NPVMs, non-perivascular macrophages; PVMs, perivascular macrophages; P-LAMs, proliferating LAMs; W, week. Source Data
Fig. 3
Fig. 3. Adipocyte promoters retain an epigenetic memory.
a, Experimental setup of the WL study in AdipoERCre x NuTRAP mice. b, Workflow of paired CUT&Tag, ATAC–seq and TRAP–seq from one AT depot. Biotinylated nuclei and GFP-tagged ribosomes are isolated from frozen tissue, pulled down and subjected to CUT&Tag, ATAC–seq (nuclei) and TRAP–seq (ribosomes). c, PCA of translatome (TRAP–seq) of labelled adipocytes from C, CC_s, CC_l, CCC, H, HH, HC and HHC. Each dot represents an individual biological replicate. d, MOFA plots showing the sample clustering along latent Factors 1 and 2 (left) and Factor 1 value distribution (right) across labelled adipocytes. Each dot corresponds to one biological replicate. For each replicate all six modalities are represented in one dot. e, Percentage of variance explained by each MOFA factor across one of six modalities. f, Dynamics of differentially H3K4me3-marked promoters (y axis) from H to HC. g, Dynamics of differentially H3K27me3-marked promoters (y axis) from H to HC. h, Scaled enrichment of H3K4me3 (left), H3K27me3 (middle) and H3K27ac (right) at selected promoters of genes and the log2FC of TRAP–seq from comparisons against controls for the same genes. i, Distribution of normalized reads of H3K4me3 and H3K27me3 at the Cyp2e1 and Icam1 loci across conditions. Scaling of reads was performed per hPTM. NS, not significant; v, versus. Source Data
Fig. 4
Fig. 4. Adipocyte enhancers retain an epigenetic memory.
a, Correlation coefficient R (Pearson) of quantified peaks of H3K4me1 and H3K4me3 against a hypothetical healthy control (n = 2–3 each) with s.d. Each dot represents an individual biological replicate. b, PCA plots of quantified adipocyte-specific enhancers as marked by H3K4me1. Each dot represents an individual biological replicate. c, Dynamics of differentially H3K4me1-marked enhancers (y axis) from H to HC (left) and HH to HHC (right). d, H3K27ac status of genes linked to newly emerged enhancers marked by H3K4me1 (from c) in different conditions identified by the presence of an H3K27ac peak associated to the gene. n = 218 left and n = 127 right. e, Top (significant) pathway terms for genes linked to newly emerged acetylated enhancers for H and HC (left) and HH and HHC (right) on the basis of WikiPathways database (Fisher’s exact test, adjusted P < 0.05 by the Benjamini–Hochberg method for correction). f, Proportion of down- and upregulated memory DEGs from TRAP–seq that can be explained by one or more epigenetic modality in HC (n = 13; n = 72) and HHC (n = 7; n = 36). Source Data
Fig. 5
Fig. 5. Memory primes adipocytes and mice for an accelerated response to obesogenic stimuli.
a,b, Experiments with isolated, cultured primary epiAT adipocytes. Each dot represents an individual biological replicate of a pool of three mice. a, Glucose uptake. b, Palmitate uptake. c, HC and CC_s mice were put on HFD for 4 weeks. Body weight (n = 12 each). d–g, Experiments with HHC and CCH mice. Each dot indicates an individual biological replicate from two experiments. d, Fasting blood glucose (n = 10). e,f, Fed insulin (e) and leptin (f) (C, H, CC_s, HC: n = 6 each; CCH: n = 8; HCH: n = 5). g, Weights of ingAT, epiAT and BAT, normalized to body weight (n = 10). h, Representative images of epiAT. The ruler is in cm. i, Relative cell type abundance. j, Proportion of up- and downregulated DEGs in HCH adipocytes that can be explained by DEG status at HC time point or transcriptional memory. k, Normalized expression of selected DEGs in HCH adipocytes that were recovered in HC but were still differentially marked by one or more epigenetic modalities (Wilcoxon rank-sum test, adjusted P < 0.05 by the Bonferroni correction method; FC > ±0.5). l, Distribution of normalized reads of H3K4me3, H3K27me3, H3K27ac and H3K4me1 of HC and CC_s adipocytes at loci of Tmsbx4 and Gpam. Scaling of reads was performed per hPTM. m, Proportion of up- and downregulated DEGs in HCH adipocytes that can be explained by an epigenetic memory. Significance was calculated between age-matched controls and experimental groups. Significance for a, b, d, e, f and g was calculated using two-tailed Mann–Whitney tests. Significance for c was calculated using unpaired, multiple t-tests with Benjamini, Krieger and Yekutieli post-hoc test for multiple comparisons. **FDR < 0.01, ***FDR < 0.001. Error bars represent s.d. Boxplots represent minimum, maximum and median. Source Data
Extended Data Fig. 1
Extended Data Fig. 1. Human AT retains cellular transcriptional changes after bariatric surgery induced WL.
a, UMAP of 19,494 nuclei representing omAT pools from lean subjects (n = 5; 1 male, 4 females) and paired omAT from T0 and T1 (n = 8 each; 2 males, 6 females) from the MTSS study. b,c Proportion of retained transcriptional changes in highly abundant cell types of MTSS omAT. d, UMAP of 31,721 nuclei representing scAT pools from lean subjects (n = 8; 8 females) and paired scAT from T0 and T1 (n = 7 each; 7 females) from the NEFA study. e,f Proportion of retained transcriptional changes in highly abundant cell types of NEFA scAT. g-j Number of upregulated and downregulated DEGs per cell type obese donor scaled by column at T0 for omAT (left) and scAT (right) from MTSS, LTSS and NEFA studies. k, Number of persistently deregulated genes from T0 to T1 per cell type across AT pools from all studies. l, UMAP of 4,958 nuclei representing adipocytes from MTSS omAT and LTSS omAT (total lean n = 10; total T0/T1 n = 13). m, UMAP of 13,231 nuclei representing adipocytes from NEFA scAT and LTSS scAT (total lean n = 13; total T0/T1 n = 12). Wilcoxon Rank Sum test, with adjusted p-value < 0.01 by the Bonferroni correction method and FC > ±0.5 was used for DEG identification in b, c, e-k. APCs, adipocyte progenitor cells; ASDCs, AXL+ dendritic cells; DCs, dendritic cells; EndoCs, endothelial cells; EndoACs, arteriolar EndoCs; EndoSCs, stalk EndoCs; EndoVCs, venular EndoCs; LECs, lymphatic endothelial cells; FAPs, fibro-adipogenic progenitors; Macro, macrophages; MastCs, mast cells; MesoCs, mesothelial cells; NeurCs, neuronal like cells; SMCs, (vascular) smooth muscle cells. Source Data
Extended Data Fig. 2
Extended Data Fig. 2. Characterization of omAT composition.
a,b, Cluster markers used for annotating cell clusters in human omAT of the MTSS (left) and LTSS (right) study. c,d, UMAP visualization representing omAT pools from the MTSS study (c) and LTSS study (d) coloured by predicted cell subtypes from the Emont et al. visceral AT dataset from Caucasian individuals. Feature plots showing reference mapping scores illustrating how well omAT dataset maps to the Emont et al. dataset. e,f, Relative cell type abundance in omAT per condition and tissue donor of the LTSS (e) and MTSS (f) study. Lines connecting dots indicate paired samples. Significance between T0 and T1 for e-f was calculated using paired multiple Wilcoxon tests with Benjamini, Krieger and Yekutieli post hoc test for multiple comparisons. Error bars represent s.d. Source Data
Extended Data Fig. 3
Extended Data Fig. 3. Characterization of scAT composition.
a,b, Cluster markers used for annotating cell clusters in human scAT of the LTSS (left) and NEFA (right) study. c,d, UMAP visualization representing scAT pools from the LTSS study (c) and NEFA study (d) coloured by predicted cell subtypes from the Emont et al. subcutaneous AT dataset from Caucasian individuals. Feature plots showing reference mapping scores illustrating how well scAT dataset maps to the Emont et al. dataset. e,f, Relative cell type abundance in scAT per condition and tissue donor of the LTSS (e) and NEFA (f) study. Lines connecting dots indicate paired samples. Significance between T0 and T1 for e-f was calculated using paired multiple Wilcoxon tests with Benjamini, Krieger and Yekutieli post hoc test for multiple comparisons. Error bars represent s.d. Source Data
Extended Data Fig. 4
Extended Data Fig. 4. GSEA of retained DEGs in adipocytes.
a,b, Top (significant) persistently downregulated (memory) pathway terms in omental adipocytes of the MTSS (a) and LTSS (b) study based on Wikipathways database. c,d, Top (significant) persistently downregulated (memory) pathway terms in subcutaneous adipocytes of the LTSS (c) and NEFA (d) study based on Wikipathways database. e,f, Top (significant) persistently upregulated (memory) pathway terms in omental adipocytes of the MTSS (e) and LTSS (f) study based on Wikipathways database. g,h, Top (significant) persistently downregulated (memory) pathway terms in subcutaneous adipocytes of the LTSS (g) and NEFA (d) study based on Wikipathways database. In g enrichment is not significant. Significance was calculated using Fisher’s exact test, with adjusted P-value < 0.05 by the Benjamini-Hochberg method for correction. Source Data
Extended Data Fig. 5
Extended Data Fig. 5. Weight loss largely resolves obesity induced physiological changes in mice.
Data from mouse experiments. For n<11, each dot represents an biological replicate. Data from 2-3 independent experiments. a, Glucose tolerance tests (GTTs) and area of the curve (AOC) for GTTs; (n = 10 each). b, Insulin tolerance tests (ITTs) and AOC for ITTs (n = 10 each). c, Fasting blood glucose (n = 10 each). d, GTTs and AOCs for GTTs; (n = 10 each from 2 independent experiments). e, ITTs and AOC for ITTs (n = 10 each from 2 independent experiments). f, Fasting blood glucose (CC_s&HC: n = 10 each, CCC&HHC: n = 20 each; from 2 independent experiments). g,h, Fasting insulin levels (n = 6). i,j Postprandial insulin and leptin levels. C, H, CC_s, HC, HH, HHC: n = 6 each; CC_l, CCC: n = 5 each. Boxplot represents minimum, maximum and median. k, Cumulative food intake from HC and CC_s mice in the last 3 days of WL chow diet feeding. (n = 10 mice each). l, Energy expenditure of HC and CC_s mice in the last 3 days of WL chow diet feeding. (n = 10 mice each). m, Liver triglycerides (tg) per μg liver tissue (C&H: n = 6, CC_s: n = 10, HC, CC_l, HHC: n = 9, HH&CCC: n = 8). Boxplot represents minimum, maximum and median. n, Haematoxylin and eosin (HE) staining liver sections, 20x magnification. Scale bar, 200 μm. o, Lean mass of HC and CC_s mice relative to lean mass measured at C and H timepoints of the same mice (right) (n = 19 each). p, weights of ingAT, epiAT and BAT, normalized to body weight (C&H: n = 6, HC&CC_s: n = 10, from 2 experiments). q, Representative photos of epiAT depots. Ruler is in cm. r, Weights of ingAT, epiAT and BAT, normalized to body weight (HH&CC_l: n = 6, CCC&HHC: n = 10). s, Representative photos of epiAT depots. Ruler is in cm. t, Representative photo of a HHC mouse. u, Representative image of a histological and HE stained section of a whole epiAT depot from a HHC mouse. Scale bar 2000 μm. v, Haematoxylin and eosin (HE) staining of epiAT, 20x magnification. Scale bar, 100 μm. Representative pictures. w, ingAT adipocyte area across conditions. (n = 4 mice each, 5-8 pictures each). x, HE staining of scAT, 20x magnification. Scale bar, 200 μm. y, epiAT adipocyte area across conditions. (n = 4 mice each, 5-8 pictures each). z, Quantification of collagen content from Maison’s Trichome staining. (n = 4 mice each, 20 pictures each). Significance was calculated between age matched controls and experimental groups. Significance a, b, d, e, i, j, z was calculated using two-tailed Mann-Whitney tests. Significance for c, f-h, m was calculated using unpaired, two-tailed t-tests with Welch’s correction. Error bars represent s.d. Significance for p and r was calculated using unpaired, multiple t-tests with Benjamini, Krieger and Yekutieli post hoc test for multiple comparisons. ns = FDR > 0.01, **FDR < 0.01, ***FDR < 0.001, ****FDR < 0.0001. Source Data
Extended Data Fig. 6
Extended Data Fig. 6. Annotation of mouse epiAT.
a, Cluster markers used to annotate cell clusters of mouse epiAT. b, UMAP visualization representing epiAT samples coloured by predicted cell subtypes from the Emont et al. mouse epididymal AT dataset. Feature plots showing reference mapping scores illustrating how well this dataset maps to the Emont et al. dataset. c, Macrophage subcluster markers. d, UMAP of 16,567 nuclei representing macrophage subclusters. APCs, adipocyte progenitor cells; DCs, dendritic cells; EpiCs, epithelial cells; EndoCs, endothelial cells; FIPs, fibro-inflammatory progenitors; LECs, lymphatic endothelial cells; MastCs, mast cells; MesoCs, mesothelial cells; SMCs, (vascular) smooth muscle cells; NPVMs, non-perivascular macrophages; LAMs, lipid-associated macrophages; PVMs, perivascular macrophages; P-LAMs, proliferating LAMs. Source Data
Extended Data Fig. 7
Extended Data Fig. 7. Transcriptional changes persist weight loss in epiAT.
a, Number of upregulated (left) and downregulated (right) DEGs per cell type per comparison (H vs C, HC vs CC, HH vs CC, HHC vs CCC) scaled by column. b, Proportion of retained transcriptional changes in different cell types. (Wilcoxon Rank Sum test, adjusted p-value < 0.05 by the Bonferroni correction method; FC > ±0.5). c,d, Top (significant) persistently upregulated (memory) (c) and downregulated (d). pathway terms in HC adipocytes based on Wikipathways database. e,f, Significant Wikipathways term enrichment scores related to persistently upregulated genes in HHC (f) and HC (g) per cell type. g,h, Significant Wikipathways term enrichment scores related to persistently downregulated genes in HHC (f) and HC (g) per cell type. Significance for c-h was calculated using Fisher’s exact test, with adjusted P-value < 0.05 by the Benjamini-Hochberg method for correction. APCs, adipocyte progenitor cells; DCs, dendritic cells; EpiCs, epithelial cells; EndoCs, endothelial cells; FIPs, fibro-inflammatory progenitors; LECs, lymphatic endothelial cells; MastCs, mast cells; MesoCs, mesothelial cells; SMCs, (vascular) smooth muscle cells; NPVMs, non-perivascular macrophages; LAMs, lipid-associated macrophages; PVMs, perivascular macrophages; P-LAMs, proliferating LAMs. Source Data
Extended Data Fig. 8
Extended Data Fig. 8. Epigenetic memory persists after weight loss.
a, Peak fold enrichment of called peaks from each CUT&Tag library for genomic features, scaled from −2 to 2. b, Peak fold enrichment of called peaks from each CUT&Tag library for ENCODE cCREs, scaled from −2 to 2. c, Scatterplots of pairwise correlation of average normalized expression of pseudo bulk adipocytes from snRNA-seq (log2 cpm) and average normalized expression of translating RNA (TRAPseq) from labelled adipocytes (log2 cpm) per condition. Spearman’s correlation coefficient R is indicated. d, PCA plots of H3K4me3, H3K27me3 and ATAC-seq across all conditions quantified over peaks overlapping promoters with reads summed up at gene level; each dot represents one biological replicate. e, Dynamics of differentially H3K4me3-marked (left) and H3K27me3-marked promoters (y-axis) from HH to HHC. f, Significant Wikipathways term enrichment scores related to genes associated with persistently differentially marked promoters by H3K27me3 (from Fig. 4f) or H3K4me3 (from Fig. 4g) in HC adipocytes. g, Significant Wikipathways term enrichment scores related to genes associated with persistently differentially marked promoters by H3K27me3 (from e) or H3K4me3 (from e) in HHC adipocytes. h, Expression of genes encoding for epigenetic modifiers significantly deregulated either in H (*) or HH (#) adipocytes. (Wilcoxon Rank Sum test, adjusted p-value < 0.05 by the Bonferroni correction method; fold change (FC) > ±0.5). None of the epigenetic modifiers are deregulated in HC or HHC adipocytes. Significance for f-g was calculated using Fisher’s exact test, with adjusted P-value < 0.05 by the Benjamini-Hochberg method for correction. cCREs, candidate cis-regulatory elements as defined by ENCODE. CTCF, not TSS-overlapping and with high DNase and CTCF signals only; DNase–H3K4me3, not TSS-overlapping and with high DNase and H3K4me3 signals only; dELS, TSS-distal with enhancer-like signatures; PLS, TSS-overlapping with promoter-like signatures; pELS, TSS-proximal with enhancer-like signatures. Source Data
Extended Data Fig. 9
Extended Data Fig. 9. Adipocyte specific enhancers retain an epigenetic memory.
a, Correlation coefficient R (Pearson) of quantified peaks of H3K27ac against a hypothetical healthy control (n = 2-3 each) with s.d. Each dot represents an individual biological replicate. b,c, ChromHMM analysis of the adipocyte hPTM profiles for conditions C, CC_s, H and HC (b) and CC_l, CCC, HH and HHC (c). The colour scale corresponds to the emission parameter of each hPTM for each state. d,e, Fold enrichment of ChromHMM states from b and c for total genomic fraction coverage, ENCODE cCREs, and genomic features scaled from −2 to 2. State 5, 6 and 7 are identified as enhancers. f, PCA plot of quantified adipocyte specific enhancers from all conditions as marked by H3K4me1. Each dot represents an individual biological replicate. g, PCA plot of quantified adipocyte specific enhancers as marked by H3K27ac. Each dot represents an individual biological replicate. h, PCA plot of quantified adipocyte specific enhancers as marked by H3K27ac. Each dot represents an individual biological replicate. i, Top (significant) GO Cellular Component terms for genes linked to newly emerged and acetylated enhancers for H and HC (left) and HH and HHC (right). (Fisher’s exact test, adjusted p-value < 0.05 by the Benjamini-Hochberg method for correction). cCREs, candidate cis-regulatory elements as defined by ENCODE. CTCF, not TSS-overlapping and with high DNase and CTCF signals only; DNase–H3K4me3, not TSS-overlapping and with high DNase and H3K4me3 signals only; dELS, TSS-distal with enhancer-like signatures; PLS, TSS-overlapping with promoter-like signatures; pELS, TSS-proximal with enhancer-like signatures. Source Data
Extended Data Fig. 10
Extended Data Fig. 10. Other responses of primed mice and cells to obesogenic stimuli.
a, Glucose uptake of isolated, cultured primary adipocytes from ingAT from CC_s and HC (left) and CCC and HHC (right) mice. Each dot represents an individual biological replicate of a pool of 3 mice. b,c, AdipoRed signal of dividing SVF (MM), SVF stimulated with 10 nm insulin only (MM + Ins) and induced SVF with 10 nm insulin (IMM + Ins) 10 days after induction/no induction of differentiation from epiAT (b) and ingAT (c) SVF from CC_s, HC, CCC and HHC mice. Each dot represents an individual biological replicate of a pool of 3 mice. Every SVF pool was tested in all three conditions. d, GTT of HCH and CCH mice; blood glucose levels (n = 5 each). e, AOC of GTTs from d. f, ITT of CCH and HCH mice; blood glucose levels (n = 5 each). g, AOC from ITTs from e. h, Distribution of epiAT adipocyte area. (n = 4 mice each, 10 pictures each). i, Representative images of liver HE stained sections from CCH and HCH, 20x magnification, scale bar 200 μm. j, Liver tg per μg liver tissue (C&H:n = 6 each, CC_s: n = 10, HC: n = 9, CCH: n = 11, HCH: n = 12, from 2-3 experiments). Boxplot represents minimum, maximum and median. k, Pathological scoring of liver sections per group (n = 4 each). l, UMAP of 15,665 nuclei representing epiAT pools (n = 5 pooled mice each) from CCH and HCH split by condition. m, Relative abundance of macrophage subclusters. n,o, Top significant pathway terms from upregulated (n) and downregulated (o) HCH DEGs that are explained by the epigenetic state in HC adipocytes based on Reactome database. (Fisher’s exact test, adjusted p-value < 0.05 by the Benjamini-Hochberg method for correction). Significance was calculated between age matched controls and experimental groups. Significance for a, e, g, was calculated using two-tailed Mann-Whitney tests. Significance for b, c was calculated using unpaired, two-tailed Student’s t-tests with Welch’s correction and Benjamini, Krieger, and Yekutieli correction for multiple testing. Significance for j was calculated using unpaired two-tailed Student’s t-tests with Welch’s correction. Error bars represent s.d. APCs, adipocyte progenitor cells; DCs, dendritic cells; EpiCs, epithelial cells; EndoCs, endothelial cells; FIPs, fibro-inflammatory progenitors; LECs, lymphatic endothelial cells; MastCs, mast cells; MesoCs, mesothelial cells; SMCs, (vascular) smooth muscle cells; NPVMs, non-perivascular macrophages; LAMs, lipid-associated macrophages; PVMs, perivascular macrophages; P-LAMs, proliferating LAMs. Source Data
Extended Data Fig. 11
Extended Data Fig. 11. Quality metrics of mouse snRNAseq data.
a, Gene counts and the number of unique molecular identifiers (UMIs) per condition of mouse epiAT samples. b, UMAP visualization representing integrated epiAT samples from the weight loss study (C, CC, CCC, H, HH, HC, HHC) and from the “yoyo” study (CCH, HCH) coloured by predicted cell subtypes from the Emont et al. mouse epididymal AT dataset. Feature plots showing reference mapping scores illustrating how well these datasets maps to the Emont et al. dataset. c, gene counts and the number of UMIs per cell type from mouse epiAT samples.
Extended Data Fig. 12
Extended Data Fig. 12. Quality metrics of human snRNAseq data.
a, Gene counts and the number of UMIs per condition in the omAT samples from the MTSS (left), LTSS (second left) and in scAT samples from the LTSS (second from right) and NEFA (right) study. b,c, Gene counts and the number of UMIs per donor in the omAT samples from the MTSS (b) and LTSS (c) study. d,e, Gene counts and the number of UMIs per donor in scAT samples from the LTSS (d) and NEFA (e) study. f, Gene counts and the number of UMIs per assigned cell type in the omAT samples from the MTSS (left) and LTSS (right) study. g, Gene counts and the number of UMIs per assigned cell type in the scAT samples from the LTSS (left) and NEFA (right) study.
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