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Randomized Controlled Trial
. 2025 Apr;17(4):e70083.
doi: 10.1111/1753-0407.70083.

Association of Lifestyle-Induced Weight Loss With Gene Expression in Subcutaneous Adipose Tissue in Metabolic Syndrome

Silke Zimmermann  1 , Kirsten Roomp  2 , Hans-Jonas Meyer  3 , Akash Mathew  1 , Manuel Florian Struck  4 , Matthias Blüher  5   6   7 , Hugo N G Martin  5 , Maria Keller  5   6 , Kathrin Landgraf  5   8 , Antje Körner  5   7   8 , Anne Hoffmann  5 , Yvonne Böttcher  9   10 , Kathleen Biemann  1 , Adhideb Ghosh  11 , Christian Wolfrum  11 , Falko Noé  11 , Berend Isermann  1 , Jochen G Schneider  2   12   13 , Ronald Biemann  1
Affiliations
Randomized Controlled Trial

Association of Lifestyle-Induced Weight Loss With Gene Expression in Subcutaneous Adipose Tissue in Metabolic Syndrome

Silke Zimmermann et al. J Diabetes. 2025 Apr.

Abstract

Aims: Lifestyle-induced weight loss (LIWL) is considered an effective therapy for the treatment of metabolic syndrome (MetS). The role of differentially expressed genes (DEGs) in adipose tissue function and in the success of LIWL in MetS is still unclear. We investigated the effect of 6 months of LIWL on transcriptional regulation in subcutaneous adipose tissue (SAT). Aiming to identify a LIWL-associated "gene signature" in SAT, DEGs were fitted into a linear regression model.

Materials and methods: The study is embedded in a prospective, two-arm, controlled, monocentric, randomized, 6-month interventional trial in individuals with MetS following LIWL. The trial included 43 nonsmoking, nondiabetic men aged 45-55 years with MetS.

Results: In total, we identified 642 DEGs in SAT after 6 months of LIWL. The identified DEGs were validated in two cross-sectional cohorts analyzing SAT from individuals with and without obesity. Gene enrichment analysis of the DEGs revealed the strongest association with cholesterol metabolic processes. Accordingly, DEGs were correlated with the lipid parameters HDL cholesterol, LDL cholesterol, and triglycerides in corresponding serum samples. We identified 3 genes with an AUC of 0.963 (95% CI: 0.906-1.0) associated with a loss of more than 10% of initial body weight that was maintained for at least 12 months after LIWL, namely SUMO3 (Small ubiquitin-related modifier 3), PRKG2 (Protein Kinase CGMP-Dependent 2), and ADAP2 (ArfGAP with Dual PH Domains 2).

Conclusion: In summary, we have identified DEGs in SAT after LIWL, which may play an important role in metabolic functions. In particular, altered gene expression in SAT may predict sustained weight loss.

Keywords: differentially expressed genes (DEGs); lifestyle‐induced weight loss (LIWL); metabolic syndrome (MetS); subcutaneous adipose tissue (SAT).

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Conflict of interest statement

M.B. received honoraria as a consultant and speaker from Amgen, AstraZeneca, Bayer, Boehringer‐Ingelheim, Lilly, Novo Nordisk, Novartis, and Sanofi. All other authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

FIGURE 1
FIGURE 1
Three‐dimensional principal component analysis (PCA) of adipose tissue samples before and after lifestyle‐induced weight loss. The PCA plot was used to visualize the variance in gene expression between corresponding subcutaneous adipose tissue samples before (red spheres, n = 43) and after weight loss (blue spheres, n = 43). For optimal visual separation, we used a 3D PCA plotting approach, showing the PC2, PC3, and PC4‐axes (black lines) capturing the linear combinations comprising the second, third and fourth largest percentages of variance, respectively. The proportion of variance explained by PC2 = 0.0591, PC3 = 0.0562, and PC4 = 0.0347. The PCA was generated using the affycoretools package MacDonald [26].
FIGURE 2
FIGURE 2
Enrichment analysis for biological processes of DEGs in MetS participants undergoing LIWL. The 10 most enriched biological processes are shown. DEGs = differentially expressed genes, FDR = false discovery rate, LIWL = lifestyle‐induced weight loss, MetS = metabolic syndrome.
FIGURE 3
FIGURE 3
Heatmap showing the expression of genes enriched in the biological process “cholesterol metabolic process” before (BL) and after lifestyle‐induced weight loss (LIWL) in subcutaneous adipose tissue. ABCA1 = ATP‐binding cassette transporter, ABCG1 = ATP‐binding cassette sub‐family G member 1, APOE = apolipoprotein E, BL = baseline, Blue = negatively changed genes, CES1 = carboxylesterase 1, CETP = cholesteryl ester transfer protein, CLN6 = ceroid‐lipofuscinosis neuronal protein 6, CUBN = cubilin, INSIG1 = insulin induced gene 1, LEP = leptin, LIWL = lifestyle‐induced weight loss, SQLE = squalene epoxidase, SREBF2 = sterol regulatory element binding transcription factor 2, VLDLR = very‐low‐density‐lipoprotein receptor, yellow = positively changed genes.
FIGURE 4
FIGURE 4
Correlation of differentially expressed genes (DEGs) with HDL cholesterol, LDL cholesterol, total cholesterol or triglycerides in lifestyle‐induced weight loss (LIWL). Heatmap representation of Spearman's correlation coefficient analysis for all DEGs with a Spearman's correlation coefficient p value < 0.05 (comprising 242 DEGs) for lipid and cholesterol related parameters in the cohort: Triglycerides, LDL cholesterol (LDL), HDL cholesterol (HDL), total cholesterol (Cholesterol). Positive rhos (red) indicate a positive relationship between the two variables, negative rhos (blue) indicate that the variables are inversely related. The dendrogram groups genes with a more similar significant correlation pattern together. The values in tabular format can be found in Supporting Information Table 2.
FIGURE 5
FIGURE 5
Combination of weight loss‐associated genes SUMO3, PRKG2 and ADAP2 predict long term weight loss. ROC analysis was performed to predict successful weight loss in LIWL. Predicted probability (blue line) and reference line (red). AUC was 0.963 (95% CI: 0.906–1.0). AUC = area under the curve.
See this image and copyright information in PMC

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