Molecular remodeling of adipose tissue is associated with metabolic recovery after weight loss surgery

Abstract

Background: Bariatric surgery is an effective therapy for individuals with severe obesity to achieve sustainable weight loss and to reduce comorbidities. Examining the molecular signature of subcutaneous adipose tissue (SAT) following different types of bariatric surgery may help in gaining further insight into their distinct metabolic impact.

Results: Subjects undergoing biliopancreatic diversion with duodenal switch (BPD-DS) showed a significantly higher percentage of total weight loss than those undergoing gastric bypass or sleeve gastrectomy (RYGB + SG) (41.7 ± 4.6 vs 28.2 ± 6.8%; p = 0.00005). Individuals losing more weight were also significantly more prone to achieve both type 2 diabetes and dyslipidemia remission (OR = 0.75; 95%CI = 0.51-0.91; p = 0.03). Whole transcriptome and methylome profiling showed that bariatric surgery induced a profound molecular remodeling of SAT at 12 months postoperative, mainly through gene down-regulation and hypermethylation. The extent of changes observed was greater following BPD-DS, with 61.1% and 49.8% of up- and down-regulated genes, as well as 85.7% and 70.4% of hyper- and hypomethylated genes being exclusive to this procedure, and mostly associated with a marked decrease of immune and inflammatory responses. Weight loss was strongly associated with genes being simultaneously differentially expressed and methylated in BPD-DS, with the strongest association being observed for GPD1L (r2 = 0.83; p = 1.4 × 10-6).

Conclusions: Present findings point to the greater SAT molecular remodeling following BPD-DS as potentially linked with higher metabolic remission rates. These results will contribute to a better understanding of the metabolic pathways involved in the response to bariatric surgery and will eventually lead to the development of gene targets for the treatment of obesity. Trial registration ClinicalTrials.gov NCT02390973.

Keywords: Bariatric surgery; Dyslipidemia; Methylomic; Obesity; Remission; Subcutaneous adipose tissue; Transcriptomic; Type 2 diabetes; Whole genome.

Conflict of interest statement

AT and LB received research funding from Johnson & Johnson for the present study in conjunction with a team grant from the Canadian Institutes of Health Research. They also receive funding from Medtronic and GI Windows for studies unrelated to the present article. AT received consulting fees from Novo Nordisk, Eli Lilly and Bausch Health. The remaining authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1

Flow diagram of study participants

Fig. 2

Gene expression changes in subcutaneous adipose tissue were more pronounced following BPD-DS. Panel A shows differentially expressed genes (DEGs) exclusive for BPD-DS (green dots) and common to both surgery groups (red dots). Panel B shows DEGs exclusive for RYGB-DS (blue dots) and common to both surgery groups (purple dots). DEGs were considered significant when false discovery rate (FDR)-corrected p-value < 0.05 and fold change (FC) > 1.5. Panels C and D show density plots of FC distribution among down-regulated and up-regulated DEGs, respectively. Green and blue colors stand for DEGs exclusive for BPD-DS and RYGB + SG, respectively. Red and purple colors stand for DEGs common to both surgery groups but showing the specific FC distribution for each BPD-DS and RYGB + SG surgery, respectively. Dotted lines stand for mean FC values for each surgery group

Fig. 3

Most of gene methylation changes in subcutaneous adipose tissue occur following BPD-DS. Panel A shows differentially methylated genes (DMGs) exclusive for BPD-DS (green dots) and common to both surgery groups (red dots). Panel B shows DMGs exclusive for RYGB-DS (blue dots) and common to both surgery groups (purple dots). DMGs were defined as loci with at least one differentially methylated CpG site (false discovery rate (FDR)-corrected p-value < 0.05 and fold change (FC) > 1.5. Panels C and D show density plots of FC distribution among hypermethylated and hypomethylated DMGs, respectively. Green and blue colors stand for DEGs exclusive for BPD-DS and RYGB + SG, respectively. Red and purple colors stand for DMGs common to both surgery groups but showing the specific FC distribution for each BPD-DS and RYGB + SG surgery, respectively. Dotted lines stand for mean FC values for each surgery

Fig. 4

Immune-related pathways were markedly down-regulated following bariatric surgery. Left panel shows top Gene Ontology-Biological Process (GO-BP) terms significantly enriched with up-regulated (red blocks, up) and down-regulated (blue blocks, down) differentially expressed genes (DEGs). Right panel shows top GO-BP terms significantly enriched with hypermethylated (red blocks, up) and hypomethylated (blue blocks, down) differentially methylated genes (DMGs). Each column represents pathways enriched with DEGs specific to BPD-DS, RYGB + SG or common to both surgery groups. Pathways were considered significantly enriched when composed with at least 20 DEGs or DMGs and with FDR-adjusted p-value 

Fig. 5

Genes being simultaneously differentially expressed and methylated largely belonged to the BPD-DS surgery group. A and B show respectively the proportion of differentially expressed genes (DEGs) down- and up-regulated that are simultaneously identified as differentially methylated genes (DMGs). The proportion of DEGs common to both surgery groups (COMMON), as well as exclusive to BPD-DS (BPD) and RYGB + SG (GAS) is shown in the inner ring. The proportion of hypermethylated and hypomethylated DMGs is shown in the outer ring. C and D show respectively the proportion of hypermethylated and hypomethylated CpG sites located within body or promoter regions of genes being simultaneously DEGs and DMGs. The proportion of genes being simultaneously DEGs and DMGs is shown in the inner ring, and the proportion of CpG sites for each gene location and surgery group is shown in the outer ring

Fig. 6

Differentially expressed and methylated genes were associated with weight loss, adipocyte size and neck circumference. A to C show the predicted probability (red dots from 0 to 1), obtained by binomial logistic regression, of each participant to have a complete (0) or a partial remission (1), based on %TWL, %adipocyte size and %neck circumference. OR is the odds ratio with 95% confidence intervals (CI) and P is the p value for the linear trend of association. Gray and blue dots refer BPD-DS and RYGB + SG, respectively. D to F respectively show associations between differentially expressed genes (DEGs) in each surgery group with the percentage of total weight loss (%TWL), adipocyte size change (%Adipocyte) and neck circumference change (%Neck). Green, blue and red dots respectively stand for associations at non-adjusted p < 0.05 with DEGs exclusive to BPD-DS, RYGB + SG or common to both surgery groups. Grey dots represent not significant associations. Dot size is proportional to the magnitude (r2) of the association. Results are from multivariate linear regression models adjusted for sex, age and BMI