Transcriptome Profiling of Adipose Tissue Reveals Depot-Specific Metabolic Alterations Among Patients with Colorectal Cancer

Abstract

Context Adipose tissue inflammation and dysregulated energy homeostasis are key mechanisms linking obesity and cancer. Distinct adipose tissue depots strongly differ in their metabolic profiles; however, comprehensive studies of depot-specific perturbations among patients with cancer are lacking. Objective We compared transcriptome profiles of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) from patients with colorectal cancer and assessed the associations of different anthropometric measures with depot-specific gene expression. Design Whole transcriptomes of VAT and SAT were measured in 233 patients from the ColoCare Study, and visceral and subcutaneous fat area were quantified via CT. Results VAT compared with SAT showed elevated gene expression of cytokines, cell adhesion molecules, and key regulators of metabolic homeostasis. Increased fat area was associated with downregulated lipid and small molecule metabolism and upregulated inflammatory pathways in both compartments. Comparing these patterns between depots proved specific and more pronounced gene expression alterations in SAT and identified unique associations of integrins and lipid metabolism–related enzymes. VAT gene expression patterns that were associated with visceral fat area poorly overlapped with patterns associated with self-reported body mass index (BMI). However, subcutaneous fat area and BMI showed similar associations with SAT gene expression. Conclusions This large-scale human study demonstrates pronounced disparities between distinct adipose tissue depots and reveals that BMI poorly correlates with fat mass–associated changes in VAT. Taken together, these results provide crucial evidence for the necessity to differentiate between distinct adipose tissue depots for a correct characterization of gene expression profiles that may affect metabolic health of patients with colorectal cancer.

Putative Positive Role of Inflammatory Genes in Fat Deposition Supported by Altered Gene Expression in Purified Human Adipocytes and Preadipocytes From Lean and Obese Adipose Tissues

“…We found that in ammatory genes such as IL-6 and TNF-α were actually expressed at lower levels in obese ACs than in lean ACs, indicating that in ammatory genes are downregulated in the obese condition. In fact, contrary to what was conventionally believed, several recent studies have reported that obese ATs do not show increased expression of in ammatory genes, as described in the Background section [27,28]. In addition, studies addressing the possible enhancement of in ammatory genes by analyzing DEGs between obese ATs and lean ATs collected from obese and lean cohorts, respectively, are surprisingly rare.…”

“…However, we think this is unlikely because the in uence of cancer over changes in gene expression in AT between the lean and obese conditions are mutually offset in the gene expression pro les and would not be detected in the DEG analysis. Moreover, Haffa et al (2019) showed that the correlation between obesity and AT gene expression exceeds the potential impact of colorectal cancer or cancer therapy when investigating the expression of genes in SAT and VAT from 233 colorectal cancers [28].…”

“…According to Rakotoarivelo et al (2018), the expression of in ammatory cytokines such as IL-6, TNF-α and IL-1β in AT is highly heterogeneous among obesity-associated diabetes patients, and 30% of obese patients do not express most of these in ammatory cytokines in the AT [27]. Haffa et al (2019) showed that these cytokines do not show obesity-related gene expression levels in AT [28]. Baranova et al (2005) reported a paradoxical decrease in the expression of pro-angiogenic genes, which is another gene class that is expected to increase in obese individuals [29].…”

Putative positive role of inflammatory genes in fat deposition supported by altered gene expression in purified human adipocytes and preadipocytes from lean and obese adipose tissues

“…We found that in ammatory genes such as IL-6 and TNF-a were actually expressed at lower levels in obese ACs than in lean ACs, indicating that in ammatory genes are downregulated in the obese condition. In fact, contrary to what was conventionally believed, several recent studies have reported that obese ATs do not show increased expression of in ammatory genes, as described in the Background section [28,29]. In addition, studies addressing the possible enhancement of in ammatory genes by analyzing DEGs between obese ATs and lean ATs collected from obese and lean cohorts, respectively, are surprisingly rare.…”

“…According to Rakotoarivelo et al (2018), the expression of in ammatory cytokines such as IL-6, TNF-a and IL-1b in AT is highly heterogeneous among obesity-associated diabetes patients, and 30% of obese patients do not express most of these in ammatory cytokines in the AT [28]. Haffa et al (2019) showed that these cytokines do not show obesity-related gene expression levels in AT [29]. Baranova et al (2005) reported a paradoxical decrease in the expression of pro-angiogenic genes, which is another gene class that is expected to increase in obese individuals [30].…”