Stanley Woo | ALES Graduate Seminar

Patients with cancer undergoing chemotherapy often lose adipose tissue, which is associated with poor outcomes. Adipose tissue regulates lipid metabolism and inflammation through the release of adipokines and proinflammatory cytokines. Visceral (VAT) and subcutaneous adipose tissue (SAT) have different properties. The presence of a tumour and its treatment disrupts adipose tissue function and whole body energy homeostasis. Incorporation of dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into adipose phospholipids modifies adipose tissue function but have not been characterized in cancer. The purpose of this study is to discern differences in the concentrations of metabolic rate limiting enzymes, adipokines, and proinflammatory cytokines between VAT and SAT in response to the presence of a tumour and chemotherapy treatment, and to explore the potential protective effect of EPA+DHA on VAT and SAT. It is hypothesized that the presence of a tumour will increase biomarkers of inflammation and lipid depletion in rat adipose tissue, and the provision of chemotherapy will exacerbate these changes which will occur sooner and at a greater magnitude in VAT than in SAT. Consuming an EPA+DHA enriched diet will mitigate these changes.

To study VAT and SAT alterations due to the presence of a tumour, Fischer 344 rats bearing Ward colon tumour were compared to healthy rats. The effect of chemotherapy can be studied by comparing tumour bearing rats with or without a clinically relevant dose of irinotecan and 5-fluorouracil. To examine the effect of diet, chemotherapy receiving rats were either fed a semi-purified diet (control) resembling a western diet throughout the study, or switched to an EPA+DHA enriched diet (purified fish oil; 3% w/w) when chemotherapy was initiated. Rats were euthanised and VAT and SAT were collected at 2, 4, or 8 days following chemotherapy. The concentration of proinflammatory cytokines (TNF-α, IL-1β, IL-6, IFN-γ, and CXCL1) were measured as biomarkers for inflammation. Adiponectin and leptin concentrations were measured to track changes in metabolic signalling and physiology in VAT and SAT. The expression of rate limiting enzymes, ATP citrate lyase (ACLY), adipose triglyceride lipase (ATGL), and hormone sensitive lipase (HSL), were measured in adipose tissue to estimate metabolic activity. Lastly, the fatty acid composition of VAT and SAT phospholipid species were analyzed to assess incorporation of dietary fatty acids.

Within eight days after chemotherapy administration, both VAT and SAT had significantly increased proportions of EPA and DHA in all phospholipid species. VAT and SAT had significantly higher IL-1β (VAT +100%, SAT +70%, p<0.05) and CXCL1 (VAT +2400%, SAT +650%, p<0.05) due to chemotherapy. Only SAT showed higher IL-6 by day 8 (+400%, p<0.05) whereas TNF-α was significantly elevated in VAT (+45%, p<0.05). The increase of proinflammatory cytokines coincided with greater expression of HSL (+100%, p<0.01), and decreased ACLY levels (-20%, p<0.01) in VAT only. Dietary EPA+DHA lowered TNF-α concentrations in VAT (-37%, p<0.05). ACLY, HSL, and ATGL levels were not significantly impacted by the EPA+DHA diet. Adipokine levels were mostly influenced by food intake rather than by the tumour or chemotherapy. The presence of a tumour had no effect on any measured parameters.

In conclusion, increased lipolysis and proinflammatory cytokine concentrations, and decreased lipogenesis contribute to chemotherapy associated adipose tissue loss. The results also show that VAT and SAT respond differently to chemotherapy and diet. Chemotherapy induces greater catabolic enzyme activity in VAT, and an EPA+DHA enriched diet reduces inflammation as indicated by TNF-α reduction. These results are evidence that dietary EPA+DHA may be beneficial for patients with cancer by reducing chemotherapy induced adipose tissue dysfunction.