(OR09-05-26) Omega 3 Fatty Acids Mitigate Early, but Not Late, High-Fat Diet-Driven Pancreatic Carcinogenesis in Mice by Modulating the Gut Barrier and the Adipose-Pancreas Axis

Objectives: Obesity is a recognized risk factor for pancreatic cancer. The mechanisms linking excess adiposity to early pancreatic carcinogenesis are multifactorial and involve gut barrier dysfunction, endotoxemia, and adipose-pancreas crosstalk. However, how dietary fat composition modulates these processes remains unknown.

Methods: We conducted an initial short-term study on cohorts of male and female Kras^LSL-G12D/+; Ptf1a^Cre/+ (KC) mice (9-12 per diet per sex) that were randomly assigned to a high-fat diet (HFD) with an omega-6: omega-3 fatty acid (FA) ratio of 10:1 or a high fat, high omega-3 fatty acid diet (HFHO) with an omega-6: omega-3 FA ratio of 1:1 (matched at 60% kcals from fat), and fed their respective diets during eight weeks. Then, to study the effects of a dietary switch in the context of obesity, cohorts of male and female KC mice were fed a HFD with an omega-6: omega-3 FA ratio of 10:1 during 8 weeks. Then, half the of the mice remained on the HFD while the other half underwent a dietary switch to a HFHO diet. Mice were fed these diets for an additional 13 weeks.

Results: HFD for 8 weeks increased body and fat mass, leptin, acinar-to-ductal-metaplasia (ADM), proliferation, ERK/STAT3 activation, and inflammatory macrophage infiltration. HFD also induced intestinal gut barrier disruption, NF‑κB and JNK activation, endotoxemia, and increased pancreatic TLR4 expression. KC mice fed a HFHO diet prevented these effects, reducing ADM, proliferation, while increasing M2 macrophages and anti‑inflammatory lipid metabolites. In contrast, dietary switching after obesity improved metabolic and adipose parameters but did not mitigate pancreatic carcinogenesis.

Conclusions: Our findings suggest that gut barrier preservation, suppression of endotoxemia/TLR4 signaling, and remodeling of adipose-pancreas networks are key mechanisms by which omega-3 FA mitigate HFD-driven early pancreatic carcinogenesis. This mitigating effect is more pronounced in mice before they develop obesity.

Funding Sources: Supported by NIFA-USDA, and the Academy of Nutrition and Dietetics