Timing-Dependent Effects of ω-3 Fatty Acids on Adipose Tissue and Tumorigenesis in Obesity-Driven Pancreatic Cancer in Mice.

[BACKGROUND] Pancreatic ductal adenocarcinoma is a deadly cancer linked to obesity. Adipose tissue contributes to tumor progression by promoting inflammation and supplying lipids and cytokines that support cancer growth. Although omega-6 fatty acid (FA)-rich diets accelerate pancreatic carcinogenesis, the role of ω-3 FA, particularly within the adipose-tumor microenvironment in obesity, remains unclear.

[OBJECTIVE] The objective of this was to investigate the impact of ω-3 FA on obesity-driven early pancreatic carcinogenesis and adipose-tumor interactions.

[METHODS] Using genetically engineered LSL-Kras; Ptf1-Cre (KC) mice, we conducted 2 dietary studies. In the first, mice (n = 9-12/sex/group) were fed either a high-fat diet (HF; ω-6:ω-3 ratio of 9:1) or an ω-3 FA-rich high-fat diet (HO; ratio of 1:1) for 8 wk. In the second, obese mice (n = 9-12/sex/group) initially fed HF for 8 wk were either maintained on HF or switched to HO for 13 additional weeks. We analyzed tissue histology, immune infiltration, gene expression, serum biomarkers, and lipid/metabolite profiles.

[RESULTS] In the 8-wk intervention, HO-fed mice showed reduced pancreas and mesenteric adipose tissue weights, acinar-to-ductal metaplasia (ADM), cell proliferation, and adipocyte size. HO also increased anti-inflammatory M2 macrophages and reduced serum IL-6. In contrast, dietary switch after obesity onset led to reduced fat mass, elevated adiponectin, increased anti-inflammatory ω-3-derived metabolites, and sex-specific changes in peripancreatic adipose tissue metabolites. However, it failed to improve ADM, cell proliferation, or cancer incidence.

[CONCLUSIONS] ω-3 FA-rich diets mitigate early pancreatic and adipose tissue abnormalities, with greater benefits when introduced before obesity onset, highlighting the importance of early dietary interventions for pancreatic cancer prevention.