The Impact of Fat Quantity and Composition in Pancreatic Carcinogenesis in Mice: Mitigating Obesity-Induced Tumor Progression With Dietary Changes

Objectives: Although obesity is a modifiable risk factor of pancreatic cancer, the role of obesity-reversal through dietary changes from a high-fat diet (HFD) to low-fat diets (LFD) or to diets high in omega-3 (ω-3) fatty acids (FA) on pancreatic carcinogenesis are unknown. Thus, we determined the effect of dietary changes in fat quantity and composition on pancreatic carcinogenesis and the associated mechanisms.

Methods: 5-week-old LSL-KrasG12D/+; p48Cre/+ (KC) mice (8-12/group/sex) were fed a HFD, low ω-3 diet (HFLω-3; 60% energy from fat; with a ω-6:ω-3 FA ratio of ∼9:1) or a LFD, low in omega-3 FA (LFLω-3; 11% energy from fat; with a ω-6:ω-3 FA ratio of ∼9:1) until 6 months old. A subset of mice fed a HFLω-3 for 8 weeks, until 3 months old, underwent a dietary switch to one of the following groups: a) from a HFLω-3 to a LFLω-3, b) from a HFLω-3 to a HFD high in ω-3 FA (HFHω-3; 60% energy from fat; with a ω-6:ω-3 FA ratio of ∼1:1); or c) from a HFLω-3 to a LFD high in ω-3 FA (LFHω-3; 11% energy from fat; with a ω-6:ω-3 FA ratio of ∼1:1); Mice were fed these diets for 3 additional months. Cancer incidence was evaluated by histology. RNAseq followed by bioinformatics was done to identify possible mechanisms. Gut microbiome was evaluated by 16s rRNA sequencing.

Results: After 21 weeks on the HFLω-3 diet, KC mice had significantly higher cancer incidence compared to the other 4 groups. While 1 out of 21 mice fed a LFLω-3 diet, 7 out of 21 in the HFLω-3-fed mice developed cancer. Switching back to a LFLω-3 diet mitigated cancer incidence with only 1 out of 17 mice developing cancer. Moreover, only 3 out of 22 mice that switched their diet to HFHω-3 developed cancer. Finally, no mouse that switched to a LFHω-3 diet had cancer (0 out of 18 mice). Mechanistically, the HFLω-3 diet affected the expression of genes regulating cellular metabolism, immune function and cell-signaling. Finally, compared to a LFLω-3 control diet, the HFLω-3 altered the gut microbiome, increasing the abundance of: (class) Firmicutes clostridia, (genus) Lachnospiraceae blautia and roseburia, as well as Oscillospiracea oscillibacter, intestimonas, and colidextribacter.

Conclusions: Dietary changes in fat quantity and composition mitigate obesity-induced pancreatic carcinogenesis, in part, by affecting immune and cell signaling pathways and modulating the gut microbiome.