Normalizing body weight with a dietary strategy mitigates obesity-accelerated pancreatic carcinogenesis in mice

Background: Obesity is a modifiable risk factor for pancreatic cancer, but the impact of dietary changes leading to weight loss in pancreatic carcinogenesis remains unknown. Objectives: This study aims to determine the effects of weight normalization via dietary switch on pancreatic carcinogenesis and associated mechanisms. Methods: Five-wk-old male and female LSL-Kras ^G12D/+; p48 ^Cre/+ (KC) mice (8–12/diet group/sex) were fed a high-fat, diet-induced obesity diet (DIO; 60% kcal from fat) or a low-fat, control diet (CD; 11% kcal from fat) for 21 wk. A subset of mice was fed the DIO for 8 wk, then switched to CD for 13 additional wk (DIO→CD). Cancer incidence was evaluated by histology. Lipidomics and RNAseq followed by bioinformatic analysis identified potential mechanisms. The gut microbiome was characterized using 16s rRNA amplicon sequencing. Data were analyzed using 1-way analysis of variance. Results: After 21 wk, DIO-fed mice had 1.7-fold higher body weight gain, and a 60% increase (P < 0.05 DIO compared with CD) in pancreatic acinar-to-ductal metaplasia, compared with the other 2 groups. None of the 21 mice fed a CD developed cancer, whereas 2 of 21 DIO-fed male mice did. Switching from a DIO to a CD-normalized body weight and composition to CD levels, slowed acinar-to-ductal metaplasia and prevented cancer incidence, with no mice developing cancer. Mechanistically, DIO affected gene expression related to cellular metabolism, pancreatic secretions, immune function, and cell signaling, whereas CD and DIO→CD had similar global gene expression. Moreover, DIO increased epoxy metabolites of linoleic acid, which were mitigated by the dietary switch. Finally, compared with a CD, DIO altered the gut microbiome, and switching from a DIO to a CD restored the gut microbiome profile to resemble that of CD-fed mice. Conclusions: Body weight normalization slowed obesity-accelerated pancreatic carcinogenesis, in part, by affecting inflammatory and cell signaling pathways, reducing epoxy metabolites, and modulating the gut microbiome.