Normalizing body weight with a dietary strategy mitigates obesity-accelerated pancreatic carcinogenesis in mice
Although obesity is a modifiable risk factor for pancreatic cancer, the role of dietary changes that lead to weight loss in pancreatic carcinogenesis remains unknown. Thus, we determined the effects of weight normalization via dietary switch on pancreatic carcinogenesis and the associated mechanisms. Five-week-old male and female LSL-KrasG12D/+; p48Cre/+ (KC) mice (8-12/diet group/sex) were fed a high-fat, diet-induced obesity diet (DIO; 60 kCal% energy from fat) or a low-fat, control diet (CD; 11 kCal% energy from fat) for 21 weeks. A subset of mice was fed the DIO for 8 weeks, then switched to a CD for 13 additional weeks (DIO?CD). Cancer incidence was evaluated by histology. Lipidomics and RNAseq followed by bioinformatic analysis were conducted to identify possible mechanisms. The gut microbiome was characterized using 16s rRNA amplicon sequencing. After 21 weeks, DIO-fed mice had significantly higher body weight, fat mass, and pancreatic acinar-to-ductal metaplasia compared to the other 2 groups.  While none of the 21 mice fed a CD developed cancer, 2 out of 21 DIO-fed mice did. Switching from a DIO to a CD normalized body weight and composition, reduced acinar-to-ductal metaplasia and prevented cancer incidence with no mice developing cancer. Mechanistically, the DIO affected the expression of genes regulating cellular metabolism, immune function, and cell-signaling, while 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 to a CD, DIO altered the gut microbiome and switching from a DIO to a CD restored the gut microbiome profile to one close to the mice fed a CD. Body weight normalization mitigates obesity-accelerated pancreatic carcinogenesis, in part, by affecting inflammatory and cell signaling pathways, reducing epoxy metabolites, and modulating the gut microbiome. Overall design: RNA-seq of the pancreas from female LSL-KrasG12D/+; p48Cre/+ (KC) mice fed either: 1) a high-fat, diet-induced obesity diet (DIO) for 21 weeks, 2) a low-fat control diet (CD) for 21 weeks, or 3) a DIO diet for 8 weeks followed by a CD diet for 13 weeks (DIO?CD).