Ketogenic Diet Prevents Obesity-Associated Pancreatic Cancer Independent of Weight Loss and Induces Pancreatic Metabolic Reprogramming

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor outcomes. Obesity increases the risk of PDAC through metabolic dysregulation and inflammation. Ketogenic diet (KD) can alter metabolism and has been evaluated for its effects on tumor progression in nonobese PDAC using genetically engineered mouse models (GEMM). We hypothesized that KD may also prevent obesity-associated PDAC progression by altering body composition and cancer metabolism. Therefore, male PDAC GEMMs were subjected to diet-induced obesity (DIO) using high-fat diets or maintained on a low-fat diet (LFD) for 15 weeks. Mice were then randomized to continue the initial diets or switch to a KD or matched control diet for 6 weeks. Body weight and composition, glucose tolerance, ketone levels, pancreas histology, and tissue metabolomics were assessed. Furthermore, murine pancreas-derived organoids from DIO or LFD-fed GEMMs were treated with a ketone body and analyzed using untargeted metabolomics. In obese PDAC GEMMs, KD delayed cancer progression independent of weight loss, an effect not observed in nonobese LFD-fed mice. KD-mediated PDAC suppression was associated with enrichment of pancreatic metabolic pathways that support nonglucose energy production. Ketone-treated organoids recapitulated a subset of the KD-associated metabolic differences observed in vivo, suggesting a direct metabolic effect on cancer cells. These findings suggest potential benefits of a KD in preventing obesity-associated PDAC. The diet-cancer metabolic interactions highlight potential opportunities for dietary or metabolic interventions to prevent PDAC in high-risk obese populations. SIGNIFICANCE: Ketogenic diet prevents pancreatic cancer progression in obese, but not in nonobese, genetically engineered mouse models and modifies pancreatic metabolic pathways, informing future dietary and therapeutic strategies for high-risk obese populations.