A high-fat diet induces changes in mesenteric adipose tissue accelerating early-stage pancreatic carcinogenesis in mice

Increased adiposity is a significant risk factor for pancreatic cancer development. Multiple
preclinical studies have documented that high-fat, high calorie diets, rich in omega-6 fatty acids
(FA) accelerate pancreatic cancer development. However, the effect of a high-fat, low sucrose
diet (HFD), on pancreatic carcinogenesis remains unclear. We evaluated the impact of a HFD
on early-stage pancreatic carcinogenesis in the clinically relevant Kras LSL-G12D/+ ; Ptf1a Cre/+  (KC)
genetically engineered mouse model, and characterized the role of the mesenteric adipose
tissue (MAT). Cohorts of male and female KC mice were randomly assigned to a control diet
(CD) or a HFD, matched for FA composition (9:1 of omega-6 FA: omega-3 FA), and fed their
diets for 8 weeks. After 8 weeks on a HFD, KC mice had significantly higher body weight, fat
mass, and serum leptin compared to CD-fed KC mice. Furthermore, a HFD accelerated
pancreatic acinar-to-ductal metaplasia (ADM) and proliferation, associated with increased
activation of ERK and STAT3, and macrophage infiltration in the pancreas, compared to CD-fed
KC mice. Metabolomics analysis of the MAT revealed sex differences between diet groups. In
females, a HFD altered metabolites related to FA (α-linolenic acid and linoleic acid) and amino
acid metabolism (alanine, aspartate, glutamate). In males, a HFD significantly affected
pathways related to alanine, aspartate, glutamate, linoleic acid, and the citric acid cycle. A HFD
accelerates early pancreatic ADM through multifaceted mechanisms, including effects at the
tumor and surrounding MAT. The sex-dependent changes in MAT metabolites could explain
some of the sex differences in HFD-induced pancreatic ADM.