MON-323 - Disentangling the Effects of Obesity and High-Fat Diet on Pancreatic Ductal Adenocarcinoma Development in Mice

Numerous studies have demonstrated a robust association of elevated BMI and chronic high-fat diet consumption with pancreatic ductal adenocarcinoma (PDAC) risk and mortality. Given the tight coupling of obesity and high-fat diet (HFD) in humans, the relative contributions of dietary composition and adiposity to PDAC growth remain experimentally challenging to disentangle. Here, we employed complementary diet switch and voluntary exercise paradigms to distinguish the metabolic and oncogenic effects of obesity and high-fat diet in vivo.

In diet switch experiments, mice received either normal chow (ND) or an HFD for 20 weeks before being orthotopically inoculated with PDAC tumor cells, either switching or maintaining their diet regimen, then followed for 20 days until sacrifice. ND-ND and ND-HFD animals remained lean at necropsy, whereas HFD-HFD and HFD-ND animals remained obese despite diet reversal. Obese mice displayed significantly greater tumor burden relative to lean counterparts, suggesting that body weight at tumor induction and obesity—rather than only high-fat diet feeding—is a major determinant of tumor growth.

We then utilized an orthogonal exercise paradigm where tumor-bearing mice were maintained on either ND or HFD for 12 weeks, with half of each group given access to a running wheel (RW). HFD-fed sedentary animals developed significant weight gain and glucose intolerance relative to ND-fed mice. HFD-fed RW mice, conversely, maintained body weights similar to ND-fed animals as well as displayed mildly improved glucose tolerance to sedentary counterparts. Relative to ND-fed controls, HFD-fed sedentary mice developed significantly increased tumor burden and distinct histopathologic features. In contrast, HFD-RW mice grew tumors similar in size and histology to ND-fed animals despite relative glucose intolerance.

Together, these studies establish an experimental framework to disentangle the effects of high-fat diet and obesity on tumor growth. Our findings further indicate that obesity, independent of HFD exposure, is a key contributor to promoting PDAC tumor growth.

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