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ToolsWirkus, Joanna, Ead, Aya S., Krga, Irena, Wang, Yige, Pontifex, Matthew G., Muller, Michael, Vauzour, David, Matsukuma, Karen E., Zhang, Guodong and Mackenzie, Gerardo G. (2025) Normalizing body weight with a dietary strategy mitigates obesity-accelerated pancreatic carcinogenesis in mice. The Journal of Nutrition. ISSN 0022-3166
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | gut microbiome,high-fat diet,obesity,pancreatic cancer,pancreatic carcinogenesis,nutrition and dietetics,medicine (miscellaneous),sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/2900/2916 |
| Faculty \ School: | Faculty of Medicine and Health Sciences > School of Health Sciences Faculty of Medicine and Health Sciences > Norwich Medical School |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Groups > Nutrition and Preventive Medicine Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 04 Jul 2025 13:30 |
| Last Modified: | 14 Jul 2025 11:32 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/99837 |
| DOI: | 10.1016/j.tjnut.2025.05.039 |
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