Chronic High-Fat Diet Does Not Alter Overall Cancer Incidence in Trp53R270H/+ Mice.
Chronic high-fat diet-induced obesity does not universally accelerate tumorigenesis in Trp53R270H/+ mice, with lung cancer being a notable exception.
Where it sits
this study against the rest of the tesofensine corpusSummary and findings
The study investigated the impact of chronic high-fat diet-induced obesity on cancer progression in Trp53R270H/+ mice, a model for human Li-Fraumeni syndrome. Over more than a year, the diet did not significantly affect overall survival, tumor burden, or spectrum across over 20 anatomic sites, except for an increased prevalence of lung tumors. The findings suggest tissue-specific effects of obesity on cancer development.
Abstract
Obesity is a complex chronic disease characterized by excessive adiposity and multiple comorbidities, including an elevated risk of several cancers. Despite long-standing epidemiologic links, the causal relationship between body mass index and reduced cancer survival remains controversial, underscoring the need to define how obesity-related factors-such as chronic high-fat diet (HFD) exposure-influence tumor development in the context of defined oncogenic lesions. Here, we report the effects of chronic HFD-induced obesity on cancer progression in Trp53R270H/+ mice, a model of human Li-Fraumeni syndrome characterized by spontaneous multicancer susceptibility. Surprisingly, despite rapid, sustained, and highly penetrant obesity, more than 1 year of HFD had no significant effect on overall survival, tumor burden, or tumor spectrum across more than 20 anatomic sites in Trp53-mutant mice. Crucially, we did identify a single, tissue-specific exception in the lung, with HFD-fed animals showing increased prevalence of lung tumors that correlated with unique, diet-specific changes in Trp53 allelic and protein profiles. Notably, chronic HFD in this model triggered adipose-specific, not systemic, inflammation. These robust findings, replicated independently in two cohorts totaling 359 mice, suggest that Trp53R270H-driven multicancer syndrome is largely refractory to HFD-driven acceleration. Our results provide evidence that chronic diet-induced obesity does not universally enhance tumorigenesis, highlighting the complexity, tissue specificity, and context-dependent nature of obesity-cancer interactions.<h4>Significance</h4>Obesity is widely linked to cancer risk, yet causality remains debated. Using large, longitudinal cohorts of Li-Fraumeni Trp53R270H/+ mice, this study shows that chronic HFD-induced obesity does not broadly accelerate tumor burden or shorten survival, revealing strong tissue specificity, with lung cancer as a notable exception.
Background
The study addresses the question of how chronic high-fat diet-induced obesity influences cancer development in the context of defined oncogenic lesions. Obesity is linked to increased cancer risk, but the causal relationship remains controversial. This research is important as it explores the tissue-specific effects of obesity on cancer progression using a mouse model of Li-Fraumeni syndrome.
Methods
The study used Trp53R270H/+ mice, a model for human Li-Fraumeni syndrome, to investigate the effects of chronic high-fat diet-induced obesity on cancer progression. The study spanned more than a year and included two cohorts totaling 359 mice. The primary outcomes measured were overall survival, tumor burden, and tumor spectrum across more than 20 anatomic sites.
Results
The primary finding was that chronic high-fat diet-induced obesity did not significantly affect overall survival, tumor burden, or tumor spectrum in Trp53R270H/+ mice, except for an increased prevalence of lung tumors. The study also noted that chronic HFD triggered adipose-specific inflammation rather than systemic inflammation. These results were consistent across two independent cohorts.
Interpretation
The study's findings suggest that the effects of obesity on cancer development are highly tissue-specific and context-dependent. While obesity is generally associated with increased cancer risk, this study indicates that such effects may not be universal across all tissues. The increased prevalence of lung tumors highlights the need for further research into tissue-specific mechanisms. The findings are limited to the Trp53R270H/+ mouse model and may not directly apply to humans.
Key findings
- No significant effect on overall survival or tumor burden in Trp53R270H/+ mice after more than 1 year of HFD.
- Increased prevalence of lung tumors in HFD-fed Trp53R270H/+ mice.
- Chronic HFD triggered adipose-specific inflammation, not systemic.
- Findings replicated in two cohorts totaling 359 mice.
Limitations
- Specific to Trp53R270H/+ mouse model.
- May not translate to human cancer biology.
- Findings limited to specific genetic background.
- Tissue-specific effects observed.