High-Fat Diet Impacts on Tumor Development in the Gut
Authors: Milou S. van Driel, Sanne M. van Neerven, Louis Vermeulen
Journal: Trends in cancer (2021)

A high-fat diet (HFD) directly acts on intestinal stem cells by increasing their numbers and proliferation, resulting in an elevated risk of developing colorectal cancer (CRC). In a recent study, Mana et al. revealed that HFD-mediated intestinal tumor formation can be reduced by inhibiting fatty acid oxidation. A high-fat diet (HFD) directly acts on intestinal stem cells by increasing their numbers and proliferation, resulting in an elevated risk of developing colorectal cancer (CRC). In a recent study, Mana et al. revealed that HFD-mediated intestinal tumor formation can be reduced by inhibiting fatty acid oxidation. Robust evidence suggests a link between excess body weight and CRC incidence [1.Lauby-Secretan B. et al.Body fatness and cancer – viewpoint of the IARC Working Group.N. Engl. J. Med. 2016; 375: 794-798Crossref PubMed Scopus (1212) Google Scholar,2.Khandekar M.J. et al.Molecular mechanisms of cancer development in obesity.Nat. Rev. Cancer. 2011; 11: 886-895Crossref PubMed Scopus (582) Google Scholar]. Given the enormous impact of both obesity and CRC on public health, resolving the underlying mechanism connecting the two is a topic of intense study. The intestinal epithelium is in direct contact with dietary constituents, and earlier studies focused on the role of diet composition and CRC development. Of particular interest is the direct functional impact of a pro-obesity HFD on CRC development by influencing the intestinal stem cell (ISC) compartment [3.Beyaz S. et al.High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.Nature. 2016; 531: 53-58Crossref PubMed Scopus (332) Google Scholar]. ISCs reside at intestinal crypt bottoms and are able to renew the intestinal lining throughout the adult life of mammals. Given the high turnover rate of the intestinal epithelium and the longevity of ISCs, it has been suggested that ISCs are the cells that acquire mutations and initiate CRC development [4.Barker N. et al.Crypt stem cells as the cells-of-origin of intestinal cancer.Nature. 2009; 457: 608-611Crossref PubMed Scopus (1527) Google Scholar]. Previous research reported that a HFD facilitates carcinogenesis in the gut by increasing ISC numbers and proliferation [3.Beyaz S. et al.High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.Nature. 2016; 531: 53-58Crossref PubMed Scopus (332) Google Scholar]. This observation was found to be mediated through a HFD-induced upregulated peroxisome proliferator-activated receptor (PPAR) signature [3.Beyaz S. et al.High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.Nature. 2016; 531: 53-58Crossref PubMed Scopus (332) Google Scholar]. PPARs include a superfamily of lipid-activated nuclear receptors (α, δ, and γ) that form heterodimers with the retinoid X receptor (RXR) and regulate essential metabolic processes through PPAR-specific transcriptional programs [3.Beyaz S. et al.High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.Nature. 2016; 531: 53-58Crossref PubMed Scopus (332) Google Scholar,5.Berger J.P. et al.PPARs: therapeutic targets for metabolic disease.Trends Pharmacol. Sci. 2005; 26: 244-251Abstract Full Text Full Text PDF PubMed Scopus (579) Google Scholar]. It was previously suggested that PPARδ signaling is implicated in ISC adaptation induced by a HFD, potentially through PPARδ-mediated upregulation of genes involved in fatty acid oxidation (FAO) [3.Beyaz S. et al.High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.Nature. 2016; 531: 53-58Crossref PubMed Scopus (332) Google Scholar]. New research by the laboratory of Yilmaz sheds light on how a HFD-induced PPAR-mediated FAO metabolic program drives ISC adaptation and promotes tumorigenesis in the gut [6.Mana M.D. et al.High-fat diet activated fatty acid oxidation mediates intestinal stemness and tumorigenicity.Cell Rep. 2021; 35109212Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. Furthermore, Mana et al. [6.Mana M.D. et al.High-fat diet activated fatty acid oxidation mediates intestinal stemness and tumorigenicity.Cell Rep. 2021; 35109212Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar] describe the potential opportunity of inhibiting HFD-induced FAO to reverse the effect of a HFD on intestinal cancer formation. By performing loss-of-function experiments, Mana et al. [6.Mana M.D. et al.High-fat diet activated fatty acid oxidation mediates intestinal stemness and tumorigenicity.Cell Rep. 2021; 35109212Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar] demonstrated that, in addition to PPARδ, as previously reported, PPARα participates in the effect of a HFD on the ISC compartment [3.Beyaz S. et al.High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.Nature. 2016; 531: 53-58Crossref PubMed Scopus (332) Google Scholar]. Similarly to PPARδ, PPARα contributes to increasing stem cell numbers and enhancing crypt clonogenicity, indicating functional redundancy between these factors. To explore to what extent a HFD activates a FAO transcriptional program, RNA sequencing was performed, which revealed high expression of carnitine palmitoytransferase 1a (CPT1A), the rate-controlling enzyme of FAO. Because Cpt1a-mediated FAO is also known to be a signaling target of PPARα/δ, the authors sought to explore Cpt1a-regulated FAO inhibition as a therapeutic opportunity [7.Mascaró C. et al.Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator-activated receptor.J. Biol. Chem. 1998; 273: 8560-8563Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar]. Using the CPT1A inhibitor etomoxir, intestinal crypt clonogenicity was robustly reduced. This phenomenon was more pronounced by PPARα/δ agonist treatment, thereby highlighting the functional impact of FAO as a downstream target of PPARs in ISC adaptation to a HFD [6.Mana M.D. et al.High-fat diet activated fatty acid oxidation mediates intestinal stemness and tumorigenicity.Cell Rep. 2021; 35109212Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. To translate these findings to a more relevant setting, the authors used an inducible Apc knockout mouse model to explore tumor initiation in response to diet [6.Mana M.D. et al.High-fat diet activated fatty acid oxidation mediates intestinal stemness and tumorigenicity.Cell Rep. 2021; 35109212Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. As expected, a HFD resulted in considerably larger tumor numbers, as well as greater tumor size, compared with mice fed with a control diet. This effect was greatly reduced upon genetic loss of Cpt1a, as assessed utilizing a mouse model with a double knockout of both Cpt1a and Apc. Loss of Cpt1a, and thereby inhibition of FAO, in combination with a HFD resulted in considerably lower tumor numbers, as well as diminished tumor size (Figure 1). Loss of Cpt1a had no effect on tumors in animals that were on a normal diet. The impact of CPT1A-mediated FAO on established adenomas was investigated using the CPT1A inhibitor etomoxir. Pharmacological inhibition of CPT1A-mediated FAO using etomoxir in HFD or control-fed Apc KO mice did not impact on established adenoma numbers; however, it did reduce the growth-enhancing effects on adenoma size induced by a HFD and treatment with a PPARδ agonist. These findings highlight the important role of HFD-mediated FAO in tumor initiation and development. Furthermore, the authors indicate a potential chemoprevention strategy via inhibition of the FAO metabolic program in a HFD-induced state. As the study by Mana et al. demonstrates, understanding the role of diet and its impact on key metabolic processes potentially contributes to novel preventive and therapeutic opportunities for CRC [6.Mana M.D. et al.High-fat diet activated fatty acid oxidation mediates intestinal stemness and tumorigenicity.Cell Rep. 2021; 35109212Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. Furthermore, the work highlights the impact of altered ISC properties on tumor formation in the intestine. Mana et al. show that increased ISC numbers induced by a HFD are associated with enhanced intestinal tumor formation. This finding contrasts with previous work demonstrating that increased ISC numbers contribute to a reduced risk of developing CRC [8.Bruens L. et al.Calorie restriction increases the number of competing stem cells and decreases mutation retention in the intestine.Cell Rep. 2020; 32: 107937Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar,9.van Neerven S.M. et al.Apc-mutant cells act as supercompetitors in intestinal tumour initiation.Nature. 2021; 594: 436-441Crossref PubMed Scopus (16) Google Scholar]. ISCs are capable of symmetric self-renewal in a stochastic manner, a phenomenon referred to as 'neutral drift'. Neutral drift can be disrupted by oncogenic mutations that confer a competitive advantage to mutant ISCs, ultimately leading to the permanent fixation of mutations in ISCs in crypt bottoms [10.Lopez-Garcia C. et al.Intestinal stem cell replacement follows a pattern of neutral drift.Science. 2010; 330: 822-825Crossref PubMed Scopus (433) Google Scholar]. A calorie-restriction diet results in increased ISC numbers, thereby enhancing the ability of wild-type competitors to outcompete the mutant cells in an individual crypt [8.Bruens L. et al.Calorie restriction increases the number of competing stem cells and decreases mutation retention in the intestine.Cell Rep. 2020; 32: 107937Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar]. This mechanism lowers the retention of mutations and ultimately tumor development. The importance of stem cell dynamics on tumor initiation is also supported by another study that utilized the Wnt activator, lithium chloride, to boost wild-type ISC numbers, thereby strengthening their participation in competition and limiting the expansion of mutant clones [9.van Neerven S.M. et al.Apc-mutant cells act as supercompetitors in intestinal tumour initiation.Nature. 2021; 594: 436-441Crossref PubMed Scopus (16) Google Scholar]. Conversely, a reduced number of stem cells resulted in a diminished number of wild-type ISCs to compete against mutant competitors [11.Huels D.J. et al.Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells.Nat. Commun. 2018; 9: 1132Crossref PubMed Scopus (31) Google Scholar]. ISCs carrying oncogenic mutations could therefore ensure rapid crypt population and fixation of mutations in crypt bottoms, resulting in accelerated tumorigenesis [11.Huels D.J. et al.Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells.Nat. Commun. 2018; 9: 1132Crossref PubMed Scopus (31) Google Scholar]. The opposite findings in the recent studies by Mana et al. – a HFD results in increased stem cell numbers and increased tumorigenesis – indicates that metabolic rewiring of ISCs promotes tumor development predominantly in a cell-intrinsic fashion. Future studies should explore the precise roles of downstream diet-induced metabolic activity of ISCs on stem cell dynamics because this understanding could provide researchers with potent, novel therapeutic and preventive strategies for CRC. The authors declare no conflicts of interest.