Molecular Medicine Israel

High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity


  • HFD augments intestinal stemness through PPARδ and PPARα
  • A PPAR-FAO program enhances stemness and tumorigenicity in a HFD
  • Loss or inhibition of Cpt1a-mediated FAO blunts the HFD-enhancing effects in ISCs
  • Early intestinal tumors arising from HFD ISCs are highly sensitive to FAO inhibition


Obesity is an established risk factor for cancer in many tissues. In the mammalian intestine, a pro-obesity high-fat diet (HFD) promotes regeneration and tumorigenesis by enhancing intestinal stem cell (ISC) numbers, proliferation, and function. Although PPAR (peroxisome proliferator-activated receptor) nuclear receptor activity has been proposed to facilitate these effects, their exact role is unclear. Here we find that, in loss-of-function in vivo models, PPARα and PPARδ contribute to the HFD response in ISCs. Mechanistically, both PPARs do so by robustly inducing a downstream fatty acid oxidation (FAO) metabolic program. Pharmacologic and genetic disruption of CPT1A (the rate-controlling enzyme of mitochondrial FAO) blunts the HFD phenotype in ISCs. Furthermore, inhibition of CPT1A dampens the pro-tumorigenic consequences of a HFD on early tumor incidence and progression. These findings demonstrate that inhibition of a HFD-activated FAO program creates a therapeutic opportunity to counter the effects of a HFD on ISCs and intestinal tumorigenesis…

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