High-fat diet feeding promotes stemness and precancerous changes in murine gastric mucosa mediated by leptin receptor signaling pathway.
Obesity increases the risk for gastric cancers. However, the occurrence and mechanisms of precancerous atrophic gastritis induced by high-fat diet (HFD) remain unclear. Here, we show that HFD-associated lipotoxicity induces precancerous lesions that are accompanied by the disruption of organelle homeostasis, tissue integrity, and deregulated expression of stemness genes in the gastric epithelium mediated by leptin receptor (ObR) signaling. Following HFD feeding, ectopic fat accumulated and expression of LAMP2A in lysosome and COX IV in mitochondria increased in the gastric mucosa. HFD feeding also led to enhanced expression of activated-Notch1 and stem cell markers Lgr5, CD44, and EpCAM. In addition, HFD-fed mice showed intracellular β-catenin accumulation in the gastric mucosa with increased expression of its target genes, Nanog, Oct4, and c-Myc. These observations were abrogated in the leptin-deficient ob/ob mice and ObR-mutated db/db mice, indicating that these HFD-induced changes were responsible for effects downstream of the ObR. Consistent with this, the expression of the Class IA and III PI3Ks was increased following ObR activation in the gastric mucosa of HFD-fed mice. Together, these results suggest that HFD-induced lipotoxicity and deregulated organelle biosynthesis confer cancer stem cell-like properties to the gastric mucosa via signaling pathway mediated by leptin, PI3K and β-catenin.
Division of Host Defense, Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, 562 Nanatsuka, Shobara, Hiroshima, 727-0023, Japan.
Seiya
S
Arita
Division of Host Defense, Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, 562 Nanatsuka, Shobara, Hiroshima, 727-0023, Japan.
Yuta
Y
Kinoshita
Department of Pathology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
Kaori
K
Ushida
Department of Pathology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
Atsushi
A
Enomoto
Division of Host Defense, Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, 562 Nanatsuka, Shobara, Hiroshima, 727-0023, Japan; Research Institute, National Center for Global Health and Medicine (NCGM), 1-21-1, Toyama, Shinjuku, Tokyo, 162-0052, Japan. Electronic address: k-inagaki@pu-hiroshima.ac.jp.
Kyoko
K
Inagaki-Ohara
D000818:Animals; D059305:Diet, High-Fat; D004041:Dietary Fats; D005753:Gastric Mucosa / Q000473:pathology*; D006706:Homeostasis; D020738:Leptin / Q000378:metabolism; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011230:Precancerous Conditions / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D054411:Receptors, Leptin / Q000378:metabolism*; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism
C495267:CTNNB1 protein, mouse; D004041:Dietary Fats; D020738:Leptin; D008055:Lipids; D054411:Receptors, Leptin; D051176:beta Catenin; C515447:leptin receptor, mouse; D019869:Phosphatidylinositol 3-Kinases; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
High-fat diet; Leptin; Obesity; Stemness; Stomach; β-catenin