title: Leptin receptor signaling is required for high-fat diet-induced atrophic gastritis in mice.
abstract: BACKGROUND
  Obesity increases the risk for malignancies in various tissues including the stomach. Atrophic gastritis with precancerous lesions is an obesity-associated disease; however, the mechanisms that underlie the development of obesity-associated atrophic gastritis are unknown. Leptin is a hormone derived from stomach as well as adipose tissue and gastric leptin is involved in the development of gastric cancer. The aim of the current study is to investigate the involvement of leptin receptor signaling in the development of atrophic gastritis during diet-induced obesity.
  
  
  METHODS
  Male C57BL/6, ob/ob and db/db mice were fed a high-fat diet (HFD) or a control diet (CD) from 1 week to 5 months. Pathological changes of the gastric mucosa and the expression of molecules associated with atrophic gastritis were evaluated in these mice.
  
  
  RESULTS
  HFD feeding induced gastric mucosal hyperplasia with increased gastric leptin expression. Mucosal hyperplasia was accompanied by a higher frequency of Ki67-positive proliferating cells and atrophy of the gastric glands in the presence of inflammation, which increased following HFD feeding. Activation of ObR signaling-associated molecules such as ObR, STAT3, Akt, and ERK was detected in the gastric mucosa of mice fed the HFD for 1 week. The morphological alterations associated with gastric mucosal atrophy and the expression of Muc2 and Cdx2 resemble those associated with human intestinal metaplasia. In contrast to wild-type mice, leptin-deficient ob/ob mice and leptin receptor-mutated db/db mice did not show increased Cdx2 expression in response to HFD feeding.
  
  
  CONCLUSIONS
  Together, these results suggest that activation of the leptin signaling pathway in the stomach is required to develop obesity-associated atrophic gastritis.
authors.affiliation: Research Institute, National Center for Global Health and Medicine (NCGM), 1-21-1, Toyama Shinjuku, Tokyo, 162-0052 Japan ; Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences (NIPS), 38 Nishigonaka Myodaiji, Okazaki, Aichi 444-8585 Japan ; 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.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Inagaki-Ohara
authors.affiliation: Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences (NIPS), 38 Nishigonaka Myodaiji, Okazaki, Aichi 444-8585 Japan.
authors.forename: Shiki
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences (NIPS), 38 Nishigonaka Myodaiji, Okazaki, Aichi 444-8585 Japan.
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Takagi
authors.affiliation: Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences (NIPS), 38 Nishigonaka Myodaiji, Okazaki, Aichi 444-8585 Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Saito
authors.affiliation: 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.
authors.forename: Seiya
authors.initials: S
authors.lastname: Arita
authors.affiliation: Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences (NIPS), 38 Nishigonaka Myodaiji, Okazaki, Aichi 444-8585 Japan.
authors.forename: Lijun
authors.initials: L
authors.lastname: Tang
authors.affiliation: Yakult Central Institute for Microbiological Research, 5-11 Izumi, Kunitachi, Tokyo, 186-8650 Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Hori
authors.affiliation: Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692 Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kataoka
authors.affiliation: Yakult Central Institute for Microbiological Research, 5-11 Izumi, Kunitachi, Tokyo, 186-8650 Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences (NIPS), 38 Nishigonaka Myodaiji, Okazaki, Aichi 444-8585 Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Minokoshi
keywords: Atrophic gastritis; High-fat diet; Leptin; Obesity
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