Abstract
BackgroundObesity 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.MethodsMale 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.ResultsHFD 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.ConclusionTogether, these results suggest that activation of the leptin signaling pathway in the stomach is required to develop obesity-associated atrophic gastritis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12986-016-0066-1) contains supplementary material, which is available to authorized users.
Highlights
Obesity increases the risk for malignancies in various tissues including the stomach
high-fat diet (HFD)-fed mice develop atrophic gastritis To determine how diet-induced obesity affects the pathogenesis of gastric mucosa, C57BL/6 mice were fed either HFD (60 % calories from fat) or control diet (CD) (10 % calories from fat) and the histological changes of the gastric mucosa were examined in a time-dependent manner
HFD feeding activates early leptin receptor signaling during gastric intestinal metaplasia Because of the early morphological alterations observed in the gastric mucosa, we examined the gene expression of stomach-specific hormones, peptides, and enzymes 1 week after HFD feeding
Summary
Obesity increases the risk for malignancies in various tissues including the stomach. 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. Obesity augments the risk of a higher prevalence of gastritis [2, 3], atrophic gastritis [4,5,6], and gastric cardia adenocarcinoma [7,8,9]. It is imperative to identify signaling molecules associated with both obesity and precancerous lesions to aid in the management of high-risk individuals
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