Dietary Fat-Accelerating Leptin Signaling Promotes Protumorigenic Gastric Environment in Mice.

Seiya Arita,Yuta Murakami,Kyoko Inagaki-Ohara,Masaharu Okazaki,Takumi Ogawa,Yuta Kinoshita

doi:10.3390/nu11092127

Abstract

Excess of fat intake leads to obesity and causes a variety of metabolic diseases and cancer. We previously demonstrated that high-lard diet induces intestinal metaplasia, a precancerous lesion of the stomach mediated by leptin signaling. This study aims to investigate which kinds of dietary fat cause the intestinal metaplasia onset. We fed eight kinds of high-fat diets (HFDs) of animal or plant origin to mice evaluated their effect on gastric pathogenesis. Five types of dietary fat were divided according to their observed effects: Obese with high metaplasia (group I; beef tallow, lard, and hydrogenated coconut oil), non-obese with high metaplasia (group II; linseed oil), obese without metaplasia (group III; corn oil and olive oil), non-obese without metaplasia (group IV, soybean oil) and lean without metaplasia (group V; cocoa butter). The group I and II diets induced leptin, phosphorylated leptin receptor (ObR), signal transducer and activator 3 (STAT3), and increased intracellular β-catenin accumulation in the stomach. Moreover, mice fed these HFDs with 1-methyl-3-nitro-1-nitrosoguanidine (MNNG), a gastric carcinogen, and further accelerated dysplasia in the stomach. Lactobacillus occupancy in the stomach increased in all HFDs except hydrogenated coconut oil. Our findings suggest that HFDs inducing leptin signaling accelerate the enhancement of protumorigenic gastric microenvironment independent of body mass gain or microbiome changes.

Highlights

Gastric cancer (GC) accounts for approximately 10% of cancer-related deaths annually and is the second leading cause of cancer death worldwide [1]
We demonstrated that a high-fat diet (HFD) with lard induced intestinal metaplasia precancerous lesions of the stomach [15,16]
Lgr5-positive cells, one of target molecules of β-catenin signaling, were increased concomitantly (Figure 6B). mRNA expression of c-Myc, which is a master regulator of cellular growth and metabolism [30], and target molecules of β-catenin signaling were increased in gastric mucosa of beef tallow (Beef), Lard, and coconut oil (Coconut)-fed mice (Figure 6C). These results indicate that HFDs of group I and II that induced intestinal metaplasia accelerate intracellular β-catenin expression and stem cell-like cells such as Lgr5, activated pluripotent molecules such as c-Myc, suggesting that pathogenesis of intestinal metaplasia depended on gastric leptin signaling mediated through β-catenin signaling

Summary

Introduction

Gastric cancer (GC) accounts for approximately 10% of cancer-related deaths annually and is the second leading cause of cancer death worldwide [1]. Helicobacter pylori is the predominant cause of chronic inflammation and raises the risk of GC [2], and, in particular, is positively associated with gastric non-cardia adenocarcinoma [3]. Only a small percentage of H. pylori-infected individuals develop GC [4,5]. Obesity is a critical risk factor for gastric cardia cancer, but not total GC [6]. It has been revealed that the obese population has a higher incidence of H. pylori infections [7], providing a possible mechanism for the observed morbidity of GC in obese individuals. While H. pylori infection is a known risk factor for developing GC, stimulation and modulation of the gastric mucosa via diet and resident microbiota could have important ramifications for human health

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