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

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.

<p>A Variant of <em>Leptin</em> Gene Decreases the Risk of Gastric Cancer in Chinese Individuals: Evidence from a Case–Control Study</p>

“…26 Dietary fat-accelerating LEP signaling was shown to promote protumorigenic gastric environment in mice. 27 Overexpression of LEP was linked with the development of GC in humans and murine. 25,28 Serum LEP levels were related with insulin resistance in GC patients 29 and may be a valuable diagnostic indicator.…”

A Dynamic Transcriptome Map of Different Tissue Microenvironment Cells Identified During Gastric Cancer Development Using Single-Cell RNA Sequencing

“…The ferroptosis process is iron-dependent and is characterized by increased lipid active oxygen ( 71 ). A recent study showed that a high-lard diet induced IM ( 72 ). Therefore, the accumulation of lipid active oxygen induced by ferroptosis may be an important IM mechanism at the gastric epithelium, hence, preventing ferroptosis in epithelial cells may be effective in preventing gastric epithelial IM.…”

The Role of Microbiota in Gastrointestinal Cancer and Cancer Treatment: Chance or Curse?

“…74 This further supports a role for H pylori in accelerating gastric cancer development with the yes-associated protein 1, a key effector of the Hippo pathway, also being implicated in the process (Figure 3B). 75 HFD also has been shown induce gastric dysbiotic changes including increased Lactobacillus abundance, intestinal metaplasia, expression of leptin, phosphorylated leptin receptor Q21 and STAT3 and intracellular b-catenin accumulation (Figure 3B), 76,77 whereas loss of the leptin receptor attenuates the effect of HFD on dysbiosis and intestinal metaplasia. 77…”

“…[73][74][75] In GC, a HFD induces gastric dysbiosis (characterized by increased Lactobacillus abundance), intestinal metaplasia, the expression of leptin, phosphorylated leptin receptor and STAT3 and intracellular b-catenin accumulation. 76,77 (C) In the context of CRC, certain microbes such as pks Q41 þ E coli, P anaerobius, and B fragilis are able to produce toxins that can influence carcinogenic processes. These include the induction of the DNA damage checkpoint pathway and proinflammatory responses, TLR interaction, impairment of the antitumor T-cell response, nuclear factor-kB (NF-kB), and Wnt/b-catenin pathway activation, further promoting cell proliferation.…”