Abstract
Leptin, an adipocyte-derived hormone and its receptor (ObR) expressed in the hypothalamus are well known as an essential regulator of appetite and energy expenditure. Obesity induces abundant leptin production, however, reduced sensitivity to leptin leads to the development of metabolic disorders, so called leptin resistance. The stomach has been identified as an organ that simultaneously expresses leptin and ObR. Accumulating evidence has shown gastric leptin to perform diverse functions, such as those in nutrient absorption and carcinogenesis in the gastrointestinal system, independent of its well-known role in appetite regulation and obesity. Overexpression of leptin and phosphorylated ObR is implicated in gastric cancer in humans and in murine model, and diet-induced obesity causes precancerous lesions in the stomach in mice. While the underlying pathomechanisms remain unclear, leptin signaling can affect gastric mucosal milieu. In this review, we focus on the significant role of the gastric leptin signaling in neoplasia and tumorigenesis in stomach in the context of hereditary and diet-induced obesity.
Highlights
Humans have been exposed to malnutrition due to starvation
Overexpression of leptin and activation of ObR has been reported in various cancers, such as those of the stomach and mammary gland, and is mediated by inflammation, angiogenesis, stemness [6], and epithelial–mesenchymal transition (EMT) and progression [7] (Figure 1)
We demonstrated that high-fat diet (HFD) induces the loss of parietal cells and glandular cells, and promotes intestinal metaplasia, which transforms the gastric epithelium to an intestine-like epithelium, or precancerous lesions [85]
Summary
Humans have been exposed to malnutrition due to starvation. recently, malnutrition in the form of over-nutrition has become a serious social problem, because diet-induced obesity due to an increase in nutrient intake and insufficient energetic expenditure, has dramatically increased worldwide and is implicated in numerous metabolic disorders, including cardiovascular diseases and type 2 diabetes (T2D). ObR consists of six isoforms (ObRa, ObRb, ObRc, ObRd, ObRe and ObRf), formed from alternative RNA splicing of the db gene. These isoforms have a common leptin-binding domain, and differ in their intracellular domains [21,22]. ObRb, named as the long form, is the only isoform that contains the intracellular motif necessary for the leptin-mediated JAK-STAT pathway, whereas four short forms (ObRa, c, d, and f), differ in their cytosolic carboxy terminals. SOci.b2R0f1),9f,o2r0m, 2e6d22from alternative RNA splicing of the db gene Dysregulation of the leptin receptor signaling is involved in the onset of leptin resistance, inflammation and cancer
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