Although the most effective intervention for type 2 diabetes prevention may not yet be identified, DPP-based interventions show promise for long-term sustainability. The DPP intervention is effective in treating overweight and obesity across a variety of settings and thus may prevent chronic diseases in which overweight and obesity are risk factors. Public health practitioners can use this successful intervention to help individuals lead healthier lives.
Leucine-rich repeat-containing G protein-coupled receptor (LGR)-5 is a recently identified marker of stem cells in adult intestinal epithelium and hair follicles. Because of this characteristic, we studied the status of Lgr5 expression in the mouse uterus under various conditions. Lgr5 is highly expressed in the uterine epithelium of immature mice and is dramatically down-regulated after the mice resume estrous cycles. Surprisingly, whereas its expression is up-regulated in uteri of ovariectomized mice, the expression is down-regulated by estrogen and progesterone via their cognate nuclear receptors, estrogen receptor-alpha and progesterone receptor, respectively. Using a mouse endometrial cancer model, we also found that Lgr5 is highly expressed in the epithelium during the initial stages of tumorigenesis but is remarkably down-regulated in fully developed tumors. Lgr5 is a downstream target of Wnt signaling in the intestine. Genetic evidence shows that either excessive or absence of Wnt signaling dampens Lgr5 expression in the uterus. Collectively, our results show that Lgr5 expression in the mouse uterine epithelium is unique and dynamically regulated under various physiological and pathological states of the uterus, suggesting that this orphan receptor has important functions in uterine biology. However, identifying definitive uterine function of LGR5 will require further investigation using conditional deletion of uterine Lgr5 because systemic deletion of this gene is neonatally lethal.
Objective
Endometrial cancer (EMC) is the most common gynecological malignancy. The etiology and the cell types that are conducive to EMC are not completely understood, provoking further studies. Our objective was to determine whether deletion of Pten specifically in the uterine stroma and myometrium induces cancer or manifests different phenotypes.
Methods
PtenAmhr2(d/d) mice with conditional deletion of Pten in the mouse uterine stroma and myometrium, but not in the epithelium, were generated by mating floxed Pten mice and anti-Mullerian hormone type 2 receptor (Amhr2)-Cre mice. The phenotypes were compared between Ptenf/f and PtenAmhr2(d/d) uteri.
Results
We show that conditional deletion of Pten in the mouse uterine stroma and myometrium, but not in the epithelium, fails to generate EMC even at the age of 5 months. Surprisingly Pten deletion by Amhr2-Cre transformed a large number of myometrial cells into adipocytes with lipid accumulation, possibly a result of increased levels of SREBP1 and PPARγ which regulate adipose differentiation.
Conclusions
These results provide evidence that deletion of Pten specifically in the stroma and myometrium does not result in EMC in female mice examined up to 5 months of age but alters the myocytes to adipocytes and mimics histologic similarities with lipoleiomyomas in humans, raising the possibility of using this mouse model to further explore the cause of the disease.
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