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Gene expression of visceral adipose regulatory T cells from mice with specific deletion of insulin receptor in the cells

ABSTRACT: Visceral adipose tissue (VAT) regulatory T cells (Tregs) control inflammation and metabolism. Diet-induced obesity causes hyperinsulinemia and diminishes VAT Treg number and function, but whether these two phenomena were mechanistically linked was unknown. We hypothesized that excessive insulin signaling in obesity negatively impact VAT Tregs. Using Treg-specific insulin receptor deletion (Foxp3-cre;Insr-fl/fl) mice, we compared the gene expression of VAT Tregs from control and knockout mice in obesity and aging, two models of hyperinsulinemia. We found that genes associated with Treg functions were altered in Tregs lacking insulin receptor.

ORGANISM(S): Mus musculus

PROVIDER: GSE151016 | GEO | 2020/05/22

REPOSITORIES: GEO

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Project description:The rising incidence of pancreatic cancer is largely driven by the skyrocketing prevalence of obesity and type 2 diabetes (T2D). Hyperinsulinemia is a cardinal feature of both conditions, and is independently associated with increased cancer incidence and mortality. Our previous studies demonstrated that genetically reducing insulin production suppressed formation of pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in mice with mutant Kras. However, we found that hyperinsulinemia affected many cell types in the pancreatic microenvironment. Thus, it remained unclear whether hyperinsulinemia exerted its effects directly on the cells that give rise to PanINs or indirectly on the tumor microenvironment, and molecular mechanisms involved were unknown. Here, we tested whether insulin receptors (Insr) in KrasG12D-expressing pancreatic acinar cells are necessary for the effects of hyperinsulinemia on obesity-associated pancreatic cancer development. Loss of Insr in KrasG12D-expressing acinar cells did not prevent hyperinsulinemia or weight gain associated with high fat diet (HFD) consumption in mice. However, solely reducing Insr in KrasG12D-expressing acinar cells significantly reduced formation of PanIN and tumors, in a gene dose-dependent manner. Mechanistically, proteomic analyses showed that hyperinsulinemia acts through Insr to drive the excess production of digestive enzymes in acinar cells by modulating the activity of the spliceosome, ribosome, and secretory machinery. This resulted in increased inflammation, which was abrogated by acinar-specific Insr knockout. We confirmed that insulin increased the conversion of wild-type acinar cells into acinar-to-ductal metaplasia (ADM) in a trypsin-dependent manner. Collectively, these data demonstrate that hyperinsulinemia acting via acinar cells insulin receptors promotes inflammatory conditions that cooperate with Kras signaling to increase the risk of developing pancreatic cancer, mechanistically linking obesity and pancreatic cancer.

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Gene expression of visceral adipose regulatory T cells from mice with specific deletion of insulin receptor in the cells

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