Dicer1 deletion in myeloid-committed progenitors causes neutrophil dysplasia and blocks macrophage/dendritic cell development in mice

MicroRNAs (miRNAs) have the potential to regulate cellular differentiation programs; however, miRNA deficiency in primary hematopoietic stem cells (HSCs) results in HSC depletion in mice, leaving the question of whether miRNAs play a role in early-lineage decisions unanswered. To address this issue, we deleted Dicer1, which encodes an essential RNase III enzyme for miRNA biogenesis, in murine CCAAT/enhancer-binding protein α (C/EBPA)-positive myeloid-committed progenitors in vivo. In contrast to the results in HSCs, we found that miRNA depletion affected neither the number of myeloid progenitors nor the percentage of C/EBPA-positive progenitor cells. Analysis of gene-expression profiles from wild-type and Dicer1-deficient granulocyte-macrophage progenitors (GMPs) revealed that 20 miRNA families were active in GMPs. Of the derepressed miRNA targets in Dicer1-null GMPs, 27% are normally exclusively expressed in HSCs or are specific for multipotent progenitors and erythropoiesis, indicating an altered geneexpression landscape. Dicer1-deficient GMPs were defective in myeloid development in vitro and exhibited an increased replating capacity, indicating the regained self-renewal potential of these cells. In mice, Dicer1 deletion blocked monocytic differentiation, depleted macrophages, and caused myeloid dysplasia with morphologic features of Pelger-Huë t anomaly. These results provide evidence for a miRNA-controlled switch for a cellular program of self-renewal and expansion toward myeloid differentiation in GMPs

Des-acyl ghrelin analogs prevent high-fat-diet-induced dysregulation of glucose homeostasis

There is clinical evidence that des-acyl ghrelin (DAG) favorably modulates glucose and lipid metabolism, although its mode of action is unknown. A murine model of prediabetes was used to assess possible mechanisms of action for DAG and a newly developed bioactive analog, AZP531. C57BL/6J mice were infused with saline, DAG, or AZP531 continuously for 4 wk, and fed either normal diet (ND) or normal diet for 2 wk followed by a high-fat diet (HFD) for 2 wk. Compared with mice in the ND group, HFD increased body and fat mass, caused glucose intolerance and insulin resistance,