Beyond the taste buds, sweet taste receptors (STRs; T1R2/T1R3) are also expressed on enteroendocrine cells, where they regulate gut peptide secretion but their regulatory function within the intestine is largely unknown. Using T1R2-knock out (KO) mice we evaluated the role of STRs in the regulation of glucose absorption in vivo and in intact intestinal preparations ex vivo. STR signaling enhances the rate of intestinal glucose absorption specifically in response to the ingestion of a glucose-rich meal. These effects were mediated specifically by the regulation of GLUT2 transporter trafficking to the apical membrane of enterocytes. GLUT2 translocation and glucose transport was dependent and specific to glucagon-like peptide 2 (GLP-2) secretion and subsequent intestinal neuronal activation. Finally, high-sucrose feeding in wild-type mice induced rapid downregulation of STRs in the gut, leading to reduced glucose absorption. Our studies demonstrate that STRs have evolved to modulate glucose absorption via the regulation of its transport and to prevent the development of exacerbated hyperglycemia due to the ingestion of high levels of sugars.

Retinoids are morphogens and have been implicated in cell fate commitment of embryonic stem cells (ESCs) to neurons. Their effects are mediated by RAR and RXR nuclear receptors. However, transcriptional cofactors required for cell and gene-specific retinoid signaling are not known. Here we show that protein arginine methyl transferase (PRMT) 1 and 8 have key roles in determining retinoid regulated gene expression and cellular specification in a multistage neuronal differentiation model of murine ESCs. PRMT1 acts as a selective modulator, providing the cells with a mechanism to reduce the potency of retinoid signals on regulatory “hotspots.” PRMT8 is a retinoid receptor target gene itself and acts as a cell type specific transcriptional coactivator of retinoid signaling at later stages of differentiation. Lack of either of them leads to reduced nuclear arginine methylation, dysregulated neuronal gene expression, and altered neuronal activity. Importantly, depletion of PRMT8 results in altered expression of a distinct set of genes, including markers of gliomagenesis. PRMT8 is almost entirely absent in human glioblastoma tissues. We propose that PRMT1 and PRMT8 serve as a rheostat of retinoid signaling to determine neuronal cell specification in a context-dependent manner and might also be relevant in the development of human brain malignancy. Stem Cells 2015;33:726–741

The humoral immune system influences the development of atherosclerosis, but the contributions of specific memory B cell subsets and IgG isotypes are poorly understood. We assessed the relationship between atherosclerosis and age-associated B cells (ABCs), a T-bet–expressing memory B cell subset that is enriched for IgG2c production and implicated in humoral autoimmunity. We found increased numbers of splenic CD11c+ ABCs in 6-mo-old, chow-fed Apoe−/− mice versus C57BL/6 control mice, which were exacerbated by high-fat diet. Deletion of T-bet in the B lineage in high-fat diet–fed Apoe−/− mice reduced aortic lesion area, and this correlated with decreased splenic CD11c+ B cells and reduced serum oxidized low-density lipoprotein–specific IgG2c. Our findings suggest that T-bet–expressing B cells are atherogenic agents in the Apoe−/− model and indicate that interventions to inhibit a T-bet–driven humoral response may improve atherosclerotic disease.

Background: Fat embolism and fat embolism syndrome are rare but well-known consequences of long bone fractures and orthopedic surgeries. These sources support the mechanical theory of their development. On the other hand, as an alternative pathway suggested by the biochemical theory, lipase activation and fat breakdown are also a possible background for lipid droplets appearing in the vasculature. According to Hulman’s theory, elevated C-reactive protein levels can facilitate calcium-dependent agglutination of very low-density proteins and chylomicrons forming fat globules. The level of this acute-phase protein can increase mainly in advanced-stage cancers but also has predictive or indicative value in treatment success. Methods: This study focused on strictly selected patients with different histological types and origins of cancer, as well as advanced cancer in approximately 90% of the deceased. After collecting the tissue samples, the frozen sections were stained with Oil Red O to detect fat emboli. Results: Less than 50% of the cases showed punctiform, non-clinically relevant pulmonary fat embolism, and fat embolism syndrome was identified in none of the cases. In one, non-advanced cancer case, punctiform kidney fat embolism was observed. Conclusions: The end-of-life anergic state of patients may influence the procedure. In the case of osseous metastases, since the intramedullary sinuses are affected, both the mechanical and the biochemical backgrounds may prevail and mediate fat embolism formation.