Visceral obesity contributes to obesity-related complications; however, the intrinsic mechanism of depot-specific adipose tissue behavior remains unclear. Despite the pro-adipogenesis role of glucocorticoids (GCs) in adipogenesis, the role of GCs in visceral adiposity rather than in subcutaneous adipose tissue is not established. Because adipocyte progenitors display a striking depot-specific pattern, the regulatory pathways of novel progenitor subtypes within different depots remain unclear. This study describes a cell-specific mechanism underlying visceral adiposity.
A diverse panel of novel depot-specific adipose progenitors was screened in mice and human samples. The transcriptome distinction and various responses of novel progenitor subtypes of GCs were further measured using the GC receptor-chromatin immunoprecipitation assay and RNA sequencing. The mechanism of novel subtypes was identified using transposase-accessible chromatin analysis and bisulfite sequencing and further confirmed using precise editing of CpG methylation.
Platelet-derived growth factor receptor α (PDGFRα+ ) progenitors, which were dominant in the visceral adipose tissue, were GC-sensitive beige adipose progenitors, whereas CD137+ progenitors, which were dominant in the subcutaneous adipose tissue, were GC-passive beige adipose progenitors. Expression of miR-27b, an inhibitor of adipocyte browning, was significantly increased in PDGFRα+ progenitors treated with GCs. Using transposase-accessible chromatin analysis, bisulfite sequencing, and precise editing of CpG methylation, TEA domain transcription factor 1 (TEAD1) was discovered to be uniquely hypomethylated in PDGFRα+ progenitors.
GCs inhibited the PDGFRα+ progenitors' browning process via miR-27b, which was transcriptionally activated by the collaboration of TEAD1 with the GC receptor. These data provide insights into the mechanism of depot-specific variations in high-fat diet-induced obesity.
© 2023 The Obesity Society.

Lymph nodes (LNs) are always embedded in the metabolically-active white adipose tissue (WAT), whereas their functional relationship remains obscure. Here, we identify fibroblastic reticular cells (FRCs) in inguinal LNs (iLNs) as a major source of IL-33 in mediating cold-induced beiging and thermogenesis of subcutaneous WAT (scWAT). Depletion of iLNs in male mice results in defective cold-induced beiging of scWAT. Mechanistically, cold-enhanced sympathetic outflow to iLNs activates β1- and β2-adrenergic receptor (AR) signaling in FRCs to facilitate IL-33 release into iLN-surrounding scWAT, where IL-33 activates type 2 immune response to potentiate biogenesis of beige adipocytes. Cold-induced beiging of scWAT is abrogated by selective ablation of IL-33 or β1- and β2-AR in FRCs, or sympathetic denervation of iLNs, whereas replenishment of IL-33 reverses the impaired cold-induced beiging in iLN-deficient mice. Taken together, our study uncovers an unexpected role of FRCs in iLNs in mediating neuro-immune interaction to maintain energy homeostasis.
© 2023. The Author(s).

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have demonstrated strong immunogenicity and protection against severe disease, concerns about the duration and breadth of these responses remain. In this study, we show that codelivery of plasmid-encoded adenosine deaminase-1 (pADA) with SARS-CoV-2 spike glycoprotein DNA enhances immune memory and durability in vivo. Coimmunized mice displayed increased spike-specific IgG of higher affinity and neutralizing capacity as compared with plasmid-encoded spike-only-immunized animals. Importantly, pADA significantly improved the longevity of these enhanced responses in vivo. This coincided with durable increases in frequencies of plasmablasts, receptor-binding domain-specific memory B cells, and SARS-CoV-2-specific T follicular helper cells. Increased spike-specific T cell polyfunctionality was also observed. Notably, animals coimmunized with pADA had significantly reduced viral loads compared with their nonadjuvanted counterparts in a SARS-CoV-2 infection model. These data suggest that pADA enhances immune memory and durability and supports further translational studies.
Copyright © 2022 by The American Association of Immunologists, Inc.

The SARS-CoV-2 pandemic has necessitated the rapid development of prophylactic vaccines. Two mRNA vaccines have been approved for emergency use by the FDA and have demonstrated extraordinary effectiveness. The success of these mRNA vaccines establishes the speed of development and therapeutic potential of mRNA. These authorized vaccines encode full-length versions of the SARS-CoV-2 spike protein. They are formulated with lipid nanoparticle (LNP) delivery vehicles that have inherent immunostimulatory properties. Different vaccination strategies and alternative mRNA delivery vehicles would be desirable to ensure flexibility of future generations of SARS-CoV-2 vaccines and the development of mRNA vaccines in general. Here, we report on the development of an alternative mRNA vaccine approach using a delivery vehicle called charge-altering releasable transporters (CARTs). Using these inherently nonimmunogenic vehicles, we can tailor the vaccine immunogenicity by inclusion of coformulated adjuvants such as oligodeoxynucleotides with CpG motifs (CpG-ODN). Mice vaccinated with the mRNA-CART vaccine developed therapeutically relevant levels of receptor binding domain (RBD)-specific neutralizing antibodies in both the circulation and in the lung bronchial fluids. In addition, vaccination elicited strong and long-lasting RBD-specific TH1 T cell responses including CD4+ and CD8+ T cell memory.
© 2021 The Authors. Published by American Chemical Society.

This study is to investigate the effect of captopril when combined with irradiation.
4T1 (mouse mammary carcinoma) cells were injected in the right hind leg of Balb/c mice. Mice were randomized to four groups; control (group 1), captopril-treated (group 2), irradiated (group 3), irradiated and captopril-treated concurrently (group 4). Captopril was administered by intraperitoneal injection (10 mg/kg) daily and irradiation was delivered on the tumor-bearing leg for 15 Gy in 3 fractions. Surface markers of splenic neutrophils (G-MDSCs) and intratumoral neutrophils (tumor-associated neutrophils [TANs]) were assessed using flow cytometry and expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 alpha (HIF-1α) of tumor was evaluated by immunohistochemical (IHC) staining.
The mean tumor volumes (±standard error) at the 15th day after randomization were 1,382.0 (±201.2) mm3 (group 1), 559.9 (±67.8) mm3 (group 3), and 370.5 (± 48.1) mm3 (group 4), respectively. For G-MDSCs, irradiation reversed decreased expression of CD101 from tumor-bearing mice, and additional increase of CD101 expression was induced by captopril administration. Similar tendency was observed in TANs. The expression of tumor-necrosis factor-associated molecules, CD120 and CD137, are increased by irradiation in both G-MDSCs and TANs. Further increment was observed by captopril except CD120 in TANs. For IHC staining, VEGF and HIF-1α positivity in tumor cells were decreased when treated with captopril.
Captopril is suggested to have additional effect when combined to irradiation in a murine tumor model by modulation of MDSCs and angiogenesis.