Project description:Adipose eosinophils confer protection against obesity and metabolic disease, yet the mechanism by which adipose eosinophils mediate this process is incompletely understood. Here we found that transgenic elevation of adipose eosinophil number results in increased adipose tissue levels of vascular endothelial growth factor A (VEGFA), with resulting elevation in adipose tissue vascularisation and production of thermogenic beige fat. We found that this process is directly regulated by Activator Protein 1 (AP-1) family member activating transcription factor 3 (ATF3), with eosinophil-specific deletion of ATF3 both in vitro and in vivo resulting in decreased adipose tissue VEGFA, reduced adipose tissue vascularisation, and decreased thermogenic beige fat. We thus propose a novel mechanism by which eosinophils promote metabolic homeostasis and highlight ATF3 as a key driver of adipose eosinophil tissue specialisation.
Project description:Cold triggers VEGF dependent but hypoxia independent angiogenesis in adipose tissues and anti-VEGF agents modulate adipose metabolism The molecular mechanisms of angiogenesis in relation to adipose tissue metabolism remain poorly understood. Here we show that exposure of mice to cold led to conversion of white adipose tissue (WAT) to brown-like adipose tissue, accompanying the switch of an active angiogenic phenotype. Gene expression profile analysis showed VEGF was upregulated via most likely hypoxia-independent PGC-1 transcriptional activation. Intriguingly, VEGFR2 blockage abolished the cold-induced angiogenesis, significantly impaired nonshivering thermogenesis capacity, and markedly reduced adipose metabolism. Unexpectedly, VEGFR1 blockage resulted in opposite effects by increasing adipose vascularity and metabolism. These findings demonstrate that VEGFR2 and VEGFR1 mediate polarized activities in modulating adipose angiogenesis and metabolism. Taken together, our findings have conceptual implications in applying angiogenesis modulators for the treatment of obesity and metabolic disorders. Keywords: Time course
Project description:Cold triggers VEGF dependent but hypoxia independent angiogenesis in adipose tissues and anti-VEGF agents modulate adipose metabolism; The molecular mechanisms of angiogenesis in relation to adipose tissue metabolism remain poorly understood. Here we show that exposure of mice to cold led to conversion of white adipose tissue (WAT) to brown-like adipose tissue, accompanying the switch of an active angiogenic phenotype. Gene expression profile analysis showed VEGF was upregulated via most likely hypoxia-independent PGC-1 transcriptional activation. Intriguingly, VEGFR2 blockage abolished the cold-induced angiogenesis, significantly impaired nonshivering thermogenesis capacity, and markedly reduced adipose metabolism. Unexpectedly, VEGFR1 blockage resulted in opposite effects by increasing adipose vascularity and metabolism. These findings demonstrate that VEGFR2 and VEGFR1 mediate polarized activities in modulating adipose angiogenesis and metabolism. Taken together, our findings have conceptual implications in applying angiogenesis modulators for the treatment of obesity and metabolic disorders. Experiment Overall Design: Mice were exposed to cold and white addipose tissue was collected at different time points
Project description:Depletion of autophagy-associated protein 5 (Atg5), specifically within the eosinophil lineage in mice, resulted in increased body weight, impaired glucose metabolism, and structural alterations in adipose tissue. Our findings highlight that Atg5 influences the functional activity of eosinophils within adipose tissue rather than their quantity. To gain a deeper understanding of the molecular mechanisms underlying ATG5's role in eosinophils, we conducted total RNA-seq analyses on control and Atg5-deficient eosinophils isolated from both bone marrow and blood of mice.
Project description:Gene expression in eosinophils isolated by FACS from inguinal subcutaneous adipose tissue of WT and mice lacking the transcriptional repressor Kruppel-like factor 3 (KLF3). We aimed to investigate deregulation of pathways and genes in the absence of KLF3 in eosinophils that reside in the subcutaneous adipose tissue, in order to study the role of KLF3 and its target genes in adipose eosinophil function and activity.
Project description:Eosinophilia is associated with various persisting inflammatory diseases and often coincides with chronic fungal infections or fungal allergy as in case of allergic bronchopulmonary aspergillosis (ABPA). However, the interactions between eosinophils and fungal pathogen leading to release of inflammatory mediators from eosinophils are poorly understood. Therefore, we established a co-culture system of mouse bone marrow derived eosinophils (BMDE) with Aspergillus fumigatus (Af) that we used in part to analyse transcriptional regulation induced by Af.