Biology subjects

Desvergne, B.

Publications and source records attributed to Desvergne, B..

4 recordsLinked to original sources

bioRxiv2026

Metabolomics identifies endocannabinoid system remodeling during obesity associated inflammation in adipose tissue

Visceral white adipose tissue (vAT) is more susceptible than subcutaneous white adipose tissue (scAT) to obesity-associated metaflammation, but the metabolic pathways accompanying this depot specific transition remain incompletely defined. We profiled vAT and scAT from mice fed a control diet or a 60% kcal high-fat diet (HFD) for 1 or 8 weeks. Untargeted metabolomics was integrated with targeted endocannabinoid quantification, gene expression and promoter associated chromatin analyses, adipocyte and stromal vascular fraction (SVF) measurements, cross-omics correlation analysis, and cell-culture perturbations. After 1 week, HFD induced relatively few metabolic changes, although vAT showed early alterations associated with sphingomyelin metabolism. By week 8, both depots exhibited extensive but distinct metabolic remodeling. The KEGG retrograde endocannabinoid-signaling pathway was the highest-ranked enriched pathway in vAT, with arachidonoylglycerol (2AG) among the most strongly altered metabolites. Targeted analysis confirmed selective 2AG accumulation in vAT, accompanied by coordinated changes in genes and promoter-associated chromatin marks related to endocannabinoid synthesis, degradation and receptor expression. Cellular fractionation localized excess 2AG predominantly to vAT adipocytes, whereas Cnr2 was enriched in the SVF and induced by HFD specifically in vAT. Cross omics integration further revealed a denser and predominantly inverse transcript metabolite association network in vAT than in scAT. Using macrophage adipocyte co-culture and secretome profiling, we demonstrated that cannabinoid stimulation shifts activated macrophage outputs away from pro-inflammatory cytokines (Il1b, Ccl2) toward extracellular matrix (ECM) proteoglycan remodeling and intercellular signaling.

molecular biology↗

bioRxiv2020

Adipose-tissue derived signals control bone remodelling.

Long bones from mammals host blood cell formation and contain multiple cell types, including adipocytes. Physiological functions of bone marrow adipocytes are poorly documented. Herein, we used adipocyte-deficient PPAR{gamma}-whole body null mice to investigate the consequence of total adipocyte deficiency on bone homeostasis in mice. We first highlight the dual bone phenotype of PPAR{gamma} null mice: on the one hand the increase bone formation and subsequent trabecularization extending in the long bone diaphysis, due to the well-known impact of PPAR{gamma} deficiency on osteoblasts formation and activity; on the other hand, an increased osteoclastogenesis in the cortical bone. We then further explore the cause of this unexpected increased osteoclastogenesis using two independent models of lipoatrophy, which recapitulated this phenotype. This demonstrates that hyperosteoclastogenesis is not intrinsically linked to PPAR{gamma} deficiency, but is a consequence of the total lipodystrophy. We further showed that adiponectin, a cytokine produced by adipocytes and mesenchymal stromal cells is a potent inhibitor of osteoclastogenesis in vitro and in vivo. Moreover, pharmacological activation of adiponectin receptors by the synthetic agonist AdipoRon inhibits mature osteoclast activity both in mouse and human cells by blocking podosome formation through AMPK activation. Finally, we demonstrated that AdipoRon treatment blocks bone erosion in vivo in a murine model of inflammatory bone loss, providing potential new approaches to treat osteoporosis.

cell biology↗

bioRxiv2020

Visualization and normalization of drift effect across batches in metabolome-wide association studies

As a powerful phenotyping technology, metabolomics provides new opportunities in biomarker discovery through metabolome-wide association studies (MWAS) and identification of metabolites having regulatory effect in various biological processes. While MS-based metabolomics assays are endowed with high-throughput and sensitivity, large-scale MWAS are doomed to long-term data acquisition generating an overtime-analytical signal drift that can hinder the uncovering of true biologically relevant changes. We developed "dbnorm", a package in R environment, which allows visualization and removal of signal heterogeneity from large metabolomics datasets. "dbnorm" integrates advanced statistical tools to inspect dataset structure, at both macroscopic (sample batch) and microscopic (metabolic features) scales. To compare model performance on data correction, "dbnorm" assigns a score, which allows the straightforward identification of the best fitting model for each dataset. Herein, we show how "dbnorm" efficiently removes signal drift among batches to capture the true biological heterogeneity of data in two large-scale metabolomics studies.

bioinformatics↗

bioRxiv2019

System analysis of the functional cross-talk between PPAR , LXR and FXR in the human HepaRG liver cells

Transcriptional regulations exert a critical control of metabolic homeostasis. In particular, the nuclear receptors (NRs) are involved in regulating numerous pathways of the intermediate metabolism. The purpose of the present study was to explore in liver cells the interconnectedness between three of them, LXR, FXR, and PPAR, all three known to act on lipid and glucose metabolism, and also on inflammation. The human cell line HepaRG was selected for its best proximity to human primary hepatocytes. Global gene expression of differentiated HepaRG cells was assessed after 4 hours and 24 hours of exposure to GW3965 (LXR agonist), GW7647 (PPAR agonist), and GW4064 and CDCA (FXR synthetic and natural agonist, respectively). Our work revealed that, contrary to our expectations, NR specificity is largely present at the level of target genes, with a smaller than expected overlap of the set of genes targeted by the different NRs. It also highlighted the much broader activity of the synthetic FXR ligand compared to CDCA. More importantly, our results revealed that activation of FXR has a pro-proliferative effect and decreases polyploidy of hepatocytes, while LXR inhibits the cell cycle progression, inducing hepatocyte differentiation and a higher polyploidism. Conclusion: these results highlight the importance of analyzing the different NR activities in a context allowing a direct confrontation of each receptor outcome, and reveals the opposite role of FXR and LXR in hepatocyte cells division and maturation.

physiology↗