Biology subjects

Bluher, M.

Publications and source records attributed to Bluher, M..

7 recordsLinked to original sources

bioRxiv2026

A conserved transcriptomic model defines metabolic resilience and vulnerability in obesity

BackgroundObesity arises from a complex interplay of genetic and environmental factors, with alterations of transcriptional networks that integrate metabolic, immune, and regulatory pathways. Conventional measures such as body mass index (BMI) quantify body size but fail to capture the molecular heterogeneity underlying divergent metabolic outcomes. We therefore sought to construct a gene expression-based transcriptomic representation of obesity, using BMI as a practical training anchor, and to use this framework to delineate transcriptional programs associated with metabolically healthy and pathogenic obesity, with subsequent projection to mouse transcriptomic data for cross-species validation. MethodsTranscriptome data of human visceral adipose tissue (N= 1,298) were used to derive the transcriptomic BMI model, and genes contributing to the model were functionally annotated by gene set enrichment analysis. The human-trained model was subsequently applied to mouse selection lines (N = 18) with divergent obesity phenotypes. In the human cohort, post hoc stratification into metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) groups was performed using a downstream classification framework incorporating observed BMI together with predicted BMI, to assess whether model-derived predicted BMI reflected obesity-related pathophysiologic status. ResultsModel-selected genes were involved in coordinated regulation of lipid metabolism, immune activation, and growth signaling, extending to mitochondrial and translational pathways. Cross-species analyses uncovered conserved metabolic polarization: DU6 mice exhibited lipid-anabolic and inflammatory remodeling, whereas DU6P mice displayed oxidative, mitochondrial, and GH-axis-enriched transcriptional states. In human cohorts, MHO individuals showed upregulation of mitochondrial energetics and protein synthesis, while MUO individuals were characterized by increased autophagy, lipid catabolism, and stress-adaptive signaling on the transcriptional level. Together, these findings define a conserved molecular continuum linking oxidative efficiency to metabolic health and inflammation to metabolic vulnerability. ConclusionsThis integrative transcriptomic framework bridges human and mouse adipose biology to uncover conserved mechanisms underlying obesity phenotypes. By contrasting mitochondrial and translational programs with inflammatory and catabolic pathways, it provides mechanistic insight into metabolic resilience and a foundation for precision approaches to obesity management.

systems biology↗

bioRxiv2026

Sex-specific remodeling of the human adipose tissue vascular niche in obesity

AO_SCPLOWBSTRACTC_SCPLOWObesity remodels the subcutaneous adipose tissue (SAT) vasculature and contributes to cardiometabolic risk, yet potential sex differences in this process remain poorly defined. Here, we integrated single-nucleus transcriptomics and histological analyses of human SAT to reveal pronounced sexual dimorphism within the vascular niche. Obese males exhibit mural cell loss, increased collagen deposition, and inflammatory endothelial activation, including enhanced antigen presentation programs. In contrast, females display preserved mural coverage and increased lipid-handling and redox-adaptive pathways. These coordinated structural and transcriptional differences position the adipose endothelium as a sex-divergent regulator of obesity-associated cardiometabolic vulnerability.

cell biology↗

bioRxiv2024

Slit3 Fragments Orchestrate Neurovascular Expansion and Thermogenesis in Brown Adipose Tissue

Brown adipose tissue (BAT) is an evolutionary innovation that enables placental mammals to regulate body temperature through adaptive thermogenesis. Brown adipocytes are embedded within an intricate network of blood vessels and sympathetic nerves that support their development and thermogenic function. Cold exposure activates BAT thermogenesis through the coordinated induction of brown adipogenesis, angiogenesis, and sympathetic innervation. However, how these distinct processes are coordinated remains unclear. Here, we show that fragments of Slit guidance ligand 3 (Slit3) drive crosstalk among adipocyte progenitors, endothelial cells, and sympathetic nerves. We demonstrate that adipocyte progenitors secrete Slit3, which regulates both angiogenesis and sympathetic innervation in BAT and is essential for BAT thermogenesis in vivo. Proteolytic cleavage of Slit3 generates secreted Slit3-N and Slit3-C fragments, which bind distinct receptors to stimulate angiogenesis and sympathetic innervation, respectively. We identify Plxna1 as a previously unrecognized receptor for Slit3-C and show that it is essential for sympathetic innervation and cold-induced neurite expansion in BAT. Moreover, we introduce bone morphogenetic protein 1 (Bmp1) as the first Slit protease identified in vertebrates. In summary, this work establishes a mechanistic framework for the coordinated regulation of sympathetic innervation and angiogenesis to enhance thermogenic function. The co-regulation of neurovascular expansion by distinct Slit3 fragments offers a bifurcated yet harmonized mechanism to ensure a synchronized BAT response to environmental challenges. Finally, this study provides the first evidence that adipocyte progenitors regulate tissue innervation, revealing a previously unrecognized dimension of cellular interaction within adipose tissue.

physiology↗

bioRxiv2023

Human subcutaneous and visceral adipocyte atlases uncover classical and specialized adipocytes and depot-specific patterns

Human adipose depots are functionally distinct. Yet, recent single-nucleus RNA-sequencing (snRNA-seq) analyses largely uncovered overlapping/similar cell-type landscapes. We hypothesized that adipocytes subtypes, differentiation trajectories, and/or intercellular communication patterns could illuminate this depot similarity-difference gap. For this, we performed snRNA-seq of human subcutaneous and visceral adipose tissue. Whereas the majority of adipocytes in both depots were classical, namely enriched in lipid metabolism pathways, we also observed specialized adipocyte subtypes that were enriched in immune-related, extracellular matrix deposition (fibrosis), vascularization/angiogenesis, or ribosomal processes. Pseudo-temporal analysis suggested a developmental trajectory from adipose progenitor cells to classical adipocytes via specialized adipocytes, suggesting that the classical state stems from loss, rather than gain, of specialized functions. Lastly, intercellular communication routes were consistent with the different inflammatory tone of the two depots. Jointly, these findings provide a high-resolution view into the contribution of cellular composition, differentiation, and intercellular communication patterns to human fat depot differences.

systems biology↗

bioRxiv2023

sNucConv: A bulk RNA-seq deconvolution method trained on single-nucleus RNA-seq data to estimate cell-type composition of human subcutaneous and visceral adipose tissues

Deconvolution algorithms rely on single-cell RNA-sequencing (scRNA-seq) data applied onto bulk RNA-sequencing (bulk RNA-seq) to extract information on the cell-types composition and proportions comprising a certain tissue. Adipose tissues cellular composition exhibits enormous plasticity in response to weight changes and high variance at different anatomical locations (depots). However, adipocytes - the functionally unique cell type of adipose tissue, are not amenable to scRNA-seq, a challenge recently met by applying single-nucleus RNA-sequencing (snRNA-seq). Here we aimed to develop a deconvolution method to estimate the cellular composition of human visceral and subcutaneous adipose tissues (hVAT and hSAT, respectively) using snRNA-seq to assess the true cell-type proportions. To correlate deconvolution-estimated cell-type proportions to true (snRNA-seq -derived) proportions, we analyzed seven hVAT and 5 hSAT samples by both bulk RNA-seq and snRNA-seq. snRNA-seq uncovered 15 distinct cell types in hVAT and 13 in hSAT. Deconvolution tools - SCDC, MuSiC, and Scaden exhibited low performance in estimating cell-type proportions (median |R|= 0.12 for estimated vs. true correlations). Notably, estimation accuracy somewhat improved by decreasing the number of cell-types groups, which nevertheless remained low (|R|<0.42). We therefore developed sNuConv, a novel method that employs Scaden, a deep-learning tool, trained using snRNA-seq - based data corrected by i. snRNA-seq/bulk RNA-seq highly-correlated genes, ii. corrected estimated cell-type proportions based on individual cell-type regression models. Applying sNuConv on our bulk RNA-seq data resulted in cell-type proportion estimation accuracy with median R=0.93 (range:0.76-0.97) for hVAT, and median R=0.95 (range:0.92-0.98) for hSAT. The resulting model was depot-specific, reflecting depot-differences in gene expression patterns. Thus, we present sNuConv, a novel, AI-based, method to deduce the cellular landscape of hVAT and hSAT from bulk RNA-seq data, providing proof-of-concept for producing validated deconvolution algorithms for tissues un-amenable to single-cell RNA sequencing.

bioinformatics↗

bioRxiv2023

ScreenDMT reveals linoleic acid diols replicably associate with BMI and stimulate adipocyte calcium fluxes

Activating brown adipose tissue (BAT) improves systemic metabolism, making it a promising target for metabolic syndrome. BAT is activated by 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), which we previously identified to be inversely associated with BMI and which directly improves metabolism in multiple tissues. Here we profile plasma lipidomics from a cohort of 83 people and test which lipids association with BMI replicates in a concordant direction using our novel tool ScreenDMT, whose power and validity we demonstrate via mathematical proofs and simulations. We find that the linoleic acid diols 12,13-diHOME and 9,10-diHOME both replicably inversely associate with BMI and mechanistically activate calcium fluxes in mouse brown and white adipocytes in vitro, which implicates this pathway and 9,10-diHOME as candidate therapeutic targets. ScreenDMT can be applied to test directional mediation, directional replication, and qualitative interactions, such as identifying biomarkers whose association is shared (replication) or opposite (qualitative interaction) across diverse populations.

bioinformatics↗

bioRxiv2020

HAND2 is a novel obesity-linked adipogenic transcription factor regulated by glucocorticoid signaling

Adipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we show that Heart- and neural crest derivatives-expressed protein 2 (HAND2) is an obesity-linked adipocyte transcription factor regulated by glucocorticoids and required for adipocyte differentiation in vitro. In a large cohort of humans with obesity, white adipose tissue (WAT) HAND2 expression was correlated to body-mass-index (BMI). The HAND2 gene was enriched in white adipocytes, induced early in differentiation and responded to dexamethasone, a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1 in human multipotent adipose-derived stem cells (hMADS) or deletion of GR in a transgenic conditional mouse model results in diminished HAND2 expression, establishing that adipocyte HAND2 is regulated by glucocorticoids via GR in vitro and in vivo. Using a combinatorial RNAseq approach we identified gene clusters regulated by the GR-HAND2 pathway. Interestingly, silencing of HAND2 impaired adipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter did not mirror these effects on adipose tissue differentiation, indicating that Hand2 was required at stages prior to Adipoq expression. In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in human and mice.

molecular biology↗