Biology subjects

Wunderling, K.

Publications and source records attributed to Wunderling, K..

4 recordsLinked to original sources

bioRxiv2026

Activation of perivascular thermogenic fat improves aortic stenosis

Aim: Aortic stenosis (AS) is a common condition with exponential increases in incidence in aging populations. Perivascular adipose tissue (PVAT) forms the outer layer of the aortic wall and has - especially in the thoracic area - characteristics of thermogenic adipose tissue, which dissipates energy and releases endocrine factors. Here, we set out to investigate the role of thermogenic PVAT in AS. Methods and results: We studied the role of (PVAT) in the development of AS in a murine model of AS. To specifically delineate the role of PVAT activity in AS, we used a pharmacological {beta}3-adrenergic agonist as well as cold exposure in combination with a genetic mouse model with deficient PVAT development. To investigate the role of thermogenic adipose tissue in human AS, we used 18F-FDG PET-CT imaging. We found that pharmacological activation of thermogenic adipose tissue resulted in an improvement of AS, but not in mice genetically deficient in PVAT. Similarly, PVAT was found to be protective against AS during physiological stimulation of PVAT using cold exposure. Mechanistically, PVAT activation resulted in enhanced aortic distensibility and cellular remodeling of the aortic wall, possibly via release of polyunsaturated fatty acids and oxylipins from perivascular adipocytes. Finally, analysis of thermogenic fat activity in humans revealed that mediastinal thermogenic fat activity correlated negatively with diagnostic criteria of AS severity, suggesting an important role for PVAT activity in human AS. Conclusion: Our data indicate that PVAT activation reduces aortic stenosis and supports aortic remodeling to improve ascending aorta hemodynamics. PVAT activation might be a novel therapeutic target to ameliorate AS progression. Translational perspective: Currently, there are no effective strategies for treating AS other than valve replacement. Since the molecular mechanisms underlying the disease progression remain unclear, there are no pharmacological agents approved for either treatment or prevention of this disease. Furthermore, AS development cannot currently be predicted and is often only diagnosed when patients develop symptoms, which may be 10-20 years after disease onset. Therefore, identifying novel mechanisms that improve aortic valve function and prevent AS is of high medical need. This study identifies activation of PVAT-dependent aortic remodeling as a potential new therapeutic approach to improve or prevent AS.

physiology↗

bioRxiv2025

Insulin-like peptide secretion is mediated by peroxisome-Golgi interplay

Insulin is a peptide hormone that is secreted in Golgi-derived dense-core vesicles from mammalian pancreatic beta-cells in response to nutrients. In Drosophila melanogaster, three insulin-like peptides are secreted as neuropeptides from the insulin-producing cells in the brain. Peroxisomes are lipid-metabolizing organelles that engage into various membrane contact sites with other organelles. Impaired peroxisomal metabolism has been associated with beta-cell apoptosis and impaired insulin secretion. How peroxisomes contribute to insulin and neuropeptide secretion is unknown. Here we demonstrate that peroxisomes interact with the Golgi apparatus in Drosophila insulin-producing cells. Secretion of insulin-like peptide 2 is cell-intrinsically impaired in mutants lacking the peroxisome assembly factor Pex19. Loss of peroxisomes shifts the profile of sphingolipids towards longer sphingoid bases and leads to accumulation of sphingolipids in the Golgi. We show that peroxisomes dynamically interact with the Golgi in insulin-producing cells and that Pex19 directly contributes to peroxisome-Golgi interaction via the fatty acyl-CoA reductase FAR2/waterproof in the peroxisomal membrane. We propose that this peroxisome-Pex19-Golgi axis is required to adjust Golgi membranes upon starvation by withdrawing lipids with longer side chains, thereby optimizing Golgi membrane flexibility for dense-core vesicle secretion upon refeeding.

cell biology↗

bioRxiv2025

Pseudo-time trajectory of single-cell lipidomics: Suggestion for experimental setup and computational analysis

Cellular heterogeneity is a fundamental facet of cell biology, influencing cellular signaling, metabolism, and gene regulation. Its accurate quantification requires measurements at the single-cell level. Most high-throughput single-cell technologies provide only a snapshot of cellular heterogeneity at a specific time point because the measurement is destructive. This limits our current ability to understand the dynamics of cellular behavior and quantify cell-specific parameters. We propose an experimental setup combined with a model-based analysis framework, enabling the extraction of longitudinal data from a single destructive measurement. Although broadly applicable, we focus on lipid metabolism, a domain where obtaining longitudinal single-cell data has remained elusive due to technical constraints. Our method leverages multiple labels whose measurements are linked to a shared dynamic. This allows the estimation of cell-specific parameters and the quantification of heterogeneity. This framework establishes a foundation for future investigations, providing a roadmap toward a deeper understanding of dynamic cellular processes.

systems biology↗

bioRxiv2024

Differential cell type-specific function of the aryl hydrocarbon receptor and its repressor in diet-induced obesity and fibrosis

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor regulating xenobiotic responses as well as physiological metabolism. Dietary AhR ligands activate the AhR signaling axis in the intestine and throughout the organism, whereas AhR activation is negatively regulated by the AhR repressor (AhRR). While AhR-deficient mice are known to be resistant to diet-induced obesity (DIO), we here demonstrate that AhRR deficiency also leads to a robust, but not as profound protection from DIO and hepatosteatosis. Under conditions of DIO, AhRR-/- mice did not accumulate TCA cycle intermediates in the circulation in contrast to wild-type (WT) mice, indicating protection from metabolic dysfunction. This effect could be mimicked by dietary supplementation of AhR ligands in WT mice. Because of the predominant expression of the AhRR in myeloid cells, AhRR-deficient macrophages were analyzed for changes in metabolism and showed major metabolic alterations regarding oxidative phosphorylation and mitochondrial activity as well as increased expression of genes involved in de novo lipogenesis and mitochondrial biogenesis. Mice with a genetic deficiency of the AhRR in myeloid cells did not show alterations in weight gain after high fat diet (HFD) but demonstrated ameliorated liver damage compared to control mice. Further, deficiency of the AhR in myeloid cells also did not affect weight gain but led to enhanced liver damage and adipose tissue fibrosis compared to controls. Although conditional ablation of either the AhR or AhRR in myeloid cells did not recapitulate the phenotype of the global knockout, our findings suggest that enhanced AhR signaling in myeloid cells deficient for AhRR protects from diet-induced liver damage and fibrosis, whereas myeloid cell-specific AhR deficiency is detrimental.

immunology↗