Biology subjects

Winther, S.

Publications and source records attributed to Winther, S..

4 recordsLinked to original sources

bioRxiv2023

Exploring white matter dynamics and morphology through interactive numerical phantoms: The White Matter Generator

Brain white matter is a dynamic environment that continuously adapts and reorganizes in response to stimuli and pathological changes. Glial cells, especially, play a key role in tissue repair, inflammation modulation, and neural recovery. The movements of glial cells and changes in their concentrations can influence the surrounding axon morphology. We introduce the White Matter Generator (WMG) tool to enable the study of how axon morphology is influenced through such dynamical processes, and how this, in turn, influences the diffusion-weighted MRI signal. This is made possible by allowing interactive changes to the configuration of the phantom generation throughout the optimisation process. The phantoms can consist of axons, myelinated axons, and cell clusters, separated by extra-cellular space. Due to morphological flexibility and computational advantages during the optimisation, the tool uses ellipsoids as building blocks for all structures; chains of ellipsoids for axons, and individual ellipsoids for cell clusters. After optimisation, the ellipsoid representation can be converted to a mesh representation which can be employed in Monte-Carlo diffusion simulations. This offers an effective method for evaluating tissue microstructure models for diffusion-weighted MRI in controlled realistic white matter environments. Hence, the WMG offers valuable insights into white matters adaptive nature and implications for diffusion-weighted MRI microstructure models, and thereby holds the potential to advance clinical diagnosis, treatment, and rehabilitation strategies for various neurological disorders and injuries.

neuroscience↗

bioRxiv2023

Susceptibility-induced internal gradients reveal axon morphology and cause anisotropic effects in the dMRI signal

Diffusion-weighted MRI is our most promising method for estimating microscopic tissue morphology in vivo. The signal acquisition is based on scanner-generated external magnetic gradients. However, it will also be affected by susceptibility-induced internal magnetic gradients caused by interaction between the tissue and the static magnetic field of the scanner. With 3D in silico experiments, we show how internal gradients cause morphology-, compartment-, and orientation-dependence of spin-echo and pulsed-gradient spin-echo experiments in myelinated axons. These effects are unseen in previous 2D modelling. For an ex vivo monkey brain, we observe the orientation-dependency generated only when including non-circular cross-sections in the in silico morphological configurations, and find orientation-dependent deviation of up to 17% for diffusion tensor metrics. Our findings underline the importance of accounting for realistic 3D axon morphology in modelling. Interestingly, the morphology-specific orientation-dependency trends show potential for a novel sensitivity to morphology, which is not attainable by the theoretical diffusion-weighted MRI signal itself.

neuroscience↗

bioRxiv2023

Monocarboxylate transporters facilitate succinate uptake into brown adipocytes

Uptake of circulating succinate by brown adipose tissue (BAT) and beige fat elevates whole body energy expenditure, counteracts obesity, and antagonizes systemic tissue inflammation in mice. The plasma membrane transporters that facilitate succinate uptake in these adipocytes remain undefined. Here we elucidate a mechanism underlying succinate import into BAT via monocarboxylate transporters (MCTs). We show that succinate transport is strongly dependent on the proportion of it present in the monocarboxylate form. MCTs facilitate monocarboxylate succinate uptake, which is promoted by alkalinization of the cytosol driven by adrenoreceptor stimulation. In brown adipocytes, we show that MCT1 primarily facilitates succinate import, however other members of the MCT family can partially compensate and fulfill this role in the absence of MCT1. In mice, we show that acute pharmacological inhibition of MCT1 and 2 decreases succinate uptake into BAT. Conversely, congenital genetic depletion of MCT1 alone has little effect on BAT succinate uptake, indicative of additional transport mechanisms with high capacity in vivo. In sum, we define a mechanism of succinate uptake in BAT that underlies its protective activity in mouse models of metabolic disease.

cell biology↗

bioRxiv2020

An adipocyte-specific lncRAP2 - Igf2bp2 complex enhances adipogenesis and energy expenditure by stabilizing target mRNAs

lncRAP2 is a conserved cytoplasmic adipocyte-specific lncRNA required for adipogenesis. Using hybridization-based purification combined with in vivo interactome analyses, we show that lncRAP2 forms ribonucleoprotein complexes with several mRNA stability and translation modulators, among them Igf2bp2. Transcriptome-wide identification of Igf2bp2 client mRNAs in white adipocytes reveals selective binding to mRNAs encoding adipogenic effectors and regulators. Depleting either lncRAP2 or Igf2bp coordinately downregulates these same target proteins. Ribosome profiling and quantitative proteomics show that this occurs predominantly at the level of mRNA, as binding of the lncRAP2-Igf2bp complex does not affect mRNA translation. Suppressing lncRAP2 or Igf2bp2 selectively destabilizes many mRNAs encoding proteins essential for energy expenditure, including Adiponectin, reducing adipocyte lipolytic capacity. Genome-wide association studies reveal specific association of genetic variants within both lncRAP2 and Igf2bp2 with body mass and type 2 diabetes, and we find that adipose lncRAP2 and Igf2bp2 are suppressed during obesity and diabetes progression. Thus, the lncRAP2-Igf2bp complex potentiates adipose development and energy expenditure and is associated with susceptibility to obesity-linked diabetes.

cell biology↗