Biology subjects

Stemmer, K.

Publications and source records attributed to Stemmer, K..

3 recordsLinked to original sources

bioRxiv2023

Liver microRNA transcriptome reveals miR-182 as link between type 2 diabetes and fatty liver disease in obesity

BackgroundThe development of obesity-associated comorbidities such as type 2 diabetes (T2D) and hepatic steatosis has been linked to selected microRNAs in individual studies; however, an unbiased genome-wide approach to map T2D induced changes in the miRNAs landscape in human liver samples, and a subsequent robust identification and validation of target genes is still missing. MethodsLiver biopsies from age- and gender-matched obese individuals with (n=20) or without (n=20) T2D were used for microRNA microarray analysis. The candidate microRNA and target genes were validated in 85 human liver samples, and subsequently mechanistically characterized in hepatic cells as well as by dietary interventions and hepatic overexpression in mice. ResultsHere we present the human hepatic microRNA transcriptome of type 2 diabetes in liver biopsies and use a novel seed prediction tool to robustly identify microRNA target genes, which were then validated in a unique cohort of 85 human livers. Subsequent mouse studies identified a distinct signature of T2D-associated miRNAs, partly conserved in both species. Of those, human-murine miR-182-5p was the most associated to whole-body glucose homeostasis and hepatic lipid metabolism. Its target gene LRP6 was consistently lower expressed in livers of obese T2D humans and mice as well as under conditions of miR-182-5p overexpression. Weight loss in obese mice decreased hepatic miR-182-5p and restored Lrp6 expression and other miR-182-5p target genes. Hepatic overexpression of miR-182-5p in mice rapidly decreased LRP6 protein levels and increased liver triglycerides and fasting insulin under obesogenic conditions after only seven days. ConclusionBy mapping the hepatic miRNA-transcriptome of type 2 diabetic obese subjects, validating conserved miRNAs in diet-induced mice, and establishing a novel miRNA prediction tool, we provide a robust and unique resource that will pave the way for future studies in the field. As proof of concept, we revealed that the repression of LRP6 by miR-182-5p, which promotes lipogenesis and impairs glucose homeostasis, provides a novel mechanistic link between T2D and non-alcoholic fatty liver disease, and demonstrate in vivo that miR-182-5p can serve as a future drug target for the treatment of obesity-driven hepatic steatosis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/560594v2_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@e19015org.highwire.dtl.DTLVardef@ba6497org.highwire.dtl.DTLVardef@121f8f4org.highwire.dtl.DTLVardef@15f7773_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2022

Adipose cells and tissues soften with lipid accumulation while in diabetes adipose tissue stiffens

Adipose tissue expansion involves both differentiation of new precursors and size increase of mature adipocytes. While the two processes are well balanced in healthy tissues, obesity and diabetes type II are associated with abnormally enlarged adipocytes and excess lipid accumulation. We hypothesised that adipocyte shape and size changes with differentiation and lipid accumulation would be accompanied by changes in the mechanical phenotype at both the cell and tissue level. We quantified by optical diffraction tomography (ODT) that differentiating preadipocytes increased their volumes drastically. Atomic force microscopy (AFM)-indentation and -microrheology revealed that during the early phase of differentiation, human preadipocytes became more compliant and more fluid-like, concomitant with ROCK-mediated F-actin remodelling. Adipocytes that had accumulated large lipid droplets were more compliant, and further promoting lipid accumulation led to an even more compliant phenotype. In line with that, high fat diet-induced obesity was associated with more compliant adipose tissue compared to lean animals, both for drosophila fat bodies and murine gonadal adipose tissue. In contrast, adipose tissue of diabetic mice became significantly stiffer as shown not only by AFM but also magnetic resonance elastography (MRE). Altogether, we dissect relative contributions of the cytoskeleton and lipid droplets to cell and tissue mechanical changes across different functional states, such as differentiation, nutritional state and disease. Since preadipocytes are mechanosensitive, tissue stiffening in diabetes might be critical to the balance between hyperplasia and hypertrophy and moreover present a potential target in the prevention of metabolic disorders.

biophysics↗

bioRxiv2018

Unprocessed serum glycosylphosphatidylinositol-anchored proteins are correlated to metabolic states

To study the possibility that components of eukaryotic plasma membranes are released in spontaneous or controlled fashion, a chip-based sensor was developed for complete glycosylphosphatidylinositol-anchored proteins (GPI-AP), which may form together with (phospho)lipids so far unknown (non-vesicular) extracellular complexes (GLEC). The sensor relies on changes in phase shift and amplitude of surface acoustic waves propagating over the chip surface upon specific capturing of the GPI-AP and detection of associated phospholipids and renders isolation of the labile GLEC unnecessary. GLEC were found to be released from isolated rat adipocyte plasma membranes immobilized on the chip, dependent on the flow rate and composition of the buffer stream. Moreover, incubation medium of isolated adipocytes and serum of rats are sources for GLEC which enables their differentiation according to cell size and genotype or body weight, respectively, as well as human serum.

biochemistry↗