Biology subjects

Mandrup, S.

Publications and source records attributed to Mandrup, S..

13 recordsLinked to original sources

bioRxiv2026

Glucocorticoid signalling exerts distinct lineage-permissive and dose-dependent disruptive actions during human osteoblast differentiation

At physiological levels glucocorticoid (GC) signalling within the osteoblast lineage has been proposed to be required for skeletal homeostasis, whereas supraphysiological activation supresses bone formation and causes bone loss. While these observations suggest that GC exert dose- and context-dependent effects, the molecular mechanisms underlying these opposing actions remain unresolved. Here we systematically dissected the receptor-, lineage-, and concentration-dependent effects of GC signalling on human bone marrow stromal cell (BMSC) differentiation using integrated transcriptional, epigenomic, and functional analyses. Our findings suggest that GC opposing effects are not simply due to a GR dose-response but instead reflect distinct context- and concentration-dependent modes of action. During early BMSC differentiation, the cellular context induced GR-dependent licensing of lineage-specific gene and enhancer programs. The adverse effects of high-dose GC developed over time and could not be predicted from the early transcriptional response. We found that high-dose GC caused osteoblast maturation arrest, accompanied with a cellular stress response sustained by myeloid zinc finger 1 (MZF1) also identified as an endogenous inhibitor of osteoblast differentiation.

molecular biology↗

bioRxiv2025

Adipose tissue cell states linked to progression and clinical subtypes of MASLD in human obesity

Adipose tissue dysfunction is a key determinant of inter-individual variability in obesity-associated comorbidities, yet the underlying tissue-level mechanisms linking adipose remodeling to progression of metabolic dysfunction-associated steatotic liver disease (MASLD) remain poorly defined. We applied single-nucleus RNA sequencing to abdominal subcutaneous adipose tissue (SAT) from individuals with severe obesity, stratified by histologically defined MASLD stage, and integrated these data with bulk RNA-seq from [~]200 individuals. MASLD was associated with adipocyte hypertrophy and near-depletion of an ADH1BHI adipocyte subset linked to improved lipid buffering and systemic metabolic health. Conversely, lipid-associated macrophages (LAMs) expanded in MASLD, coordinating lipid-handling and inflammatory programs in the myeloid compartment. In advanced metabolic dysfunction-associated steatohepatitis (MASH), we identified a senescence-associated PLAUHI progenitor subpopulation with pro-inflammatory signaling potential. Whereas LAMs were broadly enriched in MASLD subtypes, PLAUHI progenitors specifically marked a cardiometabolic MASLD endotype, characterized by type 2 diabetes and cardiovascular disease. These findings highlight cellular remodeling of adipose tissue as a potential driver of MASLD heterogeneity and progression.

cell biology↗

bioRxiv2025

Acyl-CoA Binding Protein is Dispensable for White and Brown Adipose Tissue Function

Acyl-CoA binding protein (ACBP) plays a vital role in lipid metabolism by mediating the intracellular flux and utilization of long-chain acyl-CoAs. In this study we generated brown- and white adipose tissue specific knockout mice (Adipoq-Acbp-/-) and brown adipose tissue specific knockout mice (Ucp1-Acbp-/-) to investigate the role of ACBP in adipose tissue function. Here we demonstrate that loss of ACBP does not affect body weight, fat and lean mass, food intake and systemic energy expenditure, even under cold stress. Transcriptomic data show only minor changes in gene expression, whereas lipidomic profiling reveals a subtle increase in acyl-carnitines levels in brown adipose tissue. However, lipolytic activity in white adipose tissue as well as plasma glycerol, non-esterified fatty acid and triacylglycerol levels remained unaffected. In addition, no changes in mitochondrial respiration in BAT were observed. Taken together, our findings suggest that ACBP is dispensable for adipose tissue function and systemic energy metabolism, including thermoregulation.

biochemistry↗

bioRxiv2025

Single Nucleus Multiome Analysis Reveals Early Inflammatory Response to High-Fat Diet in Mouse Pancreatic Islets

In periods of sustained hyper-nutrition, pancreatic {beta}-cells undergo functional compensation through transcriptional upregulation of gene programs driving insulin secretion. This adaptation is essential for maintaining systemic glucose homeostasis and metabolic health. Using single nuclei multiomics, we have mapped the early transcriptional compensation mechanisms in murine islets of Langerhans exposed to high-fat diet (HFD) for one and three weeks. We show that {beta}-cells exhibit the largest transcriptional response to HFD, characterized by early activation of proinflammatory eRegulons and downregulation of {beta}-cell identity genes, particularly in a distinct subset of {beta}-cells. Our observations translate to humans, as we observe an increase in the inflammatory gene signatures in human {beta}-cells in pre-diabetes and diabetes. Collectively, these observations point to cellular cross-talk through proinflammatory signaling as a central and early driver of {beta}-cell dysfunction that limits the compensatory capacity of {beta}-cells, which is closely linked to the development of diabetes.

cell biology↗

bioRxiv2025

Single cell-resolved transcriptional dynamics of human subcutaneous adipose tissue during lifestyle- and bariatric surgery-induced weight loss

During sustained weight gain, human white adipose tissue undergoes dramatic remodeling that may compromise adipose tissue function and lead to obesity comorbidities such as cardiometabolic disease. These comorbidities can be at least partially reversed by weight loss; however, the degree to which human adipose tissue is remodeled during weight loss is currently unclear. Here, we have used snRNA-seq combined with bulk RNA-seq and 3D light microscopy to investigate the cellular and transcriptional alterations in abdominal subcutaneous adipose tissue (ASAT) from a unique cohort of obese individuals undergoing initially modest (8-10%) lifestyle-induced weight loss followed by a more dramatic (20-45%) bariatric surgery-induced weight loss. We show that in response to this weight loss, ASAT in both males and females underwent dramatic compositional and transcriptional remodeling. Most notably, surgery-indued weight loss led to an increase in the adipose vascular compartment, a dramatic reduction in proinflammatory immune cells, and a tissue-wide reduction in inflammatory gene signatures. In response to modest weight loss, we observed an increase in specific progenitor populations and an induction of proadipogenic genes, indicating that this process is important for the early adaptation of AT to weight loss that might contribute to the early overall beneficial effects on insulin sensitivity and systemic inflammation.

cell biology↗

bioRxiv2024

Loss of RREB1 reduces adipogenesis and improves insulin sensitivity in mouse and human adipocytes

There are multiple independent genetic signals at the Ras-responsive element binding protein 1 (RREB1) locus associated with type 2 diabetes risk, fasting glucose, ectopic fat, height, and bone mineral density. We have previously shown that loss of RREB1 in pancreatic beta cells reduces insulin content and impairs islet cell development and function. However, RREB1 is a widely expressed transcription factor and the metabolic impact of RREB1 loss in vivo remains unknown. Here, we show that male and female global heterozygous knockout (Rreb1+/-) mice have reduced body length, weight, and fat mass on high-fat diet. Rreb1+/- mice have sex- and diet-specific decreases in adipose tissue and adipocyte size; male mice on high-fat diet had larger gonadal adipocytes, while males on standard chow and females on high-fat diet had smaller, more insulin sensitive subcutaneous adipocytes. Mouse and human precursor cells lacking RREB1 have decreased adipogenic gene expression and activated transcription of genes associated with osteoblast differentiation, which was associated with Rreb1+/- mice having increased bone mineral density in vivo. Finally, human carriers of RREB1 T2D protective alleles have smaller adipocytes, consistent with RREB1 loss-of-function reducing diabetes risk.

physiology↗

bioRxiv2024

Deep Proteome Profiling of Metabolic Dysfunction-Associated Steatotic Liver Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects roughly 1 in 3 adults and is a leading cause of liver transplants and liver related mortality. A deeper understanding of disease pathogenesis is essential to assist in developing blood-based biomarkers. Here, we use data-independent acquisition mass spectrometry to assess disease-state associated protein profiles in human liver, blood plasma, and white adipose tissue (WAT). In liver, we find that MASLD is associated with an increased abundance of proteins involved in immune response and extracellular matrix (ECM) and a decrease in proteins involved in metabolism. Cell type deconvolution of the proteome indicate liver endothelial and hepatic stellate cells as main source of the ECM rearrangements, and hepatocytes as the major contributor to the changes in liver metabolism. In the blood, profiles of several MASLD-associated proteins that correlate with their expression in WAT rather than liver yet could serve as suitable liver disease predictors in a multi-protein panel marker. Moreover, our proteomics-based logistic regression models consistently outperform existing methods for predicting MASLD and liver fibrosis from human blood samples.

systems biology↗

bioRxiv2023

Transcriptomic responses of sponge holobionts to in situ, seasonal anoxia and hypoxia

Deoxygenation can be fatal for many marine animals; however, some sponge species are tolerant of hypoxia and anoxia. Indeed, two sponge species, Eurypon sp. 2 and Hymeraphia stellifera, survive seasonal anoxia for months at a time. To understand their tolerance mechanisms, we performed differential gene expression analyses on the sponges, their mitochondria and their microbial symbionts under in situ conditions of normoxia, hypoxia and anoxia. Each species possessed a unique microbiome, but the microbiomes of each species were dominated by a species-specific Thaumarchaeon and a Gammaproteobacterium. Holobiont gene expression was species-and oxygen-level dependent, though there were some shared interspecific responses to deoxygenation. In general, few changes occurred in the expression of sponge metabolic genes as a function of oxygenation level, indicating that they may remain metabolically active under anoxia. However, ATP synthesis genes were significantly upregulated under hypoxia when compared to normoxia, and genes for DNA replication were downregulated. Mitochondrial gene expression was effectively unchanged under both hypoxia and anoxia. Nevertheless, both anoxia and hypoxia caused upregulation of heat shock proteins (HSPs), indicating cellular level adaptations to deoxygenation stress. A meta-analysis demonstrated that sponge transcriptional responses to anoxia were distinct from those displayed by other invertebrates while dormant, and the hypothesis of sponge dormancy under anoxia was not supported. Thaumarchaeota symbionts also upregulated stress response genes in hypoxia, while maintaining expression of oxygen-dependent metabolic pathways under hypoxia and anoxia. Gammaproteobacteria symbionts showed relatively few noteworthy changes in gene expression in response to anoxia but decreased metabolic gene expression in hypoxia. There was no clear evidence of upregulated anaerobic respiration in the transcriptomes of the sponge holobionts under anoxia or hypoxia. The tolerance of some sponges to prolonged anoxia warrants further investigation and could give them an advantage in future oceans following climate change as well as in ancient oceans when oxygen concentrations were lower than at present.

ecology↗

bioRxiv2022

Single-molecule tracking reveals two low-mobility states for chromatin and transcriptional regulators within the nucleus

How transcription factors (TFs) navigate the complex nuclear environment to assemble the transcriptional machinery at specific genomic loci remains elusive. Using single-molecule tracking, coupled with machine learning, we examined the mobility of multiple transcriptional regulators. We show that H2B and ten different transcriptional regulators display two distinct low-mobility states. Our results indicate that both states represent dynamic interactions with chromatin. Ligand activation results in a dramatic increase in the proportion of steroid receptors in the lowest mobility state. Mutational analysis revealed that only chromatin interactions in the lowest mobility state require an intact DNA-binding domain as well as oligomerization domains. Importantly, these states are not spatially separated as previously believed but in fact, individual H2B and TF molecules can dynamically switch between them. Together, our results identify two unique and distinct low-mobility states of transcriptional regulators that appear to represent common pathways for transcription activation in mammalian cells.

biophysics↗

bioRxiv2020

The Epidermal Barrier is Indispensable for Systemic Energy Homeostasis

ObjectivesHomeostatic regulation of body temperature is fundamental to mammalian physiology and is controlled by acute and chronic responses of local, endocrine and neuronal regulators. Although the skin is the largest sensory organ of the human body, and plays a fundamental role in regulating body temperature, it is surprising that adaptive alterations in skin functions and morphology only vaguely have been associated with physiological responses to cold stress or sensation of ambient temperatures. MethodsTo unravel the physiological responses to a compromised epidermal barrier in detail we have used animal models with either defects in skin lipid metabolism (ACBP-/- and skin-specific ACBP-/- knockout mice) or defects in skin structural proteins (ma/ma Flgft/ft). The primary objective was to clarify how defects in epidermal barrier function affect 1) energy expenditure by indirect calorimetry, 2) response to high fat feeding and a high oral glucose load and 3) expression of brown-selective gene programs by quantitative PCR in inguinal WAT (iWAT). ResultsWe show that mice with a compromised epidermal barrier function exhibit increased energy expenditure, increased food intake, browning of the iWAT, and resistance to diet-induced obesity. The metabolic phenotype, including browning of the iWAT, is reversed by housing the mice at thermoneutrality (30{degrees}C) or by pharmacological {beta}-adrenergic blocking. These findings show that a compromised epidermal barrier induces a {beta}-adrenergic response that increases energy expenditure and browning of the white adipose tissue to maintain a normal body temperature. ConclusionOur findings show that the epidermal barrier plays a key role in maintaining systemic metabolic homeostasis. HighlightsEnergy expenditure is significantly augmented in mice with impaired epidermal barrier. Mice with compromised barrier display increased food intake while maintaining normal bodyweight. Mice with an impaired epidermal barrier are resistant to diet-induced obesity and insulin resistance. Compromised barrier function induces expression of brown-selective gene programs in iWAT. Thermoneutral housing or blocking {beta}-adrenergic signaling prevents induction of brite-selective genes in iWAT and reverses food intake.

biochemistry↗

bioRxiv2020

Thermogenic genes are blunted whereas brown adipose tissue identity is preserved in human obesity

Obesity associates with a reduction in cold-induced glucose tracer uptake in brown adipose tissue in humans, suggesting loss of thermogenic capacity. We therefore hypothesized that a whitening of BAT occurs in obesity and assessed the molecular characteristics of deep neck BAT in a cohort of 24 normal weight, 24 overweight and 22 obese individuals in comparison with subcutaneous abdominal white adipose tissue (WAT). We found that the major marker of BAT thermogenesis, UCP1, was associated with central but not general obesity. We performed transcriptomic analysis of BAT in a cohort of 27 individuals classified as normal weight, over-weight or obese, and additionally four subjects with type 2 diabetes (T2DM), dispersed among the 3 BMI groups. We identified 3204 differentially expressed genes between BAT and WAT in samples from normal weight individuals, including genes involved in thermogenesis, but also revealing differences in developmental and immune system related genes. In BAT from individuals with overweight or obesity, 202 genes were downregulated and 66 of these were involved in cellular respiratory pathways, likely reflecting previously observed reduction in thermogenic function with obesity. Importantly, most BAT selective genes were not affected, and isolated adipose progenitors differentiated into thermogenic adipocytes with equal frequency regardless of BMI group. In conclusion, our data suggest a retained BAT identity, with a selective reduction of thermogenic genes, in human obesity.

cell biology↗

bioRxiv2020

The gliopeptide ODN, a ligand for the benzodiazepine site of GABAA receptors, boosts functional recovery after stroke

Following stroke, the survival of neurons and their ability to re-establish connections is critical to functional recovery. This is strongly influenced by the balance between neuronal excitation and inhibition. In the acute phase of experimental stroke, lethal hyperexcitability can be attenuated by positive allosteric modulation of GABAA receptors (GABAAR). Conversely, in the late phase, negative allosteric modulation of GABAAR can correct the sub-optimal excitability and improves both sensory and motor recovery. Here, we hypothesized that octadecaneuropeptide (ODN), an endogenous allosteric modulator of the GABAAR synthesized by astrocytes, influences the outcome of ischemic brain tissue and subsequent functional recovery. We show that ODN boosts the excitability of cortical neurons, which make it deleterious in the acute phase of stroke. However, if delivered after day 3, ODN is safe and improves motor recovery over the following month in two different paradigms of experimental stroke in mice. Furthermore, we bring evidence that during the sub-acute period after stroke, the repairing cortex can be treated with ODN by means of a single hydrogel deposit into the stroke cavity. SIGNIFICANCE STATEMENTStroke remains a devastating clinical challenge because there is no efficient therapy to either minimize neuronal death with neuroprotective drugs or to enhance spontaneous recovery with neurorepair drugs. Around the brain damage, the peri-infarct cortex can be viewed as a reservoir of plasticity. However, the potential of wiring new circuits in these areas is restrained by a chronic excess of GABAergic inhibition. Here we show that an astrocyte-derived peptide (ODN), can be used as a delayed treatment, to safely correct cortical excitability and facilitate sensorimotor recovery after stroke.

neuroscience↗

bioRxiv2018

Loss of TLE3 Promotes Mitochondrial Program in Beige Adipocytes and Improves Glucose Metabolism

Prolonged cold exposure stimulates the recruitment of beige adipocytes within white adipose tissue. Beige adipocytes depend on mitochondrial oxidative phosphorylation to drive thermogenesis. The transcriptional mechanisms that promote remodeling in adipose tissue are not well understood. Here we demonstrate that the transcriptional coregulator TLE3 is induced with aging and inhibits mitochondrial gene expression in beige adipocytes. Conditional deletion of TLE3 in adipocytes prevents age- and diet-induced weight gain by promoting mitochondrial oxidative metabolism and increasing energy expenditure, thereby improving glucose control. Using chromatin immunoprecipitation and deep sequencing we found that TLE3 occupies distal enhancers in proximity to nuclear-encoded mitochondrial genes and that many of these enhancers are also enriched for EBF transcription factors. TLE3 interacts with EBF2 and blocks its ability to promote the thermogenic transcriptional program. Collectively, these studies demonstrate that TLE3 mediates age-dependent beige adipose thermogenic decline through inhibition of EBF2 transcriptional activity. Inhibition of TLE3 may provide a novel therapeutic approach for obesity and diabetes.

developmental biology↗