Biology subjects

Nielsen, S.

Publications and source records attributed to Nielsen, S..

25 records · Page 2Linked to original sources

bioRxiv2020

Do male and female heterogamety really differ in expression regulation? Lack of global dosage balance in pygopodid geckos

Differentiation of sex chromosomes is thought to have evolved with cessation of recombination and subsequent loss of genes from the degenerated partner (Y and W) of sex chromosomes, which in turn leads to imbalance of gene dosage between sexes. Based on work with traditional model species, theory suggests that unequal gene copy numbers lead to the evolution of mechanisms to counter this imbalance. Dosage compensation, or at least achieving dosage balance in expression of sex-linked genes between sexes, has largely been documented in lineages with male heterogamety (XX/XY sex determination), while ZZ/ZW systems are assumed to be usually associated with the lack of chromosome-wide gene dose regulatory mechanisms. Here we document that although the pygopodid geckos evolved male heterogamety with a degenerated Y chromosome 32-72 million years ago, one species in particular, Burtons legless lizard (Lialis burtonis), does not possess dosage balance in the expression of genes in its X-specific region. We summarize studies on gene dose regulatory mechanisms in animals and conclude that there is in them no significant dichotomy between male and female heterogamety. We speculate that gene dose regulatory mechanisms are likely to be related to the general mechanisms of sex determination instead of type of heterogamety.

evolutionary biology↗

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↗

bioRxiv2019

Isometric exercise facilitates attention to salient events in women via the noradrenergic system

The locus coeruleus (LC) plays a critical role in regulating attention via the release of norepinephrine (NE), with levels of tonic LC activity constraining the intensity of phasic LC responses. However, the effects of manipulating tonic LC-NE activity on phasic activity have yet to be demonstrated in humans. In the current fMRI study, we used isometric handgrip to modulate tonic LC-NE activity in the time period immediately afterwards. During this post-handgrip time, an oddball detection task was used to probe how changes in tonic arousal influenced functional coordination between the LC and a right frontoparietal network that supports attentional selectivity. As expected, the frontoparietal network responded more to infrequent target and novel sounds than to frequent sounds. Across participants, greater LC-frontoparietal functional connectivity, pupil dilation, and faster oddball detection were all positively associated with LC MRI contrast from a neuromelanin-sensitive structural scan. Thus, LC structural integrity was related to LC functional dynamics and attentional performance during the oddball task. We also found that handgrip led to larger phasic pupil responses to oddball sounds, faster oddball detection speed, and greater frontoparietal network activation, suggesting that something that induces strong LC activity benefits attentional performance for at least the next few minutes. In addition, older women showed a similar benefit of handgrip on frontoparietal network activation as younger women, despite showing lower frontoparietal network activation overall. Together these findings suggest that a simple exercise may improve selective attention in healthy aging, at least for several minutes afterwards.\n\nHighlightsO_LIWe examined how handgrip affects arousal-attention dynamics during an oddball task\nC_LIO_LISalient stimuli enhanced pupil dilation and were detected faster post-handgrip\nC_LIO_LIA decrease in tonic pupil size after handgrip suggests norepinephrine depletion\nC_LIO_LIMRI-assessed LC integrity was related to oddball detection and pupil dilation\nC_LIO_LILC integrity also associated with LC-frontoparietal network functional connectivity\nC_LI

neuroscience↗

bioRxiv2018

Proteomics-based comparative mapping of the human brown and white adipocyte secretome reveals EPDR1 as a novel batokine

Secreted proteins from adipose tissue play a role in metabolic cross-talk and homeostasis. We performed high sensitivity mass spectrometry-based proteomics on the cell media of in vitro differentiated, non-immortalized brown adipocytes derived from supraclavicular adipose of adult humans and white adipocytes derived from subcutaneous adipose of adult humans. We identified 471 potentially secreted proteins covering interesting protein categories such as hormones, growth factors, growth factor binding proteins, cytokines, extracellular matrix proteins, and proteins of the complement system, which were differentially regulated in brown and white adipocytes. A total of 101 proteins were exclusively quantified in brown adipocytes, among these ependymin-related protein 1 (EPDR1). Ablation of EPDR1 impaired the induction of thermogenic transcripts in response to norepinephrine in brown adipocytes, while EPDR1-treated mice increased their energy consumption, suggesting a role in brown fat commitment and activation. Our work reveals substantial differences between the secretomes of brown and white human adipocytes and identifies novel candidate batokines.

physiology↗

bioRxiv2018

Asymmetric perirenal brown adipose dormancy in adult humans is defined by local sympathetic activity

We here detect dormant brown adipose tissue (BAT) in adult humans, occurring in most of the perirenal fat depot and characterized by a unilocular morphology. This phenotype was contrasted by multilocular BAT accumulating near the adrenal gland. Transcriptomic analysis revealed a gene expression profile of unilocular BAT that was approaching, yet was still distinct from, the expression profile of subcutaneous white adipose tissue (WAT). Candidate gene signatures were recapitulated in a murine model of unilocular brown fat induced by thermoneutrality and high fat diet. We identified SPARC as a candidate adipokine representing a dormant BAT state in the absence of sympathetic activation and CLSTN3 as a novel marker for multilocular BAT. Brown fat precursor cells were present in the entire perirenal fat depot, regardless of state. When differentiated in vitro, these cells responded to acute norepinephrine stimulation by increasing UCP1 gene expression and uncoupled respiration, confirming a BAT phenotype. We thus propose a mechanism for the reduction of functionally competent BAT in adult humans and we provide a solid data set for future research on factors that can reactivate dormant BAT as a potential strategy for combatting obesity and metabolic disease.

physiology↗

bioRxiv2018

A long-non-coding RNA, LINC00473, confers the human adipose tissue thermogenic phenotype through enhanced cAMP responsiveness.

Specialized adipocytes localized in distinct depots mediate the many physiological functions of adipose tissue. In humans, paucity of thermogenic adipocytes correlates with high metabolic disease risk, raising much interest in the mechanisms by which these cells arise. Here we report molecular signatures associated with adipocyte development in different human depots and identify a long non-coding RNA, LINC00473, as the transcript most closely associated with enrichment of thermogenic adipocytes. LINC00473 expression is low in subjects with obesity or type-2 diabetes and is highly correlated with cAMP signaling and mitochondrial oxidative phosphorylation pathways. LINC00473 is localized in the nucleus and the cytoplasm, and its knockdown impairs induction of UCP1 and mitochondrial respiration. These results reveal that depot-enriched genes that modulate responsiveness to external stimuli, specifically LINC00473, are important determinants of the adipose tissue thermogenic phenotype, and potential targets for metabolic disease therapy.

cell biology↗

bioRxiv2018

The smallest intestine (TSI) - a low volume in vitro model of the small intestine with increased throughput

AimsTo develop a low volume in vitro model with increased throughput simulating the human small intestine, incorporating the presence of ileal microbiota, to study microbial behaviour in the small intestine.\n\nMethods and ResultsThe Smallest Intestine in vitro model (TSI) was developed. During the simulated passage of the small intestine bile is absorbed by dialysis and pH adjusted to physiologically relevant level. A consortium of seven representative bacterial members of the ileum microbiota is included in the ileal stage of the model. It was found that the model can be applied for the testing of survival of probiotic bacteria in upper intestine. Moreover, it was found, that the presence of the ileal microbiota significantly impacted probiotic survival.\n\nConclusionsTSI allows testing a substantial number of samples, at low cost and short time, and is thus suitable as an in vitro screening platform. Multiples of five reactors can be added to increase the number of biological and technical replicates.\n\nSignificance and Impact of the StudyTSI serves as an alternative for costly and low throughput in vitro models currently existing on the market. Above that, significance of small intestine bacteria presence on survival of probiotic bacteria in the upper intestine was proved.

microbiology↗